* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Adverse Events
Survey
Document related concepts
Compounding wikipedia , lookup
Clinical trial wikipedia , lookup
Neuropharmacology wikipedia , lookup
Drug design wikipedia , lookup
Polysubstance dependence wikipedia , lookup
Prescription drug prices in the United States wikipedia , lookup
Drug discovery wikipedia , lookup
Pharmacognosy wikipedia , lookup
Drug interaction wikipedia , lookup
Prescription costs wikipedia , lookup
Pharmaceutical industry wikipedia , lookup
Pharmacokinetics wikipedia , lookup
Pharmacogenomics wikipedia , lookup
Transcript
臨床試驗 Adverse Events: 不良反應及不良事件 簡國龍老師 2015-04-22 1 Outline Definition Reasons for collecting adverse event data Responsibility of investigators & sponsors Practical issues & statistical considerations 2 Definition of AE Unfavorable change in a patient that may occur during or after drug or device This change does not have to be caused by the treatment be called an AE Adverse experience Adverse drug reaction, adverse device effect: When a causal relationship has been established between a product and AE 3 Adverse drug reaction, ADR A response to an investigational drug that occurs at any dose and is noxious and unintended A response to a marketed drug that is noxious, unintended, and that occurs at doses normally used for prophylaxis, diagnosis, therapy, or for modification of physiological function 4 Adverse drug reactions (ADR) to an investigational product All noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions. A causal relationship is at least a reasonable possibility. 5 Adverse event (AE) Any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. 6 AE Physical signs or symptoms Abnormal laboratory values Changes in vital signs, physical examination, or on an electrocardiogram An increase in the frequency or intensity (worsening) of a condition or illness that was present before study enrollment Complications from a surgery or procedure Not included: Procedures or surgeries (the medical condition that caused the need for the procedure or surgery is the adverse effect) Pre-existing events or illness that do not worsen during the study procedure 7 Subsets of AE Expected versus unexpected adverse effects Expected for the drug based on previous experience Unexpected for the drug, not reported in brochure or package insert, greater severity or frequency than previously reported 8 Serious versus Non-serious adverse effects SAE: Any experience occurring at any dose (regardless of relationship to study agent) meets the conditions: Results in death Is life-threatening Results in persistent or significant disability/incapacity Requires or prolongs inpatient hospitalization Is a congenital anomaly/birth defect Important medical event 9 Why collect adverse effect data? Investigator’s responsibility Accurate, timely, and complete reporting of adverse effects Determine the safety profile of a drug Evaluate the benefits and risks of a drug Provide information for the package insert if a drug is marketed 10 Safety profile Monitored to determine if significant concerns that would prevent it from being used in the target population Investigator’s brochure All adverse events reported in trials of the drug to date Number of times specific events reported 11 Benefits and risk evaluation A medical risk-benefit judgment Whether the benefits of the drug outweigh its known and potential risks Package insert Adverse event information Scientific facts from clinical trials Source document by additional adverse events reported after marketing 12 Investigator responsibilities Collecting adverse event data Objectively and thoroughly observation on potential adverse effects Systematic but non-specific way Health problems, any changes vs. headache Reporting adverse event data Expedited reporting of adverse events 13 Reporting adverse event data Different mindset from clinical practice in reference to reporting adverse events Report all events to the sponsor, even when opinions the event is not related to the agent Complete reporting is necessary Different mechanisms to report Depend on type of AE, seriousness and process outlined for specific study 14 Case report forms Event: medical terminology Diagnosis or sign/symptom Relationship to study drug (causality) Evaluate whether the AE was related to, or caused by, the study drug 1. reasonable possibility 2. non a reasonable possibility Categories: 1. unrelated 2. remotely related 3. possible related (uncertain as to relationship) 4. probably (likely) related 5. definitely related 15 (Continued) Severity/intensity Seriousness Mild: patient was aware of the event but it was easily tolerated Moderate: discomfort sufficient to interfere with normal activities Severe: patient was incapacitated with an inability to perform normal activities One or more criteria in definition of SAE Outcome as a treat to life or function Distinction between severity versus seriousness of an event Examples: severe vomiting, mild stroke 16 Others in reporting AE Record data about The onset and resolution of the event Treatment provided in response to the event Action taken with regard to study treatment 17 Expedited reporting of adverse events Identify specific adverse events in an expedited manner Outline a process for expedited reports Separate SAE report form Very specific information about the event A narrative description of the event, relevant medical history, laboratory results, diagnostic tests, concomitant medications, treatment, and outcome of the event Within 24 hours learning of the event Also in the case report form or other data forms, same terminology and supporting data 18 Sponsor responsibilities Expedited and routine reporting of AE to FDA, even after the drug has been approved for marketing Expedited reporting Serious Unexpected (not in investigator’s brochure) Study treatment-related Within 15 calendar days of first knowledge of the event Fatal or life-threatening: within 7 calendar days by telephone or fax, followed by a written report within 8 additional calendar days 19 IND safety reports by sponsor A summary of the event The treatment arm the patient received (open-label trials) Analysis of similar events that have occurred in the trial and/or in past or present trials Comments on the occurrence of the same adverse event with similar therapeutic agents in the same patient population The site report form Investigator alert letter, safety letter, alert report Site’s IRB 20 Routine reporting by sponsor Semi-annual report Discontinuations due to adverse effects All deaths All serious adverse events After NDA approved Post-marketing adverse event data reports on a quarterly basis for first 3 years after approval, then on an annual basis 21 Issues in assessing safety Rates or relative risks of AE and laboratory data Extent of exposure More common adverse events and laboratory test changes Serious adverse events and other significant AE 22 Practical issues Coding system for AE COSTART: FDA WHOART: WHO MEDDRA: ICH AE data listing Summary tables of AE Graphical presentation scatterplot 23 Statistical analyses Contingency tables for AE Cochran-Mantel-Haenszel test Integrated summary: subgroup analysis Pooling the data Meta-analysis 24 Table 12.4.1 Information to be Included in the List of Adverse Events Patient identifier Age, race, sex, weight Location of case report forms if provided Adverse event Duration of the adverse event Severity Seriousness Action taken Outcome Causality assessment Date of onset or date of clinic visit at which the event was discovered Timing of onset of the adverse event in relation to the last dose of the last drug Study treatment at the time of event or the most recent study taken Test drug/investigational product dose in absolute amount, mg/kg or mg/m2, at time of event Drug concentration (if known) Duration of test drug/investigational product treatment Concomitant treatment during study 25 Figure 12.4.1 Scatter plot of adverse events versus incidence rates 26 Laboratory data Least biased and most precise data for system toxicity, efficacy and safety Routine tests Reference ranges Clinically significant changes Shift analysis Below, within and above the normal range 27 Table 12.5.1 An Example of Categories for Assessing the Degree of Concern Category I Definition All results normal 11. No two successive abnormalities 2. Last result normal II 11. Two or more successive abnormalities 2. Last result normal III 11. No two successive abnormalities 2. Last result abnormal IV V 11. Two or more successive abnormalities 2. Last result abnormal 28 Conclusions Safety hypotheses cannot be specified a priori Not designed to detect difference in safety outcomes Not prepared to test hypotheses regarding rare safety events Failure to achieve statistical significance does not mean that a safety finding can be ignored 29 FDA guidelines Frequency of treatment-emergent events Relevant Body System categories Severity categories Relationship/causality Original terms used by the investigator and group related reactions 30 Websites: http://adr.doh.gov.tw/main01.htm 藥物不良反應通報表 行政院衛生署 電話:(02) 2396-0100 傳真︰(02) 2358-4100 台北郵政 84-664 號信箱 網址:http://adr.doh.gov.tw 電子信箱:[email protected] Suggested reading: Merck feared 'unfavorable message' from Vioxx study By Alex Berenson, Gardiner Harris, Barry Meier and Andrew Pollack The New York Times (International Herald Tribune) Monday, November 15, 2004 31 版權聲明 頁碼 1-32 作品 版權圖示 來源/作者 本作品轉載自Microsoft Office 2010 PowerPoint 設計主題範本-Pixel,依據 Microsoft 服務合約及著作權法第46、52、65條合理使用。 25 《Design and analysis of clinical trials: concepts and methodologies》, 作 者:Chow, SC, Liu, JP ,出版社: Wiley(third edition ),p.596。本作品依據著作權 法第 46、52、65 條合理使用。 http://as.wiley.com/WileyCDA/WileyTitle/productCd-0470887656.html 26 《Design and analysis of clinical trials: concepts and methodologies》, 作 者:Chow, SC, Liu, JP ,出版社: Wiley(third edition ),p.598。本作品依據著作權 法第 46、52、65 條合理使用。 http://as.wiley.com/WileyCDA/WileyTitle/productCd-0470887656.html 28 《Design and analysis of clinical trials: concepts and methodologies》, 作 者:Chow, SC, Liu, JP ,出版社: Wiley(third edition ),p.605。本作品依據著作權 法第 46、52、65 條合理使用。 http://as.wiley.com/WileyCDA/WileyTitle/productCd-0470887656.html 32