FormalPara Key Points

Physicians were aware to varying degrees of the risks associated with retigabine.

Subgroup analyses showed that both the physicians who read the retigabine education letter and those who had prescribed retigabine had better recall of information.

To strengthen risk-minimization efforts for retigabine and following the identification of new emerging risks in 2013, GSK has since sent an updated ‘Dear Healthcare Professional’ letter and initiated another EU survey to assess how effectively specific risks associated with retigabine use are communicated.

1 Introduction

Retigabine (international nonproprietary name)/ezogabine (US adopted name, approved as Potiga™) is an antiepileptic drug (AED) approved in Europe [as Trobalt™, GlaxoSmithKline (GSK)] for the adjunctive treatment of drug-resistant partial-onset seizures with or without secondary generalization in patients 18 years or older with epilepsy, where other appropriate drug combinations have proved inadequate or have not been tolerated [1]. In randomized clinical studies investigating the efficacy and safety of retigabine, an increased risk of urinary retention, central nervous system (CNS) side effects (confusional state, hallucinations, and psychotic disorders), and QT prolongation was reported in patients receiving retigabine when compared with placebo [2–6].

As part of a European post-marketing commitment, GSK conducted a survey starting in November 2012 through October 2013 to assess physicians’ understanding of the significant risks associated with retigabine. The goal was to evaluate the effectiveness of the educational plan as specified in the European Risk Management Plan (RMP) [7–9].

The survey, conducted among a sample of neurologists from seven European countries (Denmark, Germany, Norway, Slovakia, Spain, Switzerland, and the UK), concentrated on the risks described in the approved EU Physician’s Guide (PG) for retigabine [10].

2 Methods

2.1 Study Design

This was a cross-sectional survey of physicians who had prescribed an AED at least once in the last 3 months and to whom an educational letter for retigabine had been sent (included as electronic supplementary material). This letter was intended to educate healthcare professionals about retigabine-associated risks, highlighting those described in the PG. The study design was based on risk-management evaluation studies previously completed by GSK and United BioSource Corporation (UBC) in the US and Europe, which were based on US FDA recommendations for Risk Evaluation and Mitigation Strategy (REMS) surveys [11]. The study did not include treatment intervention. Ethics Committee approval requirements were assessed by country; full review and approval were required in Slovakia and Spain, but were deemed not necessary in Denmark, Germany, Norway, Switzerland, and the UK. As risks of abnormal pigmentation of the lips, nails, skin, and/or mucosa associated with retigabine use were identified subsequent to conducting this survey, they were not included in the questionnaire.

2.2 Setting

The survey was conducted in the first European countries to launch retigabine. The rationale for selection was that issues regarding the effectiveness of the PG in communicating retigabine risks could be addressed early. Additionally, these countries were likely to have the most physicians with experience prescribing retigabine. The study started in November 2012 and completed recruitment of participants in October 2013.

2.3 Subjects

The survey aimed to recruit a random sample of 300 physicians who had prescribed an AED and who had been sent the educational letter including the PG for retigabine/ezogabine. The goal was to recruit 100 neurologists from Germany and 200 across the remaining countries. Just prior to the start of the survey, retigabine became unavailable in Germany for new patients, therefore only neurologists who had patients being treated with retigabine in November 2012 were targeted.

2.4 Screening and Baseline Assessments

The sample of neurologists who were invited to participate was a random sample of all neurologists who received the ‘Educational Letter’ for Trobalt. The sample of participating neurologists was self-selected since respondents voluntarily responded to the invitation to participate. However, the survey recruitment strategies were intended to recruit a heterogeneous sample of prescribers for participation. Furthermore, a subgroup of neurologists commonly referred to as ‘epileptologists’ who were known from past experience to be the specialists who first initiated prescriptions of a new AED and who were therefore specifically targeted for promotional activity by GSK were the primary target of this survey. Neurologists were invited by email or mail to participate, with an introductory educational letter, a request to complete the survey, and the survey instrument. The survey used a questionnaire comprising multiple-choice and closed-ended questions (included as electronic supplementary material).

2.5 Statistical Analysis

All statistical analyses were descriptive; no formal hypotheses were tested. Confidence intervals were calculated at the 95 % level, and no adjustments were performed for multiplicity. Counts and percentages were calculated for each item in the questionnaire.

The primary outcome was the proportion of neurologists correctly answering each question related to understanding of the risks associated with retigabine. Point estimates for the proportion with correct responses, and associated confidence intervals, were calculated for each question about retigabine-associated risks. For multiple-choice questions, the number and proportion of neurologists reporting each response were recorded.

2.6 Populations and Subgroup Analysis

The primary population for the analysis included all eligible respondents who had completed the survey. Outcomes and respondent characteristics were summarized in three ways: (1) for all seven countries combined, (2) separately for Germany, and (3) for six countries combined excluding Germany. All other analyses were performed for respondents combined from all seven countries.

A subgroup analysis of prescribers who had ever prescribed retigabine versus those who had not was performed for questions related to retigabine risks and respondent characteristics. Subgroup analysis of respondents who reported reading the retigabine education letter was performed only for questions about retigabine risks.

3 Results

3.1 Study Population

A total of 8430 invitations were issued, 301 prescribers responded and were screened for participation, and 294 (97.7 %) were eligible for analysis. Of eligible prescribers, 96 were German physicians. All eligible respondents completed the survey online.

3.2 Participants

Of the 294 physicians who completed the survey, 94.9 % had prescribed AEDs within the last month. Almost half (49.0 %) had prescribed retigabine at some time point. The geographic distribution of eligible physicians was as follows: Germany 32.7 %, Spain 20.4 %, UK 18.0 %, Slovakia 9.5 %, Switzerland 7.8 %, Norway 6.5 %, and Denmark 5.1 %.

Most physicians who completed the survey (91.8 %) reported neurology as their primary specialty, and 4.8 % specialized in epileptology. Approximately two-thirds (64.3 %) of all physicians and 80.6 % of retigabine prescribers reported having read the retigabine educational letter. About half (50.7 %) of all physicians and 63.9 % of retigabine prescribers reported learning about retigabine-associated risks from the educational letter.

3.3 Survey Results

Responses by all eligible physicians to all questions related to the understanding of retigabine-associated risks are shown in Table 1.

Table 1 Responses to all questions related to the understanding of risks associated with retigabine (Trobalt™)
Full size table

The majority of eligible physicians (91.5 %) from all seven countries understood that retigabine is approved for use in partial-onset seizures (Q6), and 78.2 % recalled that it may be prescribed only for patients aged 18 years or older (Q11). Most (88.1 %) recalled that retigabine is not indicated for monotherapy (Q7). Specific dose-related knowledge (Q8, Q9, Q10, Q12, Q13, Q19) was recalled among 57–74 % of eligible physicians.

Between 54.1 and 66.3 % of eligible physicians recalled that patients taking retigabine had a risk of specific CNS adverse events (AEs), and 64.6 % recalled the risk of urinary retention in these patients (Q14). Fewer than half (44.6 %) recalled an association between retigabine and possible QT prolongation (Q20), although 76.5 % recalled that they should warn patients prescribed retigabine about new cardiac effects (Q23).

Awareness of many details regarding management of specific risks was low. Only 20.4 % of physicians recalled that dose titration may minimize the risk of CNS side effects (Q18), and 25.9 % recalled that an electrocardiogram (ECG) is recommended for patients with congestive heart failure (Q21).

3.4 Subgroup Analyses

Compared with all physicians who completed the survey, similar but slightly higher proportions of retigabine prescribers understood the prescribing information and recalled the risks of CNS, urinary, and cardiac effects associated with retigabine, as well as the appropriate management of individual risks (Table 1).

Overall, physicians who had read the retigabine education letter recalled more correct information regarding the use of retigabine and its associated risks than those who had not (Table 1). More physicians who had read the retigabine education letter recalled that retigabine should be taken three times a day [85.2 vs. 54.3 % (Q9)], that retigabine is associated with a risk of urinary retention [74.1 vs. 47.6 % (Q14)], that urinary AEs were generally reported within 8 weeks after starting retigabine [67.2 vs. 33.3 % (Q15)], and that the ECG should be re-evaluated after achievement of the maintenance dose in patients with congestive heart failure [56.1 vs. 24.8 % (Q22)].

Slightly higher percentages of retigabine prescribers understood the prescribing information and recalled the risks associated with retigabine when compared with all physicians who completed the survey (data not shown).

4 Discussion

The results of this survey, which assessed understanding of the risks associated with retigabine by neurologists across seven countries, provide an indication of the effectiveness of risk-minimization measures for retigabine in Europe.

Generally, physicians had adequate knowledge of the indication for retigabine use, but weaker recall of dose-related information and management of specific risks. Subgroup analyses showed that both the physicians who read the retigabine education letter and those who had prescribed retigabine had better recall of information regarding the use of retigabine in patients with partial-onset seizures and the associated risks than did physicians who had not read the education letter or prescribed retigabine. Responses from physicians in Germany were analyzed separately due to the change in availability of retigabine in that country at the time of the survey, but the results largely paralleled those from physicians in the other six countries.

Although the original study design included patient and prescriber surveys, the patient survey was not conducted because of lack of patient recruitment by retigabine prescribers, the relatively low uptake of retigabine in Europe, and confidentiality regulations restricting direct contact with patients. The original survey protocol was amended to exclude Sweden because of delays in ethics committee submissions.

This study was not based on retigabine prescribing volume but, rather, targeted a geographically diverse population of physicians across Europe. The survey was conducted online, which facilitated physicians’ responses. The study design was based on GSK’s and UBC’s experience in designing RMPs and conducting similar surveys in the EU. Further, a similar US survey had been previously performed by GSK to evaluate REMS for retigabine [12]. Further guidance on risk-minimization measures was not available at the time of the survey [13, 14].

This was a voluntary survey in which the respondents were self-selected; therefore, the sample, although random, may not be representative of all physicians who prescribe retigabine. The survey focused on the risks described for retigabine in the PG, although this is not the only source of information about risks associated with medication use. While taking the survey, physicians were not restricted from referencing educational materials, which could have introduced a possible bias in the prior understanding of risks associated with retigabine. However, it was purposely not indicated which materials could be referenced to find the responses. Additionally, subsequent to data collection, retigabine was withdrawn in Germany. Therefore, the survey results may not represent the current prescribing population, as approximately one-third of respondents were practicing in Germany.

Overall, results indicate mixed physician understanding, ranging from adequate to limited recall, of the main risks associated with retigabine. To strengthen risk-minimization efforts for retigabine and following the identification of new emerging risks in 2013 [15], GSK has since sent an updated ‘Dear Healthcare Professional’ letter and initiated another EU survey to assess how effectively specific risks associated with retigabine use are communicated [16].