Adverse events methods

A systematic review brings together and evaluates all the relevant research relating to a particular question. A group known as the Cochrane Collaboration has been formed for the purpose of appraising medical treatments and publish its finding in the Cochrane Library which is available, freely in some countries, on the internet. Most of the focus has so far been on evidence of efficacy from randomised trials but an adverse event methods group has recently been formed. 

Expert opinion is a source, frequently elicited by survey, that is used to obtain information where no or few data are available. For example, in our experience with a multicountry evaluation of health care resource utilization in atrial fibrillation, very few country-specific published data were available on this subject. Thus the decision-analytic model was supplemented with data from a physician expert panel survey to determine initial management approach (rate control vs. cardioversion) first-, second-, and third-line agents doses and durations of therapy type and frequency of studies that would be performed to initiate and monitor therapy type and frequency of adverse events, by body system and the resources used to manage them place of treatment and adverse consequences of lack of atrial fibrillation control and cost of these consequences, for example, stroke, congestive heart failure. This method may also be used in testing the robustness of the analysis [30]. 

Current computerized analyses of adverse events still typically consist of a vast number of discrete, often personal, ad hoc processes that mimic paper and pencil methods. Some commercial-off-the-shelf (COTS) software tools (e.g., Adobe Acrobat , Microsoft Word , Excel ) do have the capability to search for specihc terms in electronic documents/case reports and do have navigational tools with hyperlinks and fullfull-text indexing that enable researchers to create their own hyperlinks. Some other COTS software tools (e.g., SAS , Excel , Access , IMP ) allow importation of electronic case report tabulations (ECRT) for more detailed analysis. 

Traditional analytical methods make extensive use of computers, but typically these methods still require constant restructuring of the data and multiple analytical tools. This endless restructuring wastes time and productivity and also makes the analytical processes difficult to document, audit, and reproduce in real time. This situation also makes it difficult to reconstruct and update analyses in real time when new adverse event data become available or when new questions need to be asked. The application of comprehensive data standards allows the use of integrated, reusable software for analyzing adverse event data. This integration facilitates the reproducibility of the results. 

Using array technology in pharmacogenomics, efficacy and systemic toxicity can be evalnated for the improvement of the design and development of preclinical vaccines. Methods of applying pharmacogenomics in the evaluation of efficacy and adverse events dnring clinical development of vaccines are also discnssed. 

Practically all available iodinated extracellular X-ray contrast agents have been encapsulated into liposomes using different lipids and methods of preparation. Table 1 gives a short and intentionally incomplete overview of some of the approaches. The first liposomal contrast agent preparation that was tested in humans contained diatrizoate [48]. The injected dose was up to 0.5 ml kg k The preparation was effective even in plain radiography where lesions down to 0.8-1.0 cm could be detected in patients. However, adverse events such as fever and hyperthermia, which occurred in 30% of the patients, limited further use. We have incorporated iopromide into MLVs that were prepared from phosphatidyl choline (PC), cholesterol and stearic acid at a molar ratio of 4 5 1 using the ethanol-evaporation technique [44]. The liposomes can be stored freeze-dried and they are reconstituted before use by... 

Since then there have been many publications and reviews of the UK yellow card system and spontaneous reporting systems internationally.A summary of the capabilities and limitations of the method is given in Table 15.6. Although these have been discussed in the greatest detail over the past three decades, the obligations that exist for pharmaceutical companies in the reporting of adverse events to the regulatory authorities at both national and international levels make it essential to review them in this chapter. 

In the evaluation of safety in the postmarketing phase, regulatory agencies are greatly more restricted in their enthusiasm for data derived from some of the methods available than from others. Indeed, the EC national agencies separately and the CPMP collectively have developed a legislative framework that is predominantly concerned with spontaneous adverse event monitoring and which is, for all practical purposes, silent on the matter of safety data collected by other methods. 

No doubt in part because of ethical controversies it has sometimes been difficult to mount adequate controlled studies, especially in the USA. Many women and practitioners have retained a preference for dilatation and evacuation as a means of performing abortion rather than using a medicinal technique. In a pilot study at Chapel Hill, North Carolina oral mifepristone 200 mg followed 2 days later by vaginal and oral misoprostol was compared with the surgical method (11). Of 47 women eligible for the trial, 29 declined to participate, primarily because of a preference for dilatation and evacuation. Of the 18 participants enrolled, nine were randomized to treatment with mifepristone + misoprostol and 9 to dilatation and evacuation. Mifepristone + misoprostol caused more pain and adverse events, although none was serious.)... 

Except for one study [4] which reported 32 adverse events ( ), all studies emphasized the benignity of the rare adverse effects observed. The reputed safety of this desensitization method thus seems to be true, particularly if the results of all published studies on sublingual desensitization were grouped together, regardless of the allergen employed [12, 13]. 

The DPDP ligand was synthesized in order to lower the toxicity of the man-ganese(II) ion and to provide selective tissue uptake [40]. The LD50 of an i.v. dose of Mn-DPDP is between 1.9-5.4 mmol kg1 in mice [18, 41]. No mortalities occurred in dogs injected i.v. with 1.8 mmol kg-1 [41]. With the recommended clinical dose of 0.005 mmol kg1, the safety factor for Mn-DPDP is at least 360 [41]. In the European phase III clinical trials adverse events were reported for 46 of 624 patients (7%) [42]. In comparison, 123 of 546 patients (23%) in the U.S. clinical trials reported at least one adverse event [43]. In both trials the most common complaints were headache, vomiting and nausea. In addition, 377 of 546 patients (69%) in the U.S. trials and 26 of 624 patients (4%) in the European trials reported discomfort at the site of injection. The difference between the two trials is likely due to the method of administration and formulation of the Mn-DPDP solution. In the European trials, a 0.010 mM solution of the agent was slowly infused while in the U. S. trials Mn-DPDP was administered as a bolus injection of a 0.050 mM solution. Experiments have demonstrated a lower incidence of adverse events with infusion of the agent [44]. 

The randomized controlled clinical trial is the method of choice for the objective and quantitative demonstration of the efficacy and tolerability of a new medicine. None the less, such studies have limitations in discovering possible adverse events that may occur, in particular those that are rare or develop after prolonged use, in combination with other drugs, or perhaps due to unidentified risk factors. Clinical trials are inherently limited in duration and number of patients, and, significantly, patients are selected prior to inclusion. In other words, the conditions of a trial are artificial compared with the real-life use after the introduction of a medicine (p. 229). 

It is important to acknowledge this limitation of the typical development programs and to recognize that careful postmarketing surveillance is the most feasible method for detecting the more infrequent adverse events occurring with the use of a new drug. 

Analysis of Adverse Effect Dose-Response Information. An integrated analysis of all data from animal and human studies that affect the dose-response and blood level-response relationships of adverse events, the method of dose selection, the choice of dose interval, and dosing recommendations in the package insert should be performed. The effect of demographics and other patient characteristics on the dose-response relationships should be explored. 

There should also be an explanation and justification of the method by which the clinician s words, such as lethargy, severe pain, stupor, etc., are transformed into numbers that can be manipulated in statistical calculations. The coding of case report forms entering adverse event and concomitant medication information, whether done manually or electronically, is obviously necessary. This is easily done with the use of standard references, such as the COSTART and the WHO dictionaries. 

Autoencoders are a unique and specialized class of software. One must remember that coding is a means to an end. Data consistency is the desired result. For this reason, companies will use different dictionaries and methods to code adverse events and drugs. There is no standard other than the dictionaries used for the process. Autoencoders are usually custom systems developed by a company for its own use. Commercial autoencoders do exist, and they generally provide facilities to audit the coding and provide custom dictionaries based on the general dictionaries above. 

The appropriate methods and timing in assessing cognitive and behavioral adverse events during drug development programs have been thoroughly reviewed (55). 

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