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Vascular Consequences Of Interruption Of Tnf-Inhibitor Therapy In Patients With Rheumatoid Arthritis
Clinical Therapeutics The Committee for Orphan Medicinal Products (COMP), European Medicines Agency (EMA), London, United Kingdom; and Pharmacology & Pharmacotherapy, Department of Pharmacological Sciences, Faculty of Pharmacy of the University of Lisbon, Lisbon, Portugal In 2000, regulation on orphan medicinal products was adopted in the European Union with the aim of benefiting patients who suffer from serious, rare conditions for which there is currently no satisfactory treatment. Since then, more than 1000 orphan drug designations have been granted by the European Commission based on a positive opinion from the Committee for Orphan Medicinal Products (COMP), and more than 100 orphan drugs have received marketing authorization in Europe. The COMP has dealt with innovation in several forms including cutting-edge therapies and for many years acted as the “gate-opener” at the EMA for innovative and medically plausible research. Although the market exclusivity granted for an orphan product lasts for 10 years (with a 2 years extension for paediatric development), the knowledge gained during the development process is eternal. To face the growing challenges resulting from the advancements in science, strengthened interactions between all stakeholders were necessary, providing more innovative approaches to the development of orphan medicines, thereby bringing science into regulation and regulation into science. The result of this scientific role of EMA in the field of orphan medicines can be translated into a shift of the products under assessment by the Committee of Human Medicinal Products, so that a significant number of orphan medicines are requesting marketing authorization. This undeniably represents the commitment of all stakeholders to providing further scientific innovation and more treatment options for patients affected by rare diseases. In order to translate more research into treatment, a structured responsive capacity to the continuous evolution occurring in the interface of science and regulation is expected aligned with the aim of having more, better, efficacious, and safer orphan medicines in the years to come.
2.6 Vascular Consequences Of Interruption Of Tnf-Inhibitor Therapy In Patients With Rheumatoid Arthritis G.A. Rongen1; I. Van Ingen2; and T.L. Jansen3 1 Department of Internal Medicine/Pharmacology and Toxicology, Nijmegen, the Netherlands; 2Department of Rheumatology Radboudumc, Nijmegen, the Netherlands; and 3Department of Rheumatology, VieCuri MC, Venlo & Scientific IQ HealthCare Radboudumc, Nijmegen, the Netherlands Background: Endothelium-mediated vasodilation is reduced in patients with rheumatoid arthritis (RA), an early sign of vascular damage. This vascular dysfunction is normalised by TNF-inhibitors (TNFi). To reduce costs, interruption of TNFi therapy in RA patients with prolonged remission of their disease is advocated. In this addon to the POET study, a randomised stop-trial (Arthritis Rheumatol 2016), we tested the hypothesis that interruption of TNFi results in microvascular vasodilator dysfunction. Methods: Eight patients were randomised to the continuation arm and 27 to the intervention arm of stopping the TNFi. Lost in followup were 2 and 5 patients, respectively. Forearm vasodilation to acetylcholine (ACh, endothelium-dependent vasodilator) and sodium nitroprusside (SNP; nitric oxide-donor) were assessed before cessation of TNFi therapy (visit 1) and either 6 months after (dis)continuation of TNFi or at flare of RA (based on predefined DAS28-score) whichever came first (visit 2). The vasodilators were infused into the brachial artery and forearm blood flow (FBF) was measured at both sides. Results: expressed as percentage change in FBF-ratio (FBF-infused/ FBF non-infused forearm); see table; group A: continued TNFi (no flares), group B: stopped TNFi without flare, group C: stopped TNFi with flare. Mean±SE
2.5 Safe Introduction of New Medicines Into Clinical Practice S. Maxwell Clinical Pharmacology Unit, University of Edinburgh, and Clinical Research Centre, Western General Hospital, Edinburgh, United Kingdom New medicines are constantly being made available as a result of the drug development process. This poses considerable challenges for the health care organizations responsible for overseeing their introduction and the prescribers who take immediate clinical responsibility for patient care. The difficulty of the process depends on how innovative the medicine is. Local governance processes will include an initial assessment by the Drug & Therapeutics Committee taking into account potential indications, displacement of existing treatments, and cost-effectiveness. It will also consider specific safety issues, including the likelihood of adverse effects and medication errors. Consideration should be given to risk minimization practices, such as supervision, patient advice forms, dedicated prescribing documentation, additional training, and restricted prescribing. All units should have means of monitoring for safety issues, and these may need to take into account some of the specific hazards involved (e.g., additional tests). More widely, safety will depend on regional or national pharmacovigilance systems (e.g., Yellow Card scheme). This presentation will address each of these issues and offer examples of current approaches to safe introduction of medicines.
e8
Ach-0.5
Ach-2
Ach-8
SNP-0.6
SNP-0.2
SNP-0.6
Group A N= 6
Visit 1 Visit 2
124±34 244±113
594±167 477±228
1246±575 503±136
52±21 222±45
299±128 465±133
651±223 821±256
Group B N= 14
Visit 1 Visit 2
210±45 241±49
582±156 418±74
726±143 739±95
93±16 99±14
223±42 219±33
358±54 486±94
Group C N= 8
Visit 1
274±74 * 142±33
608±185
1367±330
287±63
614±185
267±54
724±195
121±30 * 105±24
162±31
340±87
Visit 2
*P< 0.05 for comparison between visit 1 and 2 (repeated measures ANOVA).
Conclusions: Vasodilator function is reduced after interruption of TNFi, but only when RA reactivates. Without close monitoring and subsequent restart when RA reactivates, microvascular damage will occur after TNFi-interruption with potential devastating implications for cardiovascular health.
2.7 Effectiveness Assessment When Pharmacokinetics Makes A Difference, Macrolides And Azalide Example I. Francetic University Hospital Centre Zagreb and University of Zagreb Medical School (ret.), Zagreb, Croatia Ever since antimicrobial agents were discovered the effectiveness of their various members was estimated according to the minimal
Volume 38 Number 10S
2.6 Vascular Consequences Of Interruption Of Tnf-Inhibitor Therapy In Patients With Rheumatoid Arthritis G.A. Rongen1; I. Van Ingen2; and T.L. Jansen3 1 Department of Internal Medicine/Pharmacology and Toxicology, Nijmegen, the Netherlands; 2Department of Rheumatology Radboudumc, Nijmegen, the Netherlands; and 3Department of Rheumatology, VieCuri MC, Venlo & Scientific IQ HealthCare Radboudumc, Nijmegen, the Netherlands Background: Endothelium-mediated vasodilation is reduced in patients with rheumatoid arthritis (RA), an early sign of vascular damage. This vascular dysfunction is normalised by TNF-inhibitors (TNFi). To reduce costs, interruption of TNFi therapy in RA patients with prolonged remission of their disease is advocated. In this addon to the POET study, a randomised stop-trial (Arthritis Rheumatol 2016), we tested the hypothesis that interruption of TNFi results in microvascular vasodilator dysfunction. Methods: Eight patients were randomised to the continuation arm and 27 to the intervention arm of stopping the TNFi. Lost in followup were 2 and 5 patients, respectively. Forearm vasodilation to acetylcholine (ACh, endothelium-dependent vasodilator) and sodium nitroprusside (SNP; nitric oxide-donor) were assessed before cessation of TNFi therapy (visit 1) and either 6 months after (dis)continuation of TNFi or at flare of RA (based on predefined DAS28-score) whichever came first (visit 2). The vasodilators were infused into the brachial artery and forearm blood flow (FBF) was measured at both sides. Results: expressed as percentage change in FBF-ratio (FBF-infused/ FBF non-infused forearm); see table; group A: continued TNFi (no flares), group B: stopped TNFi without flare, group C: stopped TNFi with flare. Mean±SE
2.5 Safe Introduction of New Medicines Into Clinical Practice S. Maxwell Clinical Pharmacology Unit, University of Edinburgh, and Clinical Research Centre, Western General Hospital, Edinburgh, United Kingdom New medicines are constantly being made available as a result of the drug development process. This poses considerable challenges for the health care organizations responsible for overseeing their introduction and the prescribers who take immediate clinical responsibility for patient care. The difficulty of the process depends on how innovative the medicine is. Local governance processes will include an initial assessment by the Drug & Therapeutics Committee taking into account potential indications, displacement of existing treatments, and cost-effectiveness. It will also consider specific safety issues, including the likelihood of adverse effects and medication errors. Consideration should be given to risk minimization practices, such as supervision, patient advice forms, dedicated prescribing documentation, additional training, and restricted prescribing. All units should have means of monitoring for safety issues, and these may need to take into account some of the specific hazards involved (e.g., additional tests). More widely, safety will depend on regional or national pharmacovigilance systems (e.g., Yellow Card scheme). This presentation will address each of these issues and offer examples of current approaches to safe introduction of medicines.
e8
Ach-0.5
Ach-2
Ach-8
SNP-0.6
SNP-0.2
SNP-0.6
Group A N= 6
Visit 1 Visit 2
124±34 244±113
594±167 477±228
1246±575 503±136
52±21 222±45
299±128 465±133
651±223 821±256
Group B N= 14
Visit 1 Visit 2
210±45 241±49
582±156 418±74
726±143 739±95
93±16 99±14
223±42 219±33
358±54 486±94
Group C N= 8
Visit 1
274±74 * 142±33
608±185
1367±330
287±63
614±185
267±54
724±195
121±30 * 105±24
162±31
340±87
Visit 2
*P< 0.05 for comparison between visit 1 and 2 (repeated measures ANOVA).
Conclusions: Vasodilator function is reduced after interruption of TNFi, but only when RA reactivates. Without close monitoring and subsequent restart when RA reactivates, microvascular damage will occur after TNFi-interruption with potential devastating implications for cardiovascular health.
2.7 Effectiveness Assessment When Pharmacokinetics Makes A Difference, Macrolides And Azalide Example I. Francetic University Hospital Centre Zagreb and University of Zagreb Medical School (ret.), Zagreb, Croatia Ever since antimicrobial agents were discovered the effectiveness of their various members was estimated according to the minimal
Volume 38 Number 10S