SAFETY CHARACTERISTICS

Each paediatric RCT report from my database was analysed to evaluate the following safety aspects:

1. Safety Monitoring

It was assessed whether safety monitoring was mentioned in the methods section of each. Any mention of the words „safety‟, „adverse effect/event/experience/reaction‟, „side/unwanted effect‟, „toxicity‟ or any indication that adverse events were monitored for was noted.

2. SMC/DSMB and Terminated or Amended Trials

Each paper was then checked to determine whether a safety monitoring committee (SMC), data safety monitoring board (DSMB) or an independent safety evaluator was present to oversee the trial. In addition, it was determined whether any interim analysis (Fossa and Skovlund, 2000) was performed or whether stopping rules (Hedenmalm et al., 2008) for the trials were designated. These were assumed to be present whenever a SMC/DSMB is mentioned.

Any trial that was discontinued was also noted and the reason for discontinuation was determined. Any RCT that reported an alteration to the study protocol arising from an interim analysis or from new information/alerts arising from newly published reports or from the SMC/DSMB of the RCT itself was recorded.

120 3. Adverse Events (AEs) and Mortalities

Whether any adverse events were detected were determined from carefully reading the results section. The definition and classification of adverse events (AEs) used in this study was based on guidelines produced by the European Agency for the Evaluation of Medicinal Products (EMEA, 2001) in compliance with the International Conference for Harmonisation (ICH).

An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment (EMEA, ICH topic E2A, 1995). AEs are classified as serious, significant or mild according to the following groupings:

i) Serious AE - any untoward medical occurrences at any dose that results in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.

ii) Significant AE - defined as haematological and other laboratory abnormalities and any AE that led to an intervention, including withdrawal of drug treatment, dose reduction or significant additional concomitant therapy.

iii) Mild AE - defined as any AE occurring that did not need any intervention.

The most serious AE in each report was determined and used to stratify the trials. The number of papers reporting any mortality was recorded. In particular, any RCTs which indicated a positive trend in mortality in the intervention group or non-placebo comparator groups were noted.

121 4. Adverse Drug Reactions (ADRs)

An ADR is defined as an adverse event that is thought to be linked in either time or dose to a drug given to that patient (Turner et al., 1999, Sammons et al., 2008). Each randomised trial included in this study was assessed as to whether a possible ADR had occurred and were classified according to the highest severity of ADR in the report.

The classification used for ADRs are as follows:

1. Severe: fatal or potentially life threatening or causing permanent disability

2. Moderate: requiring treatment or prolonging stay in hospital

3. Mild: no treatment required and no effect on length of stay in hospital.

All trials reporting a serious AE (SAE) were further reviewed by two paediatric clinical pharmacologists, Professor Imti Choonara and Associate Professor Helen Sammons, independently to judge whether any of the serious AEs were possible ADRs. The decision by each reviewer was noted and all differing ratings were discussed at a meeting to obtain a consensus expert opinion.

122 2.2 ANALYSIS

1. ATC Drug Categories

The proportion of RCTs that reported an SAE, mortality or where a severe or moderate ADR was judged to have occurred, was calculated for each ATC drug category. This was done to assess whether certain types of drugs (or disease categories) were associated with a higher incidence of toxicity within RCTs involving children.

The proportions of RCTs reporting SAEs were cross tabulated to the median sample size of paediatric participants from RCTs in each ATC category. This was done to determine whether an artefactual relationship existed due to chance, in the assumption where a higher number of SAEs would occur naturally with greater participant numbers. For example if a certain ATC category consisted of mostly large trials, the hypothesis would be that this category would contain a higher number of SAEs due to the larger population sizes thus confounding the effect of the drug type.

2. Age Group Categories

The above comparison was also performed for each ICH age group category to assess whether a certain age group (especially neonates) experienced a higher incidence of toxicity or mortality within the RCTs.

3. SMCs/DSMBs

Trials reporting serious AEs, mortalities or that were determined to have encountered severe or moderate ADRs, were compared to the rest of the RCTs in the database in terms of whether SMCs/DSMBs were documented.

123 4. Statistical Analysis

Data from each report were retrieved using a standardised data extraction form (provided in chapter 2) then stored and analysed using SPSS version 16.0 (SPSS Inc., Chicago, IL, USA). Categorical variables were described with frequencies, percentages and 95% confidence intervals. The degree of agreement between reviewers was described by the Kappa coefficient ( ). Fisher‟s exact test was used to calculate p-values for differences in proportions. The Spearman‟s rank correlation coefficient rho (rs) was used to check whether there were any associations between the safety characteristics and sample size populations of the RCTs.

124 3. RESULTS

582 paediatric randomised drug trials were analysed. The 22 RCT reports in the database that had an English abstract but where the main text was not in English were excluded.

3.1 SAFETY CHARACTERISTICS