MAH Market authorisation holder MHRA Medicines and Healthcare products Regulatory Agency (UK) MR Mutual recognition procedure (EU) µg micrograms µg/hr micrograms per hour mEq milli-equivalents mg milligram mg/h milligrams per h MRHD maximum recommended human dose NRS Numeric Rating Scale (11 point NRS for pain) 0 = no pain, 11 = pain as bad as you can imagine NSAID Non-Steroidal Anti-Inflammatory Drug PD Pharmacodynamics PI Product information PK Pharmacokinetic PP Per protocol pg picogram pg/mL picogram per millilitre PSURs Periodic safety update reports QT QT interval for rate QTc QT interval corrected for heart rate QTci QT interval individually corrected RR relative risk SADR serious adverse drug reaction SAE serious adverse event SD standard of the mean SL Sublingual
Duration: the studies were of relatively short duration (15 days or less). Medications for chronic pain can be assumed to have use that extends over months and years. Longer clinical trials are, therefore, essential to exclude a transient effect and to investigate such issues as tachyphylaxis, tolerance, dependence and safety. It is recommended that trials investigating therapies for chronic pain have duration of at least 12 weeks. Ethnicity: all participants were Caucasian (except for one or two of African descent). Opioids are generally accepted as being ethnically sensitive, with genetic polymorphisms resulting in different responses in different ethnic populations. Although over 90% of the Australian population has Caucasian ancestry there are other ethnic groups represented, including Aboriginal and Torres Strait Islanders (2.5%), Chinese (4%) and Indian (2%). Age: only adults were included, although the elderly were not excluded. Special populations: patients with any major organ disease were excluded from the studies. Concomitant disease was, however, common. Use of opioids: the majority of study participants had previously used opioids, for both tumour related and non-tumour related pain. The use of opioids for non-tumour pain such as osteoarthritis would be unusual in Australia. Table 12: Results for the primary outcome measure (response rate) Treatment Response Rate (%) 95% Confidence Interval WIS-BUP01 placebo 31.4 16.9 – 49.3 20 mg patch 34.3 19.1 – 52.2 30 mg patch 36.6 22.1 – 53.1 40 mg patch 50.0 33.4 – 66.6 WIS-BUP02 placebo 16.2 6.2 – 32.0 20 mg patch 36.6 21.2 – 53.1 30 mg patch 47.5 31.5 – 63.9 40 mg patch 33.3 18.6 – 51.0 WIS-BUP03 Placebo 46.7 31.7 – 62.1 30 mg patch 57.5 46.4 – 68.0 As shown by the response rates (and 95% confidence interval (CI)) above, none of the three ‘pivotal’ randomised double blind placebo controlled studies (WIS-BUP01, WISBUP02 and WIS-BUP03) were able to show that the patch was significantly better than
application refers to the same product but in different strengths and therefore, it is expected that the RMP for Norspan being equally applied for Transtec. Consequently, the RMP in its current version is deficient and has to be corrected prior to potential approval. Recommendation 4 which clarifies that there is very little or significant difference between the identified Norspan and Transtec risks. formulations of the medicine, particularly where the other formulations have substantially more experience. The deficiencies in the summary of safety concerns are further discussed below (see recommendation 4). 3. It is recommended that the sponsor reworks the structure and content of the ASA, to provide all relevant information outlined in the TGA ASA template. This document will be revisited to the Advisory Committee on Prescription Medicines (ACPM). The ASA has been reworked to provide the information as outlined in the TGA ASA template. The ASA now includes a summary table of the safety concerns and the risk minimisation measures in the Australian context. This table includes the actual wording of the EU SmPC and proposed Australian PI and CMI for all of the safety concerns. The evaluator acknowledges the sponsor’s revisions. 4. The sponsor should add all ongoing safety concerns were accepted and requested for Norspan patches to the table ongoing safety concerns for Transtec, or provide compelling justification for not doing so. Pharmacovigilance and risk-minimisation activities should be assigned to all ongoing safety concerns and the pharmacovigilance and risk-minimisation plan of the EU-RMP/ASA be amended accordingly. A comparison and justification for the difference in the ongoing safety concerns of the Transtec RMP compared to the Norspan RMP is provided in Table 18. Based on the justifications in the above table and the response to recommendation 2 the sponsor does not think any alterations are required to the Transtec RMP. The ongoing safety concerns that the TGA requested to be added as potential risks for Norspan were: 1. The interaction with CYP3A4 inhibitors. 2. CNS depression, in particular the effects on driving ability. 1. The interaction with CYP3A4 inhibitors. The evaluator accepts the sponsor’s handling of the risks Drug Abuse and Addiction which are included as identified risks in the Transtec RMP/ASA. The evaluator accepts that accidental overdose will continue to be monitored under the umbrella identified risk Overdose. This is not accepted. market
regarded as included under the Transtec risks of abuse and addiction. Important identified risk; Accidental overdose Important identified risk; Overdose Section II.SVI.1 – Potential for harm from overdose and II.SVII.3 – Details of important identified and potential risks from clinical development and experience (including newly identified) of the Transtec RMP summarise the data for Transtec. The Norspan risk of accidental overdose is included under the Transtec risk of overdose. Important potential risk; Medication error No corresponding risk identified for Transtec Section II.SVI.4 of the Transtec RMP Potential for medication errors summarises the data for Transtec. No important safety concern was identified based on the data provided. Cutting the plaster into pieces was the most often observed medication error for Transtec. As no safety concern was identified in the cases related to the topic, this is not regarded to provide a basis for an important potential risk. Important Potential Risk: Off label use (cutting of the BTDS patch to achieve an intermediate dose) Important potential risk: Psychological dependence Important identified risk: Addiction The Transtec RMP covers the important potential risk ‘psychological dependence’ under it important identified risk of ‘addiction’. Missing information: use in pregnant and breastfeeding patients No corresponding missing information for Transtec As outlined in the Transtec RMP Section II.SV.3- post authorisation use in populations not studied in clinical trials there is considerable experience with the use of buprenorphine during pregnancy derived from opioid maintenance therapy and there is data on the use of transdermal buprenorphine in paediatric patients. Missing information: paediatric use Summary of recommendations Outstanding issues Issues in relation to the RMP New recommendations The ‘Potential for medication errors or other risks if applicable’ section of the revised ASA is not satisfactory in that it does not consider risks of inadvertent exposure, including