We found a significant number of ADE reports of pneumothorax in a large health authority SRS database though it was rare as a proportion of all reports. Most drugs with SDRs were oncology drugs of various mechanisms of action but the strongest statistical associations involved a small number of non-oncology drugs, namely pulmonary surfactants and pentamidine, that our analysis supports as CBI. The results are consistent with pulmonary surfactants' reported reduction in the incidence of pneumothorax in neonatal respiratory distress syndrome, and clinical-pathological correlates indicating that pneumothorax in the setting of pneumocystis pneumonia may reflect peripheral microbial inflammation, invasion and tissue necrosis corresponding to gradients in aerosol particle deposition.14-17
Of note ACBIIs for the surfactant preparations for which indication was reported were all greater than one and for pentamidine was 13.79. The two oncology drugs with a consistent finding of an ACBII <1 seem to have the most persuasive association with pneumothorax from independent datasets. Therefore this approach to CBI analysis showed preliminary hints of utility for initial exploratory analysis to provide quantitative support for initial understanding and triage of SDRs in PhV. The absence of obvious confounding indications does not necessarily rule out CBI as a causal or contributory factor. In some instances the absence of an obvious recorded indication was due to the fact that the indication was not reported in any reports (i.e. colfosceril). In other instances the reported indication could have been a confounding factor, though not as well established as in the classic examples of various oncology drugs. For instance the reported indication for alglucosidase alpha was glycogen storage disease type II, which involves serious pulmonary disease that could at least theoretically be associated with pneumothorax via natural history or iatrogenic disease.35
There are significant limitations to our analysis most notably the usual 'warnings, precautions and indications for use' for SRS data which precludes making causal inferences except in unusual circumstances24
which are amplified by the aforementioned differences in event versus indication reporting. We did not perform a case-level clinical review (case narratives are not included in AERS extracts for public use) and results of any quantitative analysis of SRS data is most meaningful when correlated with case-level clinical information. DA is based on 2x2 contingency tables methods and therefore do not accommodate the complex multivariate drug and event relationships that are characteristic of such data and which may be especially pertinent to the oncology setting where multi-drug treatment protocols are common. For example, the pulmonary toxicity of docetaxel has been reported to be enhanced by co-administered gemcitabine.36,37
Finally like any observational database, and perhaps especially so for SRS data, there are other reporting artifacts such as unrecorded confounding and effect modification which this approach does not address and which typically remain unresolved in initial signal detection in PhV.
The application of even basic disproportionality analysis has been the subject of heated debate with extreme viewpoints of “unbridled optimism” to “considerable skepticism”.38
In other words some authorities consider such analysis a “garbage in garbage out” exercise of no value and potential harm, while others unrealistically maintain that such quantitative analysis, if performed with certain proprietary software, can neutralize the enormous limitations of spontaneous reports. We take a moderate position between the aforementioned extremes. With our analysis, which went beyond the usual drug-ADE analysis to include a drug-indication analysis, so one must be even more cautious in interpretation.
While the above limitations are substantial and clearly disqualifies this approach for making inferences, it is does not necessarily disqualify its judicious application as an exploratory analysis tool to help refine an initial index of suspicion related to CBI. Quoting an author writing about another exploratory analysis tool39
“data mining and fishing expeditions are dirty words, but tempered with an awareness of the fallacies they can lead to, and supported by honest documentation, it is not a scientific crime” to use them in this context to search for a possible contribution of CBI to the reporting association between the drug and the event.
An analysis using Cornfields's inequality in this setting has advantages including the fact that it is simply an extension of the same basic calculation used for the drug-ADE pair to drug-indication pairs and thus easily implementable for front-end signal detection in PhV, as well as being transparent and intuitive but there are other alternative approaches including calculating O/E ratios within different levels of a confounding variable and/or calculating an adjusted summary measure as with Mantel-Haenzsel methods (as we did with age, gender and reporting year). Another approach applied to SRS data is to perform the DA on a subset of drugs within a pharmacological/therapeutic class or for specific indication(s).40-48
Although this has been performed at times there are limitations to these approaches as well. For example depending on the specific implementation of the DA such an approach can potentially mask24
credible associations if they exist with multiple drugs within the pharmacological/therapeutic class. Utilizing the generality of the database as a background may provide a better picture of the statistical reporting associations in the universe of drugs, rather than just differences between drugs within a subset of drugs. This may inevitably entail a trade-off between sensitivity and specificity. Finally such an approach allows analysis of only one drug class per analysis.
Finally our adjustment, while based on plausibility considerations, is still essentially somewhat ad hoc, (as are many exploratory analysis in PhV) but it provides a starting point for further discussion and research including a systematic assessment of its operating characteristics, as well as that of other potential adjustment factors. It would also be interesting to perform a systematic study to establish operating characteristics of U/ACBII that could potentially identify optimum thresholds that might obviate the need for correction.