Интеграционные процессы на постсоветском пространстве

Основываясь на теоретических и эмпирических методах исследованиях, был изучен процесс становления и развития интеграционных процессов на постсоветском пространстве. В результате изученного материала был разработан проект дальнейшего развития отношений, включающего три потенциальных сценария

Differences in Reporting of Analyses in Internal Company Documents Versus Published Trial Reports: Comparisons in Industry-Sponsored Trials in Off-Label Uses of Gabapentin

<div><h3>Background</h3><p>Details about the type of analysis (e.g., intent to treat [ITT]) and definitions (i.e., criteria for including participants in the analysis) are necessary for interpreting a clinical trial's findings. Our objective was to compare the description of types of analyses and criteria for including participants in the publication (i.e., what was reported) with descriptions in the corresponding internal company documents (i.e., what was planned and what was done). Trials were for off-label uses of gabapentin sponsored by Pfizer and Parke-Davis, and documents were obtained through litigation.</p> <h3>Methods and Findings</h3><p>For each trial, we compared internal company documents (protocols, statistical analysis plans, and research reports, all unpublished), with publications. One author extracted data and another verified, with a third person verifying discordant items and a sample of the rest. Extracted data included the number of participants randomized and analyzed for efficacy, and types of analyses for efficacy and safety and their definitions (i.e., criteria for including participants in each type of analysis). We identified 21 trials, 11 of which were published randomized controlled trials, and that provided the documents needed for planned comparisons. For three trials, there was disagreement on the number of randomized participants between the research report and publication. Seven types of efficacy analyses were described in the protocols, statistical analysis plans, and publications, including ITT and six others. The protocol or publication described ITT using six different definitions, resulting in frequent disagreements between the two documents (i.e., different numbers of participants were included in the analyses).</p> <h3>Conclusions</h3><p>Descriptions of analyses conducted did not agree between internal company documents and what was publicly reported. Internal company documents provide extensive documentation of methods planned and used, and trial findings, and should be publicly accessible. Reporting standards for randomized controlled trials should recommend transparent descriptions and definitions of analyses performed and which study participants are excluded.</p> <p> <em>Please see later in the article for the Editors' Summary</em></p> </div

Criteria used to define ITT analysis in protocols (Pro) and publications (Pub).

<p>To be eligible for inclusion in the ITT analysis, participants had to meet the criteria that are marked with an “X”. For example, per the description of ITT in the publication for study 945-209 <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001378#pmed.1001378-Pande1" target="_blank">[24]</a>, data from participants who were randomized into the trial and met criteria related to completing treatment at a minimum dose and/or for a minimum duration were included in the ITT analysis (“The efficacy analyses were carried out on the intent-to-treat (ITT) population that included all randomized patients who received at least one dose of study medication.” <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001378#pmed.1001378-Pande1" target="_blank">[24]</a>).</p

Summary of criteria used for including participants in seven types of analyses for efficacy as described in protocols, statistical analysis plans, and publications across the nine included trials.

a<p>This table summarizes data presented in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001378#pmed-1001378-t004" target="_blank">Tables 4</a> and <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001378#pmed-1001378-t005" target="_blank">5</a> and <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001378#pmed.1001378.s001" target="_blank">Text S1</a>'s <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001378#pmed-1001378-t001" target="_blank">table 1</a>. Along the top row in this table, we show every type of efficacy analysis described in the protocols, SAPs, and publications across all nine trials for which we compared these documents. The first column on the left lists the criteria used to define the types of analysis across all studies. For each type of analysis, an “X” denotes that the criterion was applied in at least one of the documents for any of the nine trials we examined. For example, the second column summarizes the five criteria used across all documents and trials to define ITT: in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001378#pmed-1001378-t004" target="_blank">Table 4</a>, four criteria were used in different combinations to define ITT analysis; in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001378#pmed.1001378.s001" target="_blank">Text S1</a>'s <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001378#pmed-1001378-t001" target="_blank">table 1</a>, one additional criterion was used in the SAP.</p>b<p>This type of analysis was specified protocols, SAPs, and publications for the trials we examined (<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001378#pmed-1001378-t004" target="_blank">Tables 4</a> and <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001378#pmed-1001378-t005" target="_blank">5</a> and <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001378#pmed.1001378.s001" target="_blank">Text S1</a>'s <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001378#pmed-1001378-t001" target="_blank">table 1</a>).</p>c<p>This type of analysis was specified only in the protocol and publications for some of the trials we examined (see <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001378#pmed-1001378-t005" target="_blank">Table 5</a>).</p>d<p>This type of analysis specified only in SAPs for some of the trials we examined (see <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001378#pmed.1001378.s001" target="_blank">Text S1</a>'s <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001378#pmed-1001378-t001" target="_blank">table 1</a>).</p><p>CGIS, clinical global impression of severity; HAM-D, Hamilton Depression Rating Scale; YMRS, Young Mania Rating Scale.</p

Total number of participants randomized and number analyzed for efficacy per research report and publication for the publication-specified primary outcome.

a<p>The only published report available to us for study 879-201, which we used as its “main publication,” was a conference abstract describing preliminary results of analyses from the trial <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001378#pmed.1001378-Wessely1" target="_blank">[27]</a>. The only published report available to us for the study, No ID Gorson, which we used as its “main publication,” was a letter to the editor describing results from the trial <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001378#pmed.1001378-Gorson1" target="_blank">[22]</a>. We did not use a conference abstract, a report describing preliminary results of analyses, or a letter to the editor as the “main publication” for any other trial listed in this table.</p>b<p>We could not compare the internal company research report and publication because the internal company research report did not report on the publication-specified primary outcome.</p>c<p>The numbers presented are for Young Mania Rating Scale, which was one of two outcomes considered “primary.” The corresponding numbers for the other outcome considered “primary,” the Hamilton Depression Rating Scale (HAM-D) are as follows: ITT: 113 in the research report and 113 in publication.</p>d<p>We could not compare the internal company document and publication because the internal company research report did not specify the type of analysis specified in the publication, even though the outcomes were the same.</p>e<p>A draft manuscript sent to Pfizer and Parke-Davis by the author reports a total of 53 patients were allocated in the trial and 40 participants were analyzed for efficacy.</p

Agreement among documents from the same trial on definitions of ITT analysis and safety analysis.

<p>Agreement among documents from the same trial on definitions of ITT analysis and safety analysis.</p

Comparison of protocol (Pro), SAPs, and publications (Pub) for description of criteria used to determine inclusion of trial participants in safety analysis.

a<p>Neither the protocol, SAP, nor the publication for Study 879-201 described criteria used to determine inclusion of trial participants in safety analysis.</p>b<p>Neither the protocol nor the publication for Study No ID - Gorson described criteria used to determine inclusion of trial participants in safety analysis.</p>c<p>“All patients who have taken study medication will be included in the evaluation of safety data.”</p>d<p>“Any patient who has taken at least one dose of study medication and has had an opportunity to report an adverse experience via clinic visit, telephone contact, etc. will be evaluable for the safety analysis.”</p

Criteria used to define additional types of analysis in protocols (Pro) and publications (Pub).

a<p>The table does not include an additional type of analysis (“Efficacy evaluable”) specified in the SAP for study 945-220. See <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001378#pmed.1001378.s001" target="_blank">Text S1</a> for details.</p>b<p>To be eligible for inclusion in a type of analysis, participants had to meet the criteria that are checked. For example, per the description of modified ITT in the publication for study 945-220 <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001378#pmed.1001378-Mathew1" target="_blank">[23]</a>, data from participants who were randomized into the trial and met criteria related to completing treatment at a minimum dose and/or for a minimum duration, and availability of measurements for the outcome variable at baseline and during follow-up, were included in the modified ITT analysis (“This population included any patient who was randomized, took at least one dose of study medication during SP2 [Stabilization Period 2], maintained a stable dose of 2400 mg/day during SP2, had baseline migraine headache data and at least 1 day of migraine headache evaluations during SP2.” <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001378#pmed.1001378-Mathew1" target="_blank">[23]</a>).</p

Completeness (number of completely-specified elements out of five possible) by outcome domain.

1<p> One protocol did not include any of the outcome domains selected for detailed data extraction.</p><p>Completeness (number of completely-specified elements out of five possible) by outcome domain.</p

Examples of extent of overlap of possible outcome domains chosen by clinical trialists and systematic reviewers.

<p>Yellow - Outcomes chosen by clinical trialists. Blue - Outcomes chosen by systematic reviewers. Grey - Outcomes chosen by BOTH clinical trialists and systematic reviewers.</p