Deaths Patients with events (%) 0 vs. 0 n.r.

Transcription

1 Resolution by the Federal Joint Committee on an amendment to the Pharmaceutical Directive (AM-RL): Appendix XII Resolutions on the benefit assessment of pharmaceuticals with new active ingredients, in accordance with the German Social Code, Book Five (SGB V), section 35a from 29 March 2012 In its session on 29 March 2012, the Federal Joint Committee resolved to amend the Pharmaceutical Directive (AM-RL), version published 18 December 2008/22 January 2009 (Federal Gazette, number 49a of 31 March 2009), last amended on 15 March 2012 (Federal Gazette, AT 16 April 2012 B6) as follows: Appendix XII shall be amended in alphabetical order to include the active ingredient fingolimod: Therapeutic indication: I. Gilenya, with the active ingredient fingolimod, is indicated as single disease modifying therapy in highly active relapsing remitting multiple sclerosis for the following adult patient groups: Patients with high disease activity despite with a beta-interferon (INF β). These patients may be defined as those who have failed to respond to a full and adequate course (normally at least one of ) of betainterferon. Patients should have had at least 1 relapse in the previous while on therapy, and have at least 9 T2- hyperintense lesions in cranial MRI or at least 1 Gadolinium-enhancing lesion. A "non-responder" could also be defined as a patient with an unchanged or increased relapse rate or ongoing severe relapses, as compared to the previous, or Patients with rapidly evolving severe relapsing remitting multiple sclerosis defined by 2 or more disabling relapses in one, and with 1 or more Gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI. 1. Additional benefit of the pharmaceutical over appropriate comparative a) Glatiramer acetate in patients with highly active relapsing remitting multiple sclerosis (RRMS) who have failed to respond to a full and adequate course (normally at least one of ) of beta-interferon (IFN β-1a or 1b) Appropriate comparator: Glatiramer acetate Extent and probability of additional benefit over glatiramer acetate: An additional benefit has not been proved. b) INF β (1a or 1b) in patients with RRMS who have not yet received an adequate course of with (INF-β). Appropriate comparator: IFN β (1a or 1b) Extent and probability of additional benefit over IFN β-1a: An additional benefit has not been proved. c) IFN β-1a in patients with rapidly evolving RRMS Appropriate comparator: IFN β (1a or 1b) Extent and probability of additional benefit over IFN β-1a: There is a hint of a slight additional benefit. Study results of the TRANSFORMS study for patient population c) according to endpoints Endpoints Patient population c) (number of patients 27) vs. INF-ß 1a (number of patients 30) p-value Mortality Deaths Patients with events (%) 0 vs. 0 n.r.

2 Endpoints Patient population c) (number of patients 27) vs. INF-ß 1a (number of patients 30) p-value Morbidity Annual relapse rate 1 Rate ratio [95% CI]: [0.238; 2.333] % of patients without relapse Hazard ratio [95% CI]: 0.76 [0.24; 2.39] Number of relapses according to severity Number of relapses Mild: 2 vs. 3 Medium: 4 vs. 5 Severe: 0 vs ,000 3 Percentage of patients without disabling relapses KM estimates 2 [95% CI] 100 [n.r.] vs [67.99; 94.73] MSFC-z score change 5 Average change (SD) 0.02 (0.033) 6 vs (0.061) MSFC subscale 25-foot timed walking test (seconds) MSFC subscale 9-hole peg test (seconds) MSFC subscale PASAT-3 (number of correct answers) Fatigue (using U-FIS) Everyday life activities (using PRIMUS activities) Health-related quality of life Average change (SD) (1.438) vs (1.360) Average change (SD) 0.55 (5.927) vs (2.675) Average change (SD) (2.988) vs (7.460) No data available on relevant population. No data available on relevant population EQ-5D (Index) EQ-5D (VAS) PRIMUS QoL Average change (SD) 0.04 (0.023) 6 vs (0.029) Average change (SD) 2.78 (4.770) 6 vs (3.006) No data available on relevant population. Side effects AE Relative risk [95% CI]: 1.02 [0.82; 1.28]

3 Endpoints Patient population c) (number of patients 27) vs. INF-ß 1a (number of patients 30) p-value SAE Patients with events (%) 1 (3.7) vs. 0 (0) Termination due to AE Patients with events (%) 1 (3.7) vs. 0 (0) Flu-like symptoms Relative risk [95% CI]: 0.12 [0.02; 0.91] Absolute risk reduction: -26.3% (3.7% vs. 30% patients with symptoms) 0,010 4 Bradycardia/ Patients with events (%) AV conduction defects 7 0 (0) vs. 1 (3.3) Macular edema Patients with events (%) 0 (0) vs. 0 (0) Reactions at the injection site Infections No applicable data available Relative risk [95% CI]: 0.97 [0.59; 1.59] Annual relapse rate: Number of confirmed relapses divided by the number of patients in the group, multiplied by After 12 months. 3 Total p-value (exact Fisher test). 4 p-value from own calculation, unconditional exact test (CSZ method in accordance with [9]). 5 Positive change means improvement. 6 Standard error. 7 Construct of various preferred terms associated with bradycardia and the SMQ "Bradyarrhythmias (incl conduction defects and disorders of sinus node function)" AV: atrioventricular; IFN: interferon; CI: confidence interval; KM: Kaplan Meier; N: number of patients evaluated; n.r. not reported; MSFC Multiple Sclerosis Functional Composite; PRIMUS: Patient Reported Indices for Multiple Sclerosis; SD: standard deviation; SAE: serious adverse event; AE: adverse event; RRMS: relapsing remitting multiple sclerosis; VAS: visual analog scale.

4 2. Number of patients and criteria for defining patients eligible for a) Patients with highly active RRMS, complete pre- with IFN-β 1a or 1b Number: approx. 4,300 b) Patients with highly active RRMS, no complete pre- with IFN-β 1a or 1b Number: approx. 3,700 c) Patients with rapidly progressing severe RRMS Number: approx. 1, Requirements for quality-assured administration The specifications outlined in the product information are to be followed. For fingolimod the urgent safety information of 26 January 2012 from the pharmaceutical company is to be followed. The manufacturer indicates in the urgent safety information that the patient's cardiovascular functions must be monitored more closely for the first 6 hours after the start of with fingolimod due to the risk of bradycardia, longer if necessary. In the first 6 hours after administering Gileny, monitoring of all patients that start should include the following measures: - A 12-channel ECG before and six hours after the first dose - Constant ECG monitoring for 6 hours - Hourly blood pressure and pulse rate measurements Patients with indications of clinically significant cardiac abnormalities should be monitored until these regress. Continued monitoring is recommended if one of the following criteria is present: Presence of any of the following 6 hours after initial administration: - Pulse rate < 40 beats per minute - Reduction in pulse rate by more than 20 beats per minute in comparison to initial value - Persistent, newly occurring, second-degree AV block, Mobitz 1 type (Wenckebach) - Occurrence of any of the following during the 6-hour monitoring: - Symptomatic bradycardia - Newly occurring, second-degree AV block, Mobitz 2 type - Newly occurring, third-degree AV block, 4. Costs of a) Glatiramer acetate in patients with highly active relapsing remitting multiple sclerosis (RRMS) who have failed to respond to a full and adequate course (normally at least one of ) of beta-interferon (IFN β-1a or 1b) Duration of : therapy Mode of ongoing, 1 daily Number of s per patient per Duration per (days) Number of days per patient per ongoing Glatiramer acetate (Copaxone ) ongoing, 1 daily ongoing

5 Consumption: therapy Strength Number of application units per pack 1 Average annual consumption 0.5 mg 28 hard capsules 365 hard capsules Glatiramer acetate (Copaxone ) 20 mg 28 pre-filled syringes s.c. 365 pre-filled syringes 1 suitable strength/pack size Costs: Cost of phamaceutical: therapy Cost (pharmacy retail price) Cost after legally mandated rebates 2, , [ ; ] Glatiramer acetate (Copaxone ) 1, , [ ; ] 1 Rebate in accordance with SGB V, section 130: 2 Rebate in accordance with SGB V, section 130a: 3 Original in lowest-cost pack size/price relation ("Lauer-Taxe", effective 1 March 2012 Costs for additional, necessary statutory health insurance (SHI) benefits: therapy additional SHI expense item Number of additional necessary SHI expense items per episode, cycle, etc. per patient per Cost per unit Annual cost 0.5 mg oral Ophthalmological follow-up examination 3 to 4 months after start of before and regularly during if uveitis or diabetes mellitus are present in the case history Supplementary ophthalmoscopy before and regularly during if uveitis or diabetes mellitus are present in the case history

6 therapy additional SHI expense item Number of additional necessary SHI expense items per episode, cycle, etc. per patient per Cost per unit Annual cost Cardiological followup examination 2 if significant cardiovascular diseases are present Varicella zoster virus (VZV) antibody test if chicken pox is not present in the case history or if the patient has not been vaccinated against VZV before start of if chicken pox is not present in the case history or if the patient has not been vaccinated for VZV VZV vaccination Additional measures before start of if VZV antibody test is negative Glatiramer acetate 20 mg/ml s.c. (Copaxone ) Cardiological followup examination Regularly during if cardiac disease is present For total target population 2 Please see also the urgent safety information on Gilenya of 26 January 2012 Annual costs: therapy Annual costs per patient 1 (Cost after legally mandated rebates) 26, Glatiramer acetate (Copaxone ) 16, Including costs for additional necessary SHI expense items for the total target population b) INF-β (1a or 1b) in patients with RRMS who have not yet received an adequate course of with (INF-β) 1a or 1b.

7 Duration of : therapy Mode of ongoing, 1 daily Number of s per patient per Number of days per Number of days per patient per ongoing INF-β 1a i.m. (Avonex ) ongoing, 1 weekly ongoing Consumption: therapy Strength (mg) Number of application units per pack 1 Average annual consumption 0.5 mg 28 hard capsules 365 hard capsules INF β-1a (Avonex ) 30 µg 12 pre-filled syringes 52 pre-filled syringes 1 suitable strength/pack size Costs: Cost of pharmaceutical: therapy Cost (pharmacy retail price) Cost after legally mandated rebates 2, , [ ; ] INF β-1a (Avonex ) 4, , [ ; ] 1 2 Rebate in accordance with SGB V, section 130: Rebate in accordance with SGB V, section 130a: 3 Original in lowest-cost pack size/price relation ("Lauer-Taxe", effective 1 March 2012 Costs for additional, necessary statutory health insurance (SHI) benefits: Description of therapy additional SHI expense item Number of additional necessary SHI expense items per episode, cycle, etc. per patient per Cost per unit Total costs per 0.5 mg oral Ophthalmological follow-up examination 3 to 4 months after start of before and regularly during if uveitis or diabetes mellitus are present in the case history Supplementary ophthalmoscopy

8 Description of therapy additional SHI expense item Number of additional necessary SHI expense items per episode, cycle, etc. per patient per Cost per unit Total costs per before and regularly during if uveitis or diabetes mellitus are present in the case history Cardiological followup examination 2 if significant cardiovascular diseases are present Varicella zoster virus (VZV) antibody test if chicken pox is not present in the case history or if the patient has not been vaccinated against VZV before start of if chicken pox is not present in the case history or if the patient has not been vaccinated for VZV VZV vaccination Additional measures before start of if VZV antibody test is negative IFN β-1a 30 μg/ 0.5 ml i.m. (Avonex ) Antipyretic analgesic Before each injection and for 24 hours after each injection months (8-24x) For total target population 2 Please see also the urgent safety information on Gilenya of 26 January 2012 Annual costs: therapy Annual costs per patient 1 (Cost after legally mandated rebates) 26, IFN β-1a (Avonex ) 18, , Including costs for additional necessary SHI expense items for the total target population

9 c) Patients with rapidly progressing severe RRMS Duration of : therapy Mode of ongoing, 1 daily Number of s per patient per Number of days per Number of days per patient per ongoing INF β-1a (Avonex ) ongoing, 1 weekly ongoing Consumption: therapy Strength Number of application units per pack1 Average annual consumption INF-β 1a i.m. (Avonex ) 0.5 mg 28 hard capsules 365 hard capsules 30 µg 12 pre-filled syringes 52 pre-filled syringes 1 suitable strength/pack size Costs: Cost of pharmaceutical: therapy Cost (pharmacy retail price) Cost after legally mandated rebates INF β-1a (Avonex ) 2, , [ ; ] 4, , [ ; ] 1 Rebate in accordance with SGB V, section 130: 2 Rebate in accordance with SGB V, section 130a: 3 Original in lowest-cost pack size/price relation ("Lauer-Taxe", effective 1 March 2012 Costs for additional, necessary statutory health insurance (SHI) benefits: Description of therapy additional SHI expense item Number of additional necessary SHI expense items per episode, cycle, etc. per patient per Cost per unit Total costs per 0.5 mg oral Ophthalmological follow-up examination 3 to 4 months after start of before and regularly during if uveitis or diabetes mellitus are

10 Description of therapy additional SHI expense item Number of additional necessary SHI expense items per episode, cycle, etc. per patient per Cost per unit Total costs per present in the case history Supplementary ophthalmoscopy before and regularly during if uveitis or diabetes mellitus are present in the case history Cardiological followup examination 2 if significant cardiovascular diseases are present Varicella zoster virus (VZV) antibody test if chicken pox is not present in the case history or if the patient has not been vaccinated against VZV before start of if chicken pox is not present in the case history or if the patient has not been vaccinated for VZV VZV vaccination Additional measures before start of if VZV antibody test is negative IFN β-1a 30 μg/ 0.5 ml i.m. (Avonex ) Antipyretic analgesic Before each injection and for 24 hours after each injection months (8-24x) For total target population 2 Please see also the urgent safety information on Gilenya of 26 January 2012 Annual costs: therapy Annual costs per patient 1 (Cost after legally mandated rebates) 26, IFN β-1a (Avonex ) 18, , Including costs for additional necessary SHI expense items for the total target population

11 II. Validity 1. This resolution takes effect on the day of its publication in the internet on the website of the Federal Joint Committee on 29 March This resolution remains valid until 29 March The justification for this resolution will be published on the website of the Federal Joint Committee at Berlin, 29 March 2012 The Federal Joint Committee in accordance with SGB V, section 91 The Chair Hess

12 Resolution by the Federal Joint Committee on an amendment to the Pharmaceutical Directive (AM-RL): Appendix XII Resolutions on the benefit assessment of pharmaceuticals with new active ingredients, in accordance with the German Social Code, Book Five (SGB V), section 35a from 21 June 2012 In its session on 21 June 2012, the Federal Joint Committee resolved to amend the Pharmaceutical Directive (AM-RL), version published 18 December 2008/22 January 2009 (Federal Gazette, number 49a of 31 March 2009), last amended on 16 August 2012 (Federal Gazette, AT 12 September 2012 B3), as follows: I. In appendix XII, the information on the active ingredient fingolimod shall be amended in point "3. Requirements for quality-assured administration" shall be amended as follows: The specifications outlined in the product information are to be followed. In the resolution on the benefit assessment for fingolimod from 29 March 2012, additional reference was made to the preliminary measures for cardiovascular monitoring at start of with Gilenya (Dear Healthcare Professional letter from January 2012). The updated Dear Healthcare Professional letter from 26 April 2012 includes additional concrete notes and recommendations resulting from a comprehensive risk-benefit assessment by the Committee for Medicinal Products for Human Use (CHMP) from the European Medicines Agency (EMA). These notes and recommendations follow in their original wording. "Following a comprehensive risk/benefit assessment of Gilenya (fingolimod) by the European Medicines Agency s scientific committee, CHMP, the following updated recommendations are effective immediately for patients treated with Gilenya. These recommendations follow case reports of cardiovascular events including a patient who died of unknown cause after the first dose of Gilenya. Gilenya is not recommended in patients a) with the following medical conditions: 2nd degree Mobitz Type II or higher degree AV block, sick-sinus syndrome, or sino-atrial heart block Significant QT prolongation (QTc>470 msec (female) or >450 msec (males)) History of symptomatic bradycardia or recurrent syncope, known ischaemic heart disease, cerebrovascular disease, history of myocardial infarction, congestive heart failure, history of cardiac arrest, uncontrolled hypertension, or severe sleep apnea b) receiving the following antiarrhythmic or heart-rate-lowering drugs: Class Ia (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol) antiarrhythmics Beta blockers Heart rate lowering calcium channel blockers (e.g. verapamil, diltiazem or ivabradine) Other substances which may decrease heart rate (e.g. digoxin, anticholinesteratic agents or pilocarpine) In such patients, with Gilenya should be considered only if the anticipated benefits outweigh the potential risks. Before start of for patients in group a) or b), advice from a cardiologist should be sought, including, if appropriate, the possibility to switch to non-heart-rate-lowering drugs. If with Gilenya is considered for these patients, monitoring at least overnight should be initiated. For all patients, monitoring should include: A 12-lead ECG and blood pressure measurement before starting the first dose and after 6 hours Blood pressure and heart rate measurement every hour after the first dose of Gilenya for 6 hours During the first 6 hours of continuous real time ECG monitoring is recommended.

13 If the patient s heart rate at the end of the 6-hour period is the lowest following first dose administration, the monitoring should be extended by at least 2 hours and until the heart rate increases. Criteria for extended monitoring: In those patients with evidence of clinically important cardiac effects during the first 6 hours, monitoring should be extended, including at least overnight monitoring, until resolution. Recommended criteria for extending monitoring include: New onset 3rd degree atrioventricular block at any time during the monitoring period after first dose The presence at the end of the 6-hour monitoring period after first dose of: Heart rate less than 45 beats per minute QTc interval 500 msec. Persistent new-onset 2nd-degree atrioventricular block, Mobitz Type I (Wenckebach) or higher degree atrioventricular block The content of this letter has been agreed with the Federal Institute for Drugs and Medical Devices." II. Validity This resolution takes effect on the day of its publication in the internet on the website of the Federal Joint Committee on 21 June The justification for this resolution will be published on the website of the Federal Joint Committee at Berlin, 21 June 2012 The Federal Joint Committee in accordance with SGB V, section 91 The Chair Hess