Retrospective safety analysis

Oppe S., (1993). Guidelines for Retrospective Safety Analysis. Internal HOPES report for DRIVE Il-Project, Horizontal Project for the Evaluation of Safety, SWOV, Netherlands, pp 94. 

Adler L, Wilens T, Zhang S, Durell T, Walker D, Schuh L, Jin L, Feldman P, Trzepacz P. Retrospective safety analysis of atomoxetine in adult ADHD patients with or without comorbid alcohol abuse and dependence. Am J Addict 2009 18(5) 393-401. 

The efficacy and safety of amphotericin in Intralipid 20% or 5 % glucose has been evaluated in a retrospective case analysis in 30 patients with AIDS and cryptococcal meningitis who received either formulation 1 mg/kg/day for 20 days with or without flucytosine (n = 20) or fluconazole (n = 4), followed by maintenance therapy with fluconazole 400 mg/day (45). Twenty patients received amphotericin deoxycholate in 500 ml 5% glucose over 5 hours, and 10 received amphotericin deoxycholate in 100 ml of 20% Intralipid given over 2 hours. Complete clinical resolution was obtained in 55 and 60% of the patients respectively. There were no differences regard-... 

Moubarak P, Zilker S, Wolf H, Hofner B, Kneib T, KUchenhoff H, Jauch KW, Hartl WH. Activity-guided antithrombin III therapy in severe surgical sepsis efficacy and safety according to a retrospective data analysis. Shock 2008 30(6) 634-41. 

A retrospective analysis of 380 patients with Wilson disease in Germany and Austria and 25 additional patients from the EUROWILSON registry was performed [70 ]. Due to changes in medication, an analysis of D-penicillamine (n=326) and trientine (n= 141) was performed. Adverse effects leading to discontinuation of treatment were more common in D-penicillamine (n = 94, 28.8%) than in trientine group (n = 10, 7.1%). Safety analysis was only performed on adverse events that led to halt of treatment. Adverse effects included sicca symptoms (n=7), fatigue... 

Occupational health and safety finds itself in abreakthrongh condition. Tasks of a traditional safety technician in the past were connected to activities in only one field. However, these tendencies are gradually changing. Peak functions in the field of complex workplace safety expect in the future to cope with tasks in the field of OHS, safety of mechanical devices (SMD), environmental protection, management of hazardous substances and critical industrial accidents, quality managanent, as well as in the field of explosion and fire protection. Classic activities aimed at retrospective accident analysis methods are replaced by prospective methods aimed at application of modern risk analysis methods at the initial stages of a machine s technical life and projection of job positions. 

The focus of this chapter has been on proactive application of these analytical methods such as safety audits, development of procedures, training needs analysis, and equipment design. However, many of these methods can also be used in a retrospective mode, and this issue deserves further attention in its own right. Chapter 6 describes analytical methods for accident investigations and data collection. 

Whether the timing of GPIIb/llla inhibitor therapy makes any difference on efficacy and safety has been explored retrospectively in six randomized STEMI trials (three with abciximab and three with tirofiban) (69). In a pooled analysis of these trials, upstream (prior to transfer to the catheterization laboratory) administration of GPIIb/llla inhibitor appeared to improve coronary patency and resulted in favorable trends for clinical outcomes compared to downstream (in cath lab) administration. However, the timing of administration was neither randomized nor prespecified. Thus, the suggestion that these drugs may be most beneficial with early (preferably prehospital) treatment of patients in the first hours of acute STEMI awaits confirmation in prospective randomized investigations. 

Kloner RA, Jackson G, Hutter AM, et al. Cardiovascular safety update of tadalafil retrospective analysis of data from placebo-controlled and open-label clinical trials of tadalafil with as needed, three times-per-week or once-a-day dosing, Am J Cardiol 2006 97 1778-1784. 

Safety data have been published in a retrospective analysis of 551 patients with invasive fungal infections intolerant of or refractory to conventional antifungal therapy, 73 of whom received ABLC initially at 3 mg/kg/day instead of 5 mg/kg/day, as recommended in the protocol (30). There were no notable differences in adverse events (increased semm creatinine, infusion-related chills) between the two gronps. Serum creatinine values were improved or stable at the end of therapy in 78 and 70% of patients respectively. 

In a retrospective analysis there were no chnically important differences in the safety profile of ciprofloxacin in patients aged under or over 65 years (65). The incidence of drug-related adverse events was higher in those under 65 years (25%) than in those aged 65 years or more (17%) the most common adverse events affected the gastrointestinal and central nervous systems. 

Heyd A, Haverstock D. Retrospective analysis of the safety profile of oral and intravenous ciprofloxacin in a geriatric population. Clin Ther 2000 22(10) 1239-50. 

Foster WR, Chen S-J, He A, et al. A retrospective analysis of toxicogenomics in the safety assessment of drug candidates. Toxicol Pathol. 2007 35(5) 621-635. 

Preclinical animal studies Human toxicity No An ultimate goal of preclinical safety assessment. However, retrospective analysis is difficult as a proper data set takes very long to acquire. Gene Logic ToxShield... 

Phase IV studies can also take the form of retrospective pooled analyses which are designed to reflect the totality of clinical research experience with a new drug which is usually obtained via analysis of pooled clinical trial databases. Such data-mining efforts should not be considered inferior to data obtained from the conduct of an individual clinical trial. In fact, there are substantial benefits of such an approach, as the results of a given trial, especially if the end point is not prespecified to be primary because of power limitations, can be a function of chance. To assure that the results obtained from pooled analyses are not biased, a prespecified data analysis plan is often formulated as the first step, outlining the clear goals of the proposed analysis as well as its methodology. Key to this type of analysis is the definition of the outcome measure. Both efficacy and safety measures can be the focus of these types of analyses. 

Cook-Bruns N. Retrospective analysis of the safety of Herceptin immunotherapy in metastatic breast cancer. Oncology 2001, 63 (suppl 2), 58-66. 

Batch analysis results—Complete batch analysis data should be included for key batches prepared throughout the development program, including, if practical, material manufactured at the site(s) that will supply material for commercial purposes. These test results should be provided against the specifications in place at the time of the release of the batch for its intended use. Often, it is valuable to include retrospective analyses of key batches using techniques established or modified subsequent to their initial release. This could be particularly beneficial for impurities, assuming the impurity profile method(s) were modified during development. It is also expected that information on the manufacture (date, size, location) and use of each listed batch (clinical, safety, stability, market product, etc.) be included in the application. 

Retrospective analysis of clinical study data found no evidence that the safety or efficacy of fluvastatin was altered by the use of beta blockers... 

Retrospective analysis of clinical study data found no evidence that the safety or efficacy of lovastatin was altered by the use of potassium-sparing diuretics (hydrochlorothiazide with triamterene or amiloride), or thiazide diuretics (mostly hydrochlorothiazide). Another retrospective study of 19 patients found that the addition of lovastatin to diuretic treat-... 

Fault trees are commonly used in safety critical industries such as aerospace. Their power is in being able to communicate complex failures in a simple graphical format which is relatively easy to learn. They can be applied to either potential failures or retrospectively in investigating actual failures. FTA has subtle limitations however especially when one needs to systematically identify aU possible causes of a particular hazard - for this, an alternative technique needs to supplement the analysis. Fault trees are also notoriously difficult to apply to complex software. 

Maiti, J. et al. 2009. Severity analysis of Indian coal mine accidents—A retrospective study for 100 years. Safety Science 47 1033-1042. 

Shorf of prospectively collecting fhe safety outcome, the outcome can be retrospectively obtained and adjudicated with a well-defined procedure. This approach was faken in fhe antidepressant meta-analysis example in this chapter. This approach requires detailed extensive patient-level data. It is also helpful to have fhe individual sfudy protocol to understand the information collected in fhe frials. Wifh fhis version of a retrospective outcome ascertainment, attention should be given to potential differential outcome ascertainment between the treatment arms. If the outcome was not actively solicited, there may be differences in reporting between the arms because of unrelated side effecfs of fhe freafmenf. For example, if a drug has more side effecfs, fhe patienf may be more likely to have encounters with the study investigators and report the safety outcome. 

The HERMES methodology was first introduced by Cacciabue (2004a,b) for analyzing the HMI in complex contexts. HERMES is strucmred in a number of steps to preserve the basic requirements of congruence and consistency between both types of retrospective and prospective studies as well as to underpin the correspondence between recurrent HMI analysis and system safety and integrity. 

Literature has many theories and concepts discussing human reliability and associated human error causal factors that always trigger incidents and accidents within safety-critical systems. The main - by definition - characteristics of such safety occurrences are their randonmess, rare predictability, sophisticated, yet vague sequence of propagation. Such characteristics can basically allow for the retrospective analysis of these occurrences and their causes at various sectors and levels within industry such that re-occurrence margins are reduced if not totally eliminated. The major drawback of such reactive treatment... 

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