Pooled bioequivalence study database from Turkey: characterization of adverse events and determination of split points based on Gini Index as a promising method
Current study could be briefly described as the pooled analysis of BE studies with regards to the adverse events. Although the BE studies are widely being conducted all over the world, a research on overall adverse event specific evaluations were not found. Research on the adverse reactions as a post-marketing safety survelliance often takes place in the scientific literature (Lazarou et al. 1998; Sibille et al. 1998; Baker et al. 2004) while BE studies were mostly focused on the pharmacokinetics, assessing the relationship between genetic polymorphisms, and safety issues of the single test (generic) and reference (originator) drugs (Zhang et al. 2006; Zhang et al. 2007; Cho et al. 2009; Esseku et al. 2013; Gao et al. 2015; Mak et al. 2015). Therefore, our study has the originality by revisiting the BE studies of 13 years period belonging to one of the CRO’s database (N-CRO) in Turkey, regarding the frequency, type, drug subgroups, cut off (split points using Gini Index) values and probable causes of adverse events.
The pooled BE dataset also evaluated the age, BMI, and sex of the 5498 volunteers. The range of age showed that younger people (min. 21.12–max. 49.08) were more eager to be involved in the studies, which could be explained by the socioeconomical status. While it was possible for both of the sexes to be involved in the BE studies of N-CRO, all the volunteers were male. This could be related to the sociocultural properties of a developing country. Reluctance of females to attend bioequivalence studies in Turkey makes restrictor effect to number and representativeness of BE studies, especially for hormone containing drugs (e.g., oral contraceptives). Moreover, pharmacokinetic parameters like Cmax and AUC for some drugs, thereby adverse events are well-known to show differences between male and female individuals (Gandhi et al. 2004; Soldin and Mattison 2009). Even tough to involve only male volunteers to the BE studies is not against to the regulations framed by the national and international guidelines (Investigation 1994; EMA 2010), for a CRO it could be a limitation for evaluating pharmacodynamics and pharmacokinetic differences due to gender in BE studies. We could suggest raising public awareness with the use of media in order to involve both sexes to the BE studies.
In the pooled BE study database, the highest frequency of adverse effects was reported in genitourinary system and sex hormones involving tadalafil and sildenafile containing drugs among the eight drug subgroups. Likewise, drugs which contain tadalafil and sildenafile also attracted attention in the post-marketing adverse event reports. (Lowe and Costabile 2012). Genitourinary system and sex hormones’ were followed by nervous system, and antineoplastic drugs indicating relatively high adverse event frequencies when compared to the other subgroups (Leung et al. 2012; Pages et al. 2014).
The finding of no difference between test and reference drugs in terms of adverse events frequency is a valuable result for safety of generic drugs while investigating a population of 1992 volunteers.
The first five highest frequent adverse events (headache, somnolence, nausea, dizziness, vomiting) in the BE studies were related with nervous system and gastrointestinal system. Probably, those adverse events could be based on the drug itself. In the adverse event forms most of the adverse events were recorded as irrelevant to the drugs used in the BE studies. While it can be speculative, some of the adverse events could be assumed to be triggered with psychological stress (Mayer 2000; Mönnikes et al. 2001; Nash and Thebarge 2006; Leistad et al. 2006; Cathcart et al. 2010). Some studies suggested that headache and functional gastrointestinal disorders might have psychological stress origin (Mayer 2000; Mönnikes et al. 2001; Leistad et al. 2006; Nash and Thebarge 2006; Cathcart et al. 2010) while fatigue and somnolence might have psychosomatic origin (Shorter 1993; Loge et al. 1998; Taylor et al. 2003). It can be speculated that to be involved in a BE study, giving biological specimen such as blood all day long, and having no other activity could be unusual to the daily routine of a person and it is possible to trigger some adverse events based upon psychological stress (Shorter 1993; Loge et al. 1998; Mayer 2000; Mönnikes et al. 2001; Taylor et al. 2003; Nash and Thebarge 2006; Leistad et al. 2006; Cathcart et al. 2010). Thus, the physical and social environment should be examined, and if necessary, in order to reduce the psychological stress that leads to adverse events, the prevailing conditions in the centers could be improved.
The investigators recorded serious adverse events (right foot fracture, laceration of achilles tendon, fall and traumatic scalp injury, death in traffic accident) to serious adverse event forms, applied specified treatment protocol to the volunteer where available, and informed both Ethical Committee and Turkish Ministry of Health. The investigators noted that none of the serious adverse events observed were showed relationship with the administrated drug in the BE studies. Our study could provide more robust and effective data about adverse events if investigators of Clinical Trial Centers have used MedDRA dictionary while classifying adverse events.
Inter-individual differences as genetic polymorphism are known to affect the drug metabolism and pharmacokinetic parameters. For example, Cmax and AUC parameters could be significantly different between poor drug metabolisers and extensive drug metabolisers resulting in toxic responses or lack of therapeutic effectiveness (Kara?niewicz-?ada et al. 2014; Al-Gahtany et al. 2014; Fowler et al. 2015). Therefore, it is possible to claim the crucial role of the inter-individual differences in the adverse events reported in the BE studies.
As we dealed with a pooled dataset of single BE studies covering 13 years, it was an opportunity to use Cmax and AUC values in order to obtain split points (cut off levels) to estimate adverse event frequencies below and above them. Gini Index is adopted from finance, where it is used to measure the inequality of wealth (Cichosz 2015). It is commonly used with well-known classification method named decision trees which h as wide usage area including finance, medicine, social sciences etc. (Tan et al. 2006). Thus, our group utilized Gini Index approach for the first time in BE studies to show the likely individual pharmacokinetic differences in the adverse event occurence with promising results. Eventually, the frequency of adverse events of the volunteers whose Cmax and AUC values above the obtained split points was found to be higher than that of the ones below. Since there were no additional data available indicating volunteers’ inter-individual differences in the dataset, split point estimation according to the Cmax and AUC values could be offered as a promising tool. Also, this approach could provide valuable outcomes when combined with genetic polymorphism data. As the pharmacokinetic parameters were strongly influenced by interindividual differences, we suggest using Gini Index in overall pharmacokinetic and pharmacovigilance evaluations in order to assess the pharmacogenomic differences via adverse event outcome.
The Gini Index based split points, with regards to the AUC and Cmax values for adverse event distribution, could be suggested for the future BE studies carried out for similar drugs to predict the frequency of likely adverse events.
However it should be emphasized that it has been found as a limitation to have only 63 BE studies (1992 volunteers) out of 261 studies with reachable Cmax and AUC data in our overall evaluation. The reason was N-CRO started to use new recording system for pharmacokinetic parameters at 2006. Previously, Cmax/AUC and some other parameters were not transferrable from N-CRO’s database.