EUROPEAN COMMISSION
DG SANCO / C2
Development of public health performance indicators for the pharmaceutical sector
CONTRACT SI2.404788 (SANCO/G1/2003/06)
CASE STUDIES report
30/05/2006
Case-studies report réf. : Case studies.doc
2 / 56 Case-studies report réf. : Case studies.doc
TABLE OF CONTENTS
1 INTRODUCTION...... 5
1.1 Case-studies choice...... 5
1.2 Methodology ...... 5
2 COMMON INDICATORS ...... 6
2.1 Profile...... 6 2.1.1 Disease status ...... 7 2.1.2 Accessibility to medicines...... 9 2.1.3 Consumption chain...... 13 2.1.4 Medicines’ accessibility to market...... 15 2.1.5 Innovation ...... 17
2.2 Conclusions and recommendations ...... 18
3 DIABETES MELLITUS ...... 20
3.1 Profile...... 20 3.1.1 Disease status ...... 20 3.1.2 Accessibility to medicines...... 30 3.1.3 Consumption chain...... 31 3.1.4 Information to patients ...... 32 3.1.5 Quality of life ...... 35 3.1.6 Medicines effectiveness ...... 36
3.2 Conclusions and recommendations ...... 38
4 ACUTE STROKE ...... 41
4.1 Profile...... 41 4.1.1 Disease status ...... 42 4.1.2 Accessibility to medicines...... 47 4.1.3 Consumption chain...... 48 4.1.4 Information to patients ...... 50 4.1.5 Medicines effectiveness ...... 51
4.2 Conclusions and recommendations ...... 53
5 CONCLUSIONS...... 55
3 / 56 Case-studies report réf. : Case studies.doc
4 / 56 Case-studies report réf. : Case studies.doc
1 Introduction
The in-depth analysis of case-studies complements the description and evaluation work of performance indicators carried out in the framework of this project. It allows applying the theoretical and global approach to specific important priority diseases in Europe.
In this report, only recommended sources are included. All research work and data extractions are available in Annex “Case-studies annex - Common indicators”, in Annex “Case-studies annex - Diabetes mellitus” and in Annex “Case-studies annex - Acute stroke”.
1.1 Case-studies choice
The intention behind being to confirm or evaluate the feasibility of the indicators, the selection criteria used for the choice of the priority diseases for the case-studies were the following: • Diseases from the priority diseases list according to burden of disease in the European Union; • Including at least one chronic and one acute condition; • Including the main patient pathway steps issues such as prevention, diagnosis, …; • May concern a specific population group, e.g elderly, women; • With some data available on each priority objective identified; • With international guidelines available.
The two conditions chosen are most leading conditions in Europe which raise a major public health problem. These conditions account for over 7% of the EU-25 total burden of disease as described in the WHO report1 with a DALY of 2.0% regarding diabetes mellitus and 5.3% for acute stroke.
1.2 Methodology
The pilot study is organised in three parts according to indicators specificity and disease breakdown as follows: 1. Common indicators broken down by country and not by disease; 2. Indicators for a chronic condition: diabetes mellitus; 3. Indicators for an acute condition: acute stroke.
For each case-study, the profile of each indicator including a short definition and data extraction are described. Only core and supplementary indicators are presented,
1 “Priority Medicines for Europe and the World.” Kaplan W. and Laing R., 2004. World Health Organization.
INTRODUCTION 5 / 56 Case-studies report réf. : Case studies.doc excluded indicators are not included. Efforts were focused on international or European data whenever possible. National data were considered for a set of a few countries otherwise, so later work would be to extend it to remaining countries not covered.
For each indicator, a box summarises information on its importance (Core/Supplementary), its available breakdowns (BK) and further work needed for the monitoring of this indicator. Each indicator is defined and presented through data tables extractions. Detailed description of each indicators is available in Annex “Phase 2 report”.
At the end of each case-study section, a synthetic table in chapter “Conclusions and recommendations” is presented according to several criteria:
Domain Each indicator is ranked according to its importance within main objectives.
Importance The categorisation Core/Supplementary is conformed to those described in Phase 2.
Collected Data of few indicators are not collected for two main reasons: • Too specific indicators • Information coming from data sources with restrictive access
Access The indicators data are classified as publicly available, with restricted access and/or on payment. It depends on data sources.
Data source Main data sources are mentioned in this table.
Coverage The classification EU-25 / Partial / Limited / EU-25 agg. is still used.
Comments and further work For each indicator, few comments are added and then known improvement of this information already available.
2 Common indicators
2.1 Profile
In our framework, common indicators are defined as indicators not disease specific or not broken down by disease. Data were mainly collected for non restrictive access sources. The 13 common indicators among the 43 non excluded ones are presented in this section are: 1. Exposure to main risk factors; 2. 5-year survival rate (for cancers only); 3. Accessibility to pharmacies; 4. Share of non marketed medicines in newly authorised medicines; 5. National reimbursement systems; 6. National co-payment systems;
COMMON INDICATORS 6 / 56 Case-studies report réf. : Case studies.doc
7. Share of public expenses on Pharmaceuticals; 8. Rx to OTC switching; 9. Market share of generics on outpatient; 10. Adherence to treatment; 11. Time from license to market; 12. Average time for orphan medicines procedures; 13. Uptake of new medicines.
2.1.1 Disease status
Importance : Core EXPOSURE TO MAIN RISK FACTORS BK : Country Further work: None
Definition Exposure to main risk factors is measured according to three indicators: Body Mass Index (BMI), exposure to tobacco and consumption of alcohol. BMI is a measure of a person’s weight relative to his or her height. Exposure to tobacco is measured as the percentage of daily smokers and consumption of alcohol corresponds to the percentage of people who drunk any alcohol the past 12 months.
Data extraction Table: Exposure to main risk factors Body Mass Index (BMI) Daily smokers Alcohol BMI<18 18
Importance : Supplementary 5-YEAR SURVIVAL RATE (FOR CANCERS ONLY) BK : Country / disease (cancers)
COMMON INDICATORS – Disease status 7 / 56 Case-studies report réf. : Case studies.doc
Further work: None
Definition The survival time of a patient is defined as the time that elapsed between diagnosis and death.
Data extraction Table: 5-year survival rate for few cancers in 2006 Country Data year Breast cancer Cervical cancer Colorectal cancer OR RR OR RR OR RR CZ 1993-1997 63.0 86.0 63.0 92.0 Men: 30.0 Women: 34.0 Men: 75.0 Women: 78.0 DK 1991-1995 68.0 77.0 63.0 67.0 Men: 32.0 Women: 39.0 Men: 45.0 Women: 49.0 DE 1993-1997 69.0 78.0 62.0 66.0 Men: 43.0 Women: 45.0 Men: 55.0 Women: 56.0 FR 1990-1994 70.6 79.7 62.7 65.9 Men: 45.6 Women: 54.1 Men: 55.8 Women: 61.7 IE 1994-1998 65.0 73.0 60.0 62.0 41.0 62.0 IT 1990-1994 74.0 81.0 59.0 64.0 42.0 52.0 NL 1993-1997 74.0 82.0 75.0 (<60) 46.0 (>60) 76.0 (<60) 55.0 (>60) Colon: 48.0 Rectum: 46.0 Colon: 60.0 Rectum: 56.0 SK 2001 67.4 : 57.1 : Men: 32.7 Women: 37.7 : FI 1995-2000 76.2 85.6 63.8 70.7 43.1 56.3 SE 1996 75.3 84.7 66.0 69.2 45.9 58.3 UK 1998-2001 77.0 80.0 70.0 72.0 55.0 57.0 IS 1995-1999 80.4 88.8 74.0 76.6 Men: 46.5 Women: 42.7 Men: 58.9 Women: 52.5 NO 1998-2003 72.1 82.8 68.3 73.2 43.1 56.6 CH 1990-1994 73.0 81.0 66.0 72.0 Men: 48.0 Women: 51.0 Men: 59.0 Women: 62.0 Source: OECD HCQI project Note: • “:” corresponds to not available • OR: Observed Rate. It corresponds to the ratio between the number of women diagnosed surviving five years after diagnosis and the number of women diagnosed • RR: Relative Rate. It corresponds to the ratio between the observed rate of women diagnosed surviving five years after diagnosis and the expected survival rate of a comparable group from the general population
COMMON INDICATORS – Disease status 8 / 56 Case-studies report réf. : Case studies.doc
2.1.2 Accessibility to medicines
Importance : Supplementary ACCESSIBILITY TO PHARMACIES BK : Country Further work: None
Definition Number of community pharmacies per inhabitant.
Data extraction Table: Accessibility to pharmacies in 2002 in Europe Country Number of community pharmacies Number of community pharmacies per 1000 inhabitants (3) BE (2) 5 256 0.51 CZ 2 107 0.21 DK 279 0.05 DE (2) 21 305 0.26 EE 307 0.23 EL 9 300 0.85 ES 20 098 0.49 FR 22 697 0.38 IE (2) 1 230 0.31 IT (2) 16 808 0.29 CY 434 0.61 LV (1) 909 0.26 LT (1) 675 0.29 LU 82 0.18 HU 2 050 0.20 MT (1) 225 0.59 NL (2) 1 707 0.11 AT (2) 1 162 0.14 PL (1) 9 693 0.25 PT 2 682 0.26 SI 260 0.13 SK (1) 1 070 0.20 FI 799 0.15 SE (2) 870 0.10 UK 10 463 0.18 HR (1) 840 0.19 TR (1) 20 628 0.30 NO 502 0.11 CH 1 650 0.23 Source: PGEU, OECD, INED (French national institute of demographic studies) Note: (1) PGEU Database 2001 (2) 2003 data (3) Estimation based on population
Table: 2003 Key community pharmacy statistics in the new EU Member States compared with those in the UK Country Population Number of community pharmacies Number of people per pharmacy Number of community pharmacists Number of people per pharmacist CZ 10 300 000 2 189 4 705 6 100 1 690 EE 1 356 000 316 4 291 745 1 839 CY 705 500 465 1 517 675 1 464 LV 2 400 000 909 2 640 1 434 1 700 LT 3 475 600 1 389 2 502 2 195 1 583 HU 10 000 000 2 029 4 928 7 774 1 350 MT (1) 386 000 225 1 715 756 1 689 PL 38 700 000 9 693 3 992 22 000 1 760 SI 1 999 740 248 8 027 655 3 040 SK 5 400 000 1 200 4 500 3 000 1 800 UK 59 000 000 12 300 4 796 23 500 2 510 Source: “As the European Union expands, what are the implications for pharmacy?” http://www.pjonline.com/Editorial/20040501/news/news_europeanunion.html Statistics supplied by the Pharmaceutical Group of the European Union Note: (1) Figures for pharmacists in Malta represent all registered pharmacists, not only community pharmacists
COMMON INDICATORS - Accessibility to medicines 9 / 56 Case-studies report réf. : Case studies.doc
Importance : Core SHARE OF NON MARKETED MEDICINES IN NEWLY BK : Country AUTHORISED MEDICINES Further work: Data source/ Feasibility study for priority diseases
Definition Share of non-marketed (launched) medicines in the Member States in last most important newly authorised medicines during the last 3 years covering the priority diseases.
Data extraction Table: Number of different ATC codes between the reference country and compared ones Compared with Reference country BE EE IE IT HU NL AT SK FI BE 1412 2036 762 1168 949 195 1566 1214 EE 920 307 383 321 538 614 388 IE 0 1280 0 981 0 967 IT 401 760 188 1337 159 HU 498 387 860 327 NL 297 986 188 AT 664 415 SK 628 Source: EURO-MED-STAT Note: The selection was based on medicines exclusively available in the reference country. The figures correspond to the total number of records of different ATC codes (EURO-MED-STAT definition)
Limitations Each record may include several trade names. Hence, further work would be required to evaluate it by active ingredient for ATC codes if the indicator is to be monitored.
COMMON INDICATORS - Accessibility to medicines 10 / 56 Case-studies report réf. : Case studies.doc
NATIONAL REIMBURSEMENT SYSTEMS – NATIONAL CO-PAYMENT SYSTEMS – Importance : Core SHARE OF PUBLIC EXPENDITURE ON PHARMACEUTICALS BK : Country Further work: None
Definition “National reimbursement systems” is a qualitative and descriptive indicator of the list of medicines reimbursed availability (positive/negative lists) and the reimbursements rates “National co-payment systems” is a qualitative and descriptive indicator of the main cost-sharing types, i.e. - Co-payment (fixed amount per service) - Deductible (fixed amount to be born before the third-party gets involved) - Co-insurance (share of the price) The last indicator gathers expenses on Pharmaceuticals including OTC and co-payments.
Data extraction There is a wide variety of pricing and reimbursement schemes within the EU as a result of differences in the way that health care systems have developed over time.
Table: National reimbursement and co-payment systems Country Share of public expenses on pharmaceuticals List type Cost-sharing type Reimbursement rates (%) Comments (e.g. specific rates for priority diseases) (%) Comparability BE 55 4 Positive A 100, 80, 75, 50, 40, 20 CZ N/A 2 Positive None No fixed rates DK 58 1 Positive A/B 85, 70, 50 DE 66 1 Negative A/B 100 EE N/A N/A Positive A/B 100, 75, 50 EL 24 3 Positive A 75 ES 78 1 Negative A 90, 60 FR 78 1 Positive A/B 100, 65, 35, 15 IE 79 3 Positive / Negative None 100 Reimbursement rate: different systems for population groups, in some schemes 100 per cent reimbursement only after payment of a deductible IT 53 3 Positive / Negative A 100, 50 “positive list”: pharmaceutical book “Prontuario” lists all pharmaceuticals which are reimbursed. Financial Act 2001 abolishes reimbursement rate of 50 per cent as of 1 July 2001 CY N/A N/A Positive A 100, 50 LV N/A N/A Positive A 100, 90, 75, 50 LT N/A N/A Positive A Diagnosis: 100, 90, 80, 50 Social criteria: 100, 50 LU 70 3 Positive / Negative A 100, 80, 40 HU N/A 1 Positive A 100, 90, 70, 50 MT N/A N/A Positive A 100 NL 70 1 Positive A 100 AT 65 3 Positive / Negative A/B 100 Reimbursement rates: refer to brands, reimbursement rates for generics are 10 per cent higher; negative list: handbook for information as a basis for prescriptions
COMMON INDICATORS - Accessibility to medicines 11 / 56 Case-studies report réf. : Case studies.doc
PL N/A 2 Positive A/B 100, 70, 50 PT 43 3 Positive / Negative A 100, 70, 40, 20 SI N/A N/A N/A A 100, 75, 25 SK N/A 2 Positive B No fixed rates FI 47 2 N/A A/B 100, 75, 50 SE 72 3 Positive / Negative A 100, 90, 75, 50 UK 65 1 Negative B 100 TR N/A 1 N/A N/A N/A Source: • OBIG - Arzneimittelausgaben. Strategien zur Kostendämpfung in der Europäischen Union. Wien. 2001 • OBIG - Pharmaceutical systems in the new EU Member States • Pharmaceutical policies in OECD countries: reconciling social and industrial goals - S. Jacobzone. 2000 Note: • Comparability classification according to the general comparability of Health Expenditure and Finance Data in OECD Health Data 2005 1. According to SHA manual 2. “Locally produced health accounts” 3. National accounts 4. OECD secretariat estimates • Cost-sharing type A. Co-payment B. Fixed fee / deductible
COMMON INDICATORS - Accessibility to medicines 12 / 56 Case-studies report réf. : Case studies.doc
2.1.3 Consumption chain
Importance : Supplementary RX TO OTC SWITCHING BK : Country Further work: None
Definition Number of non-prescription medicines (Rx) growth rate for the whole market and for main therapeutic area covering the priority diseases.
Data extraction The acronym “OTC” means that at least one dosage or form of the ingredient has the legal status of “non-prescription medicinal product” in the country concerned. This is totally independent from the reimbursement or advertising status of a product containing the ingredient or combination of ingredients in question.
Table: Legal classification status of selected ingredients in the European Union of 15 (24 October 2005) BE DK DE EL ES FR IE IT NL AT PT FI SE UK Before 1980 0 0 3 0 0 0 0 0 0 0 0 15 0 0 1980-1984 0 3 2 0 27 0 0 3 0 0 0 2 2 2 1985-1989 0 16 7 0 6 0 0 1 0 0 0 7 4 3 1990-1994 0 9 15 0 14 1 0 7 1 0 0 18 9 24 1995-1999 0 6 17 2 27 20 8 2 11 0 11 7 9 11 2000-2004 4 1 6 2 12 2 4 2 4 10 4 5 7 11 2005 0 0 1 0 0 0 0 0 0 1 0 0 0 2 Total 4 35 51 4 86 23 12 15 16 11 15 54 31 53 Source: AESGP (http://www.aesgp.be/publications/otcIngredientsTables.asp) Note : OTC = Non-prescription status – Year = Year in which the change to non-prescription status took place – Rx = Prescription only status – N.R. = Not registered or not marketed
Limitations No switching for diabetes mellitus and acute stroke.
Importance : Supplementary MARKET SHARE OF GENERICS ON OUTPATIENT BK : Country Further work: None
Definition Market share of generics sales in volume (without price effect, significant for generics) and value for the whole market and few priority diseases.
Data extraction From the table hereafter, there are three groups of country regarding politics on generics in pharmaceutical domain (% of share in volume): • Countries with a share of generics important (>50%): CZ, DK, LT, PL and TR • Countries with a share of generics very low (<10%): BE, ES, IT and PT • Countries with an intermediate share of generics: DE, EE, FR, IE, HU, NL, AT, FI, SE and UK.
Table: Generic Market Shares across Europe in 2004 Country % Share (Value) % Share (Volume) BE 6.1 8.7 CZ 33.0 55.0 DK 32.0 65.0 DE 22.7 41.1 EE 25.0 : EL : : ES 5.2 9.1
COMMON INDICATORS – Consumption chain 13 / 56 Case-studies report réf. : Case studies.doc
FR 6.4 12.0 IE 5.4 13.1 IT 2.1 4.0 LV 48.0 : LT 41.6 72.7 HU 50.4 49.6 MT : : NL 19.8 48.5 AT 7.8 12.3 PL 65.2 86.5 PT 8.8 5.4 SI 40.2 : SK 30.0 : FI 7.6 13.2 SE 12.3 39.4 UK 20.6 49.3 BG : : HR 43.0 : RO 66.1 : TR 40.0 55.0 Source: EGA – Making Medicines Affordable Note: “:” corresponds to not available
Limitations Definitions of generics are not consistent in different countries, which causes problems in data collection, and market data collected from wholesalers does not identify the status of a product within a pricing system. The headline indicator uses the most reliable data produced by national associations, which in some cases came from Government sources (DG ENTR - A Stronger European-based Pharmaceutical Industry for the Benefit of the Patient - A Call for Action).
Importance : Core BK : Country ADHERENCE TO TREATMENT Further work: Data source / Indicator Specification
Definition The extent to which a patient acts in accordance with the prescribed interval and dose of and dosing regime.
Description There is growing evidence to suggest that because of the alarmingly low rates of adherence, increasing the effectiveness of adherence interventions may have a far greater impact on the health of the population than any improvement in specific medical treatments.
In developed countries, it averages 50% for chronic illnesses. Estimates at disease level vary according to multiple factors and there is no standard approach for measuring it. Still, there is strong evidence that many patients with chronic illnesses including asthma, hypertension, diabetes and HIV/AIDS, have difficulty adhering to their recommended regimens.
Source: WHO report 2003 “Adherence to Long-term Therapies – Evidence for Action”
COMMON INDICATORS – Consumption chain 14 / 56 Case-studies report réf. : Case studies.doc
2.1.4 Medicines’ accessibility to market
Importance : Core TIME FROM LICENSE TO MARKET BK : Country Further work: Expand to all EU-25
Definition Average time delays from marketing authorisation to patient availability of new active substance.
Data extraction From the table hereafter, average time delays vary between Member States in a large range. Moreover within a country, this time delay depends also strongly on medicines.
Table: Average time delay between approval and market access (days) Country Average time delay Maximum time delay Minimum time delay BE 423 1 446 28 CZ 336 1 310 0 DK 37 816 0 DE 0 0 0 EE 112 958 0 EL 374 951 26 ES 293 1 126 0 FR 387 1 393 58 IE 169 1 261 0 IT 341 806 28 CY 108 250 0 HU 187 548 76 NL 283 1 414 56 AT 392 1 211 49 PL 2 500 2 500 2 500 PT 296 1 115 0 SK 405 730 31 FI 195 1 293 0 SE 164 1 547 0 UK 0 0 0 NO 374 1 464 20 CH 147 676 26 Source: EFPIA - Patients W.A.I.T. Indicator” – IMS Management Consulting, 2005 Note: Data combine EMEA and non-EMEA approved molecules
COMMON INDICATORS – Medicines’ accessibility to market 15 / 56 Case-studies report réf. : Case studies.doc
Importance : Supplementary AVERAGE TIME FOR ORPHAN MEDICINES PROCEDURES BK : Country Further work: Break it down by country if relevant
Definition Average duration of the overall designation process from validation by the EMEA to Commission Decision.
Data extraction Figure: Average time for orphan medicines procedures (days)
Source: EMEA - Annual reports 2005
The EMEA’s Committee for Orphan Medicinal Products (COMP) produced a 5-year report to the European Commission on the public health benefits obtained since implementation of the legislation on orphan medicinal products.
Table: Example of positive COMP opinions in 2005 on designation of orphan medicinal products
Source: EMEA - Annual reports 2005
COMMON INDICATORS – Medicines’ accessibility to market 16 / 56 Case-studies report réf. : Case studies.doc
2.1.5 Innovation
Importance : Core UPTAKE OF NEW MEDICINES BK : Country Further work: None
Definition Market share of sales in value of New Molecular Entities (NMEs) launched within the last 5 years in the whole pharmaceutical market.
Data extraction The figure below shows the percentage, by value of national pharmaceuticals markets accounted for by New Molecular Entities launched within the last 5 years at 2001.
Figure: Share of market for new products launched in previous five years at 2001
% Share of market
35% 30% 30% 27% 25% 23% 22% 22% 23% 25% 21% 20% 20% 16%
15%
10%
5%
0% UK FI PT AT IT FR BE DE CH ES
Source: DG ENTR - “A Stronger European-based Pharmaceutical Industry for the Benefit of the Patient – A Call for Action”
COMMON INDICATORS – Innovation 17 / 56 Case-studies report réf. : Case studies.doc
2.2 Conclusions and recommendations
The table hereafter describes all common indicators ranked by main objectives and importance.
Table: Common indicators summary
Domain Impor- Collected Access Data source Coverage Comments Further work tance DISEASE STATUS Exposure to main risk factors C Yes P EUROSTAT EU-25 5-year survival rate S for Yes OP / F OECD Limited For few cancers only cancer Not at disease level
ACCESSIBILITY TO MEDICINES Share of non marketed medicines C No Data source in newly authorised medicines Feasibility study for priority diseases National reimbursement systems C Yes P OBIG EU-25 National co-payment systems C Yes P OBIG, OECD EU-25 Share of public expenditure on C Yes R / OP OBIG EU-25 PPRI project: future for EU- pharmaceuticals 25 non OECD Price of medicines in number of C No Data source days wages Price definition Feasibility study Accessibility to pharmacies S Yes PGEU EU agg.
CONSUMPTION CHAIN Average number of medicines C No prescribed per inhabitant Share of medicines actually C No dispensed Adherence to treatment C No R WHO EU agg. No standard for measuring patients’ adherence Share of non-prescription market in S No outpatient market Rx to OTC switching S Yes P AESGP Partial No access to previous data Prescribed Daily Doses (PDDs) S No Market share of generics on S Yes P EGA EU-25 Definition of generics not outpatient market consistent
Importance: C=Core / S=Supplementary Access: P=Public / OP=On payment / R=Restrictive Coverage: EU-25 (≥23) / Partial (11 to 22 countries) / Limited (≤10) / EU agg. = EU aggregate only
COMMON INDICATORS 18 / 56 Case-studies report réf. : Case studies.doc
Domain Impor- Collected Access Data source Coverage Comments Further work tance
INFORMATION TO PATIENTS Public Health campaigns addressed S No Data source to citizens Indicator specification Patients’ knowledge of correct use S No Data source and diagnosis Indicator specification
QUALITY OF LIFE Medicines taken per day S No Data source Indicator specification
MEDICINES’ ACCESSIBILITY TO MARKET Time from license to market C Yes P EFPIA Partial EMEA and not EMEA data Expand to all EU-25 Average time for orphan medicines S Yes P EMEA EU agg. Break it down by country if procedures relevant
INNOVATION Uptake of new medicines C Yes P DG ENTR Limited Expand to all EU-25 Share of New Chemical Entities C No covering priority diseases within the last 5 years Innovative medicines initiatives S No Data source Indicator specification Share of New Medicines Entities S No launched covering priority diseases in the last 5 years Medicines under clinical S No development Share of R&D expenditure by S No therapeutic area
Importance: C=Core / S=Supplementary Access: P=Public / OP=On payment / R=Restrictive Coverage: EU-25 (≥23) / Partial (11 to 22 countries) / Limited (≤10) / EU agg. = EU aggregate only
COMMON INDICATORS 19 / 56 Case-studies report réf. : Case studies.doc
3 Diabetes mellitus
The fourth or fifth leading cause of death in most developed countries, diabetes mellitus (DM) has reached epidemic proportions in many developing and newly industrialised nations. Moreover, the impact of this condition and of diabetes-related illnesses places an enormous burden on the health care systems of most countries throughout the world and especially in Europe. Thirteen of twenty-five Member States had an incidence above 10 per 1 000 000 regarding Type 1 diabetes mellitus. The highest value concerns Finland (more than 40 per 1 000 000, almost the double of the second highest value: Sweden). For several years, the number of people with diabetes mellitus has strongly increased. The 2025 estimation shows that more than 30 million people will suffer from diabetes mellitus in EU-25. Moreover, complications from diabetes mellitus, such as coronary artery and peripherical vascular disease, stroke, diabetic neuropathy, amputations, renal failure and blindness are resulting in increasing disability, reduced life expectancy and enormous health costs2. Diabetes mellitus has been proposed as one of the European Community Health Indicators in the European Union sponsored program on Health Monitoring.
The number of indicators covered for diabetes mellitus is 17.
3.1 Profile
3.1.1 Disease status
There are primarily two types of diabetes mellitus3 • Type 1 or Insulin-Dependent Diabetes Mellitus (IDDM) Type 1 is a metabolic derangement in which the pancreas fails to produce the insulin which is essential for survival. This form develops most frequently in children and adolescents, but is being increasingly noted later in life. It has been estimated that the annual global increase of new cases of Type 1 diabetes mellitus is about 3%. • Type 2 or Non-Insulin-Dependent Diabetes Mellitus (NIDDM) Nine in ten diabetics have Type 2 diabetes mellitus, which usually develops later in life. Type 2 diabetes mellitus is a metabolic derangement in which the body gradually becomes insensitive to the action of insulin so that blood sugar control is also compromised. It occurs most frequently in adults, but is being noted increasingly in adolescents as well. The risk of developing Type 2 diabetes mellitus also increases with age and lack of physical activity.
2 International Diabetes Federation, Diabetes Atlas, 2nd edition 3 Source: www.diabetes.org
DIABETES MELLITUS – Disease status 20 / 56 Case-studies report réf. : Case studies.doc
Table: Main characteristics of Type 1 and Type 2 diabetes mellitus Type 1 Type 2 Diagnosis age Children and young adults Over 50 years old. Main reason (usually under 30) of overweight Complications Acute and degenerative Degenerative Disease perception Obligation to care on, evident Low therapeutical compliance, disease insidious disease Patients education Often at a high level Very insufficient Treatment Dietetics, physical exercises, Insulin and dietetics sulpha drugs, biguanides Source: French High Committee of Public Health (http://www.sante.gouv.fr/htm/actu/36_diabet.htm)
There is another condition related to diabetes mellitus: Impaired glucose tolerance (IGT). IGT is an asymptomatic condition defined by elevated (though not diabetic) levels of blood glucose two hours after a 75g oral glucose challenge. Along with impaired fasting glucose, it is now recognized as being a stage in the transition from normality to diabetes mellitus. Thus, individuals with IGT are at high risk of progressing to Type 2 diabetes mellitus, although such progression is not inevitable, and probably over 30% of individuals with IGT will return to normal glucose tolerance over a period of several years. In 2003, some 314 million people worldwide, or 8.2%, in the age group 20 - 79 had impaired glucose tolerance4.
According to the International Statistical Classification of Diseases and Related Health Problems (ICD-10), diabetes mellitus can be tackled in 4 classes: • E10: Insulin-dependent diabetes mellitus • E11: Non-insulin-dependent diabetes mellitus • E12: Malnutrition-related diabetes mellitus • E13: Other specified diabetes mellitus • E14: Unspecified diabetes mellitus
Diabetes mellitus medicines can be classified according to ATC (see table hereafter).
Table: ATC classification regarding diabetes mellitus medicines ATC codes Insulins and analogues A10AB, A10AC, A10AD, A10AE Oral blood glucose lowering drugs A10BA, A10BB, A10BG, A10BX Source: World Health Organization Collaborating Centre for Drug Statistics Methodology (http://www.whocc.no/atcddd/)
Importance : Supplementary STANDARDISED DEATH RATES (SDR) BK : Country / disease Further work: None
Definition Standardised death rate is the death rate of a population of a standard age distribution.
4 International Diabetes Federation
DIABETES MELLITUS – Disease status 21 / 56 Case-studies report réf. : Case studies.doc
Data extraction Table: Diabetes mellitus - Standardised Death Rate (SDR) per 100 000 inhabitants Country 1999 2001 2003 Country 1999 2001 2003 EU15 15.3 14.0 : MT 22.9 22.9 17.9 EU25 15.2 13.9 : NL 16.3 20.3 17.3 CZ 9.4 9.5 11.2 AT 12.3 11.6 24.9 DK 18.3 17.9 : PL 13.4 12.2 12.2 DE 16.3 16.2 16.5 PT 23.3 26.1 28.6 EE 7.8 9.6 9.0 SI 16.9 21.8 25.8 EL 5.4 4.5 5.2 SK 19.1 14.2 : ES 15.7 14.7 14.4 FI 8.0 7.3 7.2 FR 11.0 12.5 : SE 11.8 11.6 11.9 IE 11.4 9.6 9.8 UK 7.7 7.1 (1) : IT 18.8 17.7 : BG 18.3 17.4 17.4 LV 9.1 9.4 9.2 RO 8.0 7.2 8.3 LT 6.2 6.6 6.4 IS 8.6 8.3 6.5 LU 10.6 9.4 NO 10.2 10.3 9.9 HU 18.7 13.6 18.9 CH 14.1 13.7 : Note: (1): 2000 and “:” means not available Source: Eurostat (Data navigation tree: Population and social condition - Health - Public health - Cause of death - National and regional level - Annual data - Diabetes mellitus (E10-E14))
Importance : Core PREVALENCE OF DISEASE BK : Country / disease Further work: None
Definition The prevalence of a condition means the number of people who currently have the condition.
Data extraction Table: Diabetes mellitus prevalence in the 20-79 age group Country 2000 2003 Country 2000 2003 % 000's % 000's % 000's % 000's BE 4.1% 307.4 4.2% 315.1 LU 3.8% 12.1 3.8% 12.5 CZ 11.7% * 890.5 9.5% 734.9 HU 6.6% 491.5 9.7% 711.4 DK 6.1% * 561.7 6.9% 264.9 MT 9.9% 20.8 9.2% 25.8 DE 4.2% 2 600.0 10.2% 6 294.3 NL 3.6% 415.9 3.7% 432.2 EE 4.5% 45.6 9.7% 96.3 AT 3.8% 232.3 9.6% 576.0 EL 5.9% 468.2 6.1% 493.0 PL 5.7% 1 557.1 9.0% 2 506.5 ES 6.1% * 2 018.3 9.9% 3 004.3 PT 5.4% 397.0 7.8% 584.5 FR 4.0% 1 656.8 6.2% 2 653.6 SI 8.0% * 119.5 9.6% 145.2 IE 3.2% 80.2 3.4% 89.8 SK 8.6% * 324.7 8.7% 338.7 IT 7.1% 3 125.4 6.6% 2 880.1 FI 5.5% * 158.7 7.2% 273.5 CY 4.9% 25.3 5.1% 27.7 SE 6.4% * 199.6 7.3% 456.9 LV : : 9.9% 173.6 UK 3.5% 1 466.8 3.9% 1 671.5 LT 3.2% * 84.1 9.4% 248.9 Note: “*” corresponds to crude value and “:” means not available Source: Diabetes Atlas, International Diabetes Federation (http://www.eatlas.idf.org)
Limitations International Diabetes Federation employed a methodology to create smoothed curves for prevalence (with respect to age). This federation applied also the prevalence rates to the population distribution of that country, and where no data for countries were available, to those other countries of similar ethnicity and economic circumstances. It means that some values are for some of them estimations only.
Comments A number of key WHO publications on diabetes mellitus are currently being updated. A new scientifically-based review on the "Prevention of diabetes and its complications" will be available by 2006. A new WHO technical report on "Definition, diagnosis and classification of
DIABETES MELLITUS – Disease status 22 / 56 Case-studies report réf. : Case studies.doc diabetes mellitus and its complications" will be available by 2006.
Other references • Global burden of diabetes 1995–2025: Prevalence, numerical estimates and projections. King H, Aubert RE, Herman WH. 1998. Diabetes Care, 21: 1414–1431. • Global Prevalence of Diabetes: Estimates of the year 2000 and projections 2030. Wild S, Roglic G, Green A, Sicree R, King H. 2004. Diabetes Care, 27: 1047-1053.
Importance : Core DISABILITY ADJUSTED LIFE YEARS (DALY) BK : Country / disease Further work: None
Definition The Disability Adjusted Life Years (DALY) is a health gap measure, which combines information on the ‘years of life lost’ and ‘years lived with disability’. One DALY can be thought of as one lost year of ‘healthy’ life.
Data extraction Table: Diabetes mellitus DALYs in 2002 Country DALYs Population ('000) Country DALYs Population ('000) BE 20 10 296 NL 34 16 067 CZ 20 10 246 AT 16 8 111 DK 15 5 351 PL 87 38 622 DE 202 82 414 PT 42 10 049 EE 3 1 338 SI 5 1 986 EL 38 10 970 SK 13 5 398 ES 142 40 977 FI 10 5 197 FR 116 59 850 SE 20 8 867 IE 5 3 911 UK 100 59 068 IT 253 57 482 BG 37 7 965 CY 4 796 RO 63 22 387 LV 6 2 329 IS 0 287 LT 7 3 465 NO 8 4 514 LU 1 447
Source: WHO (http://www.who.int/entity/healthinfo/statistics/bodgbddeathdalyestimates.xls)
DIABETES MELLITUS – Disease status 23 / 56 Case-studies report réf. : Case studies.doc
Importance : Supplementary CO-MORBIDITY BK : Country / disease Further work: None
Definition Co-morbidity describes the effect of all other diseases an individual patient might have other than the primary disease of interest. There is currently no accepted way to quantify such co-morbidity. A qualitative indicator on co-morbidity could improve the understanding. Such an indicator could be based on prevalence estimates of the main diabetes mellitus complications.
Description
After 20 years of diabetes mellitus almost all persons with Type 1 and more than 60% of the persons with Type 2 diabetes mellitus have to some degree diabetic retinopathy.
DIABETES MELLITUS – Disease status 24 / 56 Case-studies report réf. : Case studies.doc
Disease of the circulatory system, or cardiovascular disease, accounts for 75% of all deaths among people with diabetes of European origin.
About 20-30% of patients with Type 1 or Type 2 diabetes develop evidence of nephropathy, but in Type 2 diabetes, a considerably smaller fraction of these progress to End-Stage Renal Disease. However, because of the much greater prevalence of Type 2 diabetes, such patients constitute over half of those diabetic patients currently starting on dialysis.
Peripheral vascular disease is a macrovascular complications of DM. Atherosclerosis is accelerated in Diabetes.
Diabetes increases the incidence of Coronary Atherosclerotic Heart Disease. It causes a specific diabetic cardiomyopathy and it causes a diabetic cardiac autonomic neuropathy. It secondarily increases the incidence of hypertension and through it affects the heart.
Table: Diabetes mellitus main complications indicators review Disease Indicator Availability Source Retinopathy Process indicator: percentage of persons with diabetes mellitus with fundus inspection within the last 12 months DiabCare System data collection Rahmani B, Tielsch JM, Katz J, Gottsch J, Quigley H, Javitt J, Sommer A. The cause-specific prevalence of visual impairment in an urban population. The Baltimore Eye Survey. Ophthalmology 1996; 03:1721-1726.
Davis TM, Stratton IM, Fox CJ, Holman RR, Turner RC. U.K. Prospective Diabetes Study 22. Effect of age at diagnosis on diabetic tissue damage during the first 6 years of NIDDM. Diabetes Care 1997; 20:1435-1441. Outcome indicator: percentage of persons with diabetes mellitus and a fundus inspection which reveals proliferate retinopathy DiabCare System data collection
Laser therapy within three months after the diagnosis of proliferate retinopathy DiabCare System data collection Main outcome indicator: annual incidence of end-stage retinopathy per 100 000 general population (1) 1) National registries for blindness, offering the incidence of end stage diabetic retinopathy as cause of blindness 2) DiabCare System data Collection 3) Sentinel Practice Surveillance Network Nephropathy Process indicator: percentage of persons with diabetes mellitus with serum creatinine measurement in the last 12 months. United States Renal Data System: Annual Data Report. In http://www.usrds.org/adr.htm, accessed 2002. Incidence of dialysis and/or transplantation (renal replacement therapy) in patients with diabetes mellitus (rate per million general population) Available in most countries through national or international registries Prevalence of dialysis in patients with diabetes mellitus (rate per million general population) Available in most countries through national or international registries
Transplantation (renal replacement therapy) in patients with diabetes mellitus (rate per million general population) Available in most countries through national or international registries Peripheral vascular pathology Annual incidence of non-traumatic (medical) amputations, above the ankle in persons with diabetes mellitus per 100 000 general population HDR diagnosis, surgical acts - EUDIP group Calle-Pascual AL, Redondo MJ, Ballesteros M, Martinez-Salinas MA, Diaz JA, De Matias P, Calle JR, Gil E, Jimenez M, Serrano FJ, Martin-Alvarez PJ, Maranes JP. Nontraumatic lower extremity amputations in diabetic and non-diabetic subjects in Madrid, Spain. Diabetes Metab 1997; 23:519-523. Vascular complications Annual incidence of stroke in patients with diabetes mellitus per 100 000 general population HDR (risk: underestimation of diabetes mellitus) DiabCare System data Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes mellitus and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998; 339:229-234. Source: Establishment of indicators monitoring diabetes mellitus and its morbidity - Final report - Prepared by EUDIP group – 2002. (1) Limitations: Different definitions of blindness in the different countries
DIABETES MELLITUS – Disease status 25 / 56 Case-studies report réf. : Case studies.doc
Table: Prevalence of diabetes mellitus (Type 1 and Type 2) co-morbidity Country CHD (%) Stroke (%) Overt (%) Microalbuminuria (%) Neuropathy (%) Lower limb amputations (%) Total retinopathy (%) Proliferative retinopathy (%) BE 21.0 35.4 33.7 4.2 38.5 CZ 7.3 0.9 11.3 2.4 DK 4.2 DE 7.9 14.5 16.1 EE 7.7 2.8 EL 33.5 ES 22.7 44.7 5.8 FR 13.5 4.1 1.4 IT 32.3 Max: 37.3 Min: 26.2 Max: 7.6 Min: 1.8 NL 20.9 9.1 4.0 AT 11.3 6.2 15.0 32.0 26.0 3.5 23.3 PL 9.7 18.8 PT 7.3 SK 6.0 5.6 7.6 1.3 17.4 FI 8.1 7.6 SE 11.5 11.3 12.1 27.3 1.8 43.6 Max: 21.8 Min: 2.3 UK 25.2 9.6 Max:28.5 Min:16.8 1.3 Max: 52.0 Min: 33.6 Max: 4.0 Min: 1.1 Source: International Diabetes Federation (http://www.eatlas.idf.org/Complications/Prevalence/) Note : Type 1 and Type 2 data available in Annex “Case-studies - Diabetes mellitus” CHD: Coronary Heart Disease
DIABETES MELLITUS – Disease status 26 / 56 Importance : Supplementary WRONG OR MISDIAGNOSIS ISSUES BK : Disease Further work: Data source / Indicator specification
Definition Indicator with aim to identify groups of countries with misdiagnosis or wrong diagnosis issues point out that it might be an important issue to consider before interpreting indicators on the impact of medicines for a disease.
Description There is a large gap between diabetes mellitus prevalence and treatment rates. It has been estimated that 30-50% of diabetes mellitus cases remain undiagnosed (Priority Medicines, WHO). In France, the estimation of non diagnosed people is from 800 000 to 1 500 000. (Source: EFPIA - Diffusion of Medicines in Europe – O. Schöffski, Dec. 2002 - diabetes p 29- 30)
Limitations This indicator need to be further explored at national level, for instance from national surveys. At this time, there are problems of comparability of sources.
Importance : Core THERAPIES AVAILABILITY OVERVIEW BK : Disease Further work: Data source / Indicator specification
Definition Qualitative indicator identifying the therapies available for a specific disease.
Description The mainstay of non-pharmacological diabetes mellitus treatment is diet and physical activity.
Table: Therapies availability overview for selected diseases Treatments Type Diabetes mellitus Medicines Curative No • Substitutive Insulin Short acting • Intermediate acting Long acting Other antidiabetic medicines Symptom-alleviating No Preventive No Surgery Pump installation Radiation therapy No Hormone therapy No Nutrition Dietary guidelines Psychotherapy No
Three types of insulin preparations are usually used: short-, intermediate- and long-acting. Insulin is usually given by the subcutaneous route. Intravenous or intramuscular routes may be used in emergencies. Insulin revolutionised the treatment of diabetes mellitus and prevention of its complications, transforming Type 1 diabetes mellitus from a fatal disease to one in which long-term survival became achievable. People with Type 1 diabetes mellitus are usually totally dependent on insulin injections for survival. Such people require daily administration of insulin (WHO).
NICE (Source: http://www.nice.org.uk/page.aspx?o=43424) has recommended insulin glargine as an option for people with Type 1 diabetes mellitus. For people with Type 2 diabetes mellitus who need to take insulin, NICE has recommended that insulin glargine
DIABETES MELLITUS – Disease status 27/56 should be an option only if the person: • needs help with his or her insulin injections from a carer or healthcare professional, or • has repeated and unpleasant hypoglycaemic episodes that significantly affect his or her way of life, or • would otherwise need to have two insulin injections to maintain background levels every day as well as having to take other diabetes mellitus medicines orally.
Importance : Core MAIN ACTIVE INGREDIENTS SALES AND STATUS BK : Country / disease / medicines Further work: Data source
Definition Sales in volume (to avoid price effects) in Defined Daily Dose.
Description Data on utilisation of medicines treating diabetes mellitus are not publicly available yet. If the indicator is selected for the monitoring, availability of public data of EURO-MED-STAT should be confirmed or access to IMS Health on payment data should be considered. All insulin medicines are on prescription only.
The table hereafter lists medicines used to treat diabetes mellitus. Treatment should be aimed at alleviating symptoms and minimising the risk of long-term complications by appropriate control of diabetes mellitus.
Table: Medicines and active substances used to treat diabetes mellitus Type Medicines (Disease) Category Active substance Substitutive INSULINS (TYPE 1 and TYPE 2) Short acting insulins (have a relatively rapid onset of action) • Insulin Aspart Insulin Lispro Intermediate- and long-acting insulins • (slower in onset and lasts for long periods) Insulin Detemir • Insulin Glargine • Insulin zinc suspension • Insulin zinc suspension (crystalline) • Isophane insulin • Protamine zinc insulin • Biphasic insulin Aspart • Biphasic insulin Lispro Biphasic isophane insulin ORAL ANTIDIABETIC DRUGS (TYPE 2) Sulphonylureas (to stimulate the release of insulin from the pancreas and enhance its role in glucose transport) • Chlorpropamide • Glibenclamide • Gliclazide • Glimepiride • Glipizide • Gliquidone • Tolbutamide • Tolazamide Acetohexamide Meglinitides • (useful in limiting postprandial spike in blood glucose Repaglinide • Nateglinide Mitiglinide Servier Phase d-phenyalanine derivative Nateglinide Biguanides
DIABETES MELLITUS – Disease status 28/56 (to decrease gluconeogenesis and increase peripheral utilisation of glucose) Metformin hydrochloride Thiazolidinediones (to improve the way cells in the body respond to insulin by lowering insulin resistance) • Pioglitazone Rosiglitazone Alpha glucosidase inhibitors (beneficial effects on serum triglycerides) Acarbose Source: British National Formulary (http://www.bnf.org) Priority Medicines for Europe and the World “A Public Health Approach to innovation” – Diabetes (http://mednet3.who.int/prioritymeds/report/background/diabetes.doc)
Further work An expert validation is required to confirm and complete the list of active substances used to treat diabetes mellitus.
DIABETES MELLITUS – Disease status 29/56 Case-studies report réf. : Case studies.doc
B) WIDER - Medicines for people
3.1.2 Accessibility to medicines
Importance : Core SHARE OF REIMBURSED MEDICINES ON OUTPATIENT MARKET BK : Country / disease / medicines Further work: Data source
Definition Share of active ingredients covering diabetes mellitus eligible for reimbursement.
Data extraction Reimbursement status is described in the table hereafter for a selection of countries. It is different according to medicines name, packaging dosage of medicines, medicine price or patients’ age. These cases vary according to country. If the indicator is selected, it should be expanded to remaining EU-25 Member States.
Table: Reimbursement status for main diabetes mellitus medicines Country Reimbursement status Market share Independence of medicines Depends on Medicines name Packaging dosage Price and patients’ age Oral antidiabetic drugs Insulin BE 100% 100% 100% DK 85% - 75% - 50% - 0% : : FR 65% 100% 100% IT 100% Insulin soluble and Lispro Isophane insulin Insulin zinc suspension Insulin zinc susp. (cristalline) Metformin and repaglinide : : PT Insulin: 0 or 100% Metformin: 0 or 95% Acarbose: 95% Rosiglitazone: 0 or 20% Nateglinide: 0 or 95% Pioglitazone: 0 or 20% Repaglinide: 0% : : Source : BNF website (http://www.bnf.org/bnf/bnf/current/noframes/4080.htm) - Ministero della Salute (http://www.ministerosalute.it/medicinali/bancadati/dettaglioPA.jsp) French medicines database (www.theriaque.org) - Euro Med Stat (http://www.euromedstat.cnr.it) - INFARMED (http://www.infarmed.pt/infomed/inicio.php) Note: “:” corresponds to not available
DIABETES MELLITUS – Accessibility to medicines 30 / 56 3.1.3 Consumption chain
Importance : Core UTILISATION IN DEFINED DAILY DOSES PER 1000 BK : Country / disease / medicines INHABITANTS PER DAY Further work: Expand to remaining EU-25 Member States
Definition It provides a rough estimate of the proportion of the population within a defined area treated daily with certain drugs.
Data extraction The National Agency of Medicines of Finland provides data on medicines consumption. These data are not available for all Member States. If the indicator is selected, it should be expanded to remaining EU-25 Member States.
Table: Example of medicines consumption in 2004 in Finland regarding diabetes mellitus ATC code Subgroup or chemical substance DDD/ 1 000 inhab./ day A10 DRUGS USED IN DIABETES 62.4 A10A INSULINS AND ANALOGUES 20.9 A10AB Insulins and analogues, fast-acting 5.2 A10AB01 Insulin (human) 1.5 A10AB04 Insulin lispro 2.0 A10AB05 Insulin aspart 1.8 A10AC Insulins and analogues, intermediate-acting 9.9 A10AC01 Insulin (human) 9.9 A10AD Insulins and analogues, intermediate-acting combined with fast- acting 2.8 A10AD01 Insulin (human) 1.0 A10AD04 Insulin lispro 0.2 A10AD05 Insulin aspart 1.5 A10AE Insulins, and analogues long-acting 2.9 A10AE01 Insulin (human) 0.0 A10AE04 Insulin glargine 2.9 A10AE05 Insulin detemir 0.0 A10B ORAL BLOOD GLUCOSE LOWERING DRUGS 41.6 A10BA Biguanides 16.3 A10BA02 Metformin 16.3 A10BB Sulfonamides, urea derivatives 24.6 A10BB01 Glibenclamide 4.1 A10BB07 Glipizide 1.1 A10BB12 Glimepiride 19.5 A10BG Thiazolinediones 0.5 A10BG02 Rosiglitazone 0.4 A10BG03 Pioglitazone 0.1 A10BX Other oral blood glucose lowering drugs 0.1 A10BX02 Repaglinide 0.1 A10BX03 Nateglinide 0.0 Source: National Agencies for Medicines (http://www.nam.fi) Note: rounding errors for few total values
Further work Wait for EURO-MED-STAT database availability.
Importance : Supplementary MEDICATION ERRORS BK : Country Further work: Data source
Definition Medication errors refer to errors in process or ordering, transcribing, dispensing, administering
DIABETES MELLITUS – Consumption chain 31 / 56 or monitoring medications.
Data extraction At least 30% of the 4 million patients suffering from diabetes mellitus in Germany are not treated with medicines at all5.
Importance : Supplementary ADVERSE EVENTS BK : Country Further work: Data source / Indicator specification
Definition Patient unexpected and undesirable experience occurring following administration of a medicinal product.
Example For 6 years, only one adverse event regarding diabetes Type 1 has been reported at EMEA. It is Insuman, indicated for diabetes mellitus, where treatment with insulin is required. Insuman Infusat has been specially designed for use in external portable insulin pumps.
Table: Medicine knowing an adverse event Date EMEA Product Safety Announcements 14/02/00 EMEA/3794/00 Public Statement on INSUMAN INFUSAT 100 IU/ml solution for injection in cartridges of 3.15 ml (insulin human) – Risk of leakage during use. Source: http://www.emea.eu.int/pdfs/human/press/pus/379400en.pdf
3.1.4 Information to patients
Importance : Supplementary BK : Country / disease / medicines Further work: Data source / Indicator specification / GUIDELINES FROM MAIN INSTITUTES Outcomes of the Working Group of the Pharmaceutical Forum
Definition This indicator aims at identifying if there are standard national, European or international guidelines available for priority diseases or if there are any plans or programmes to support guidance implementation for priority diseases.
Examples
Type of organisation International Programme title EPAR including diabetes Target Professional Organisation European Medicines Agency (EMEA) Website URL http://www.emea.eu.int/htms/human/epar/epar.htm
Type of organisation National: Dutch Programme title Diabetes Mellitus type 2: aanbeveling voor goede medische praktijkvoering [Diabetes Mellitus type 2: recommendation for good medical practice]
5 Costs of diabetes in Europe, Type 2; 1999
DIABETES MELLITUS – Information to patients 32 / 56 Target Professional Published By WVVH (BE) - Flemish College of General Practitioners Publication Date 1 November 2005 Primary Contact Paul Van Royen ([email protected]) Website URL http://www.wvvh.be/files/Diabetes_ab.pdf Programme Scope Assessment / Diagnosis / Management
Type of organisation National: French Programme title Type 2 diabetes mellitus Target Professional Organisation Agence Française de Sécurité Sanitaire et des Produits de Santé (AFSSAPS) Documentations Recommandations (short text) (february 1999) Rationale (Argumentaire.pdf) Website URL http://agmed.sante.gouv.fr/htm/5/rbp/indrbp.htm Programme Scope Mainly addressed to health professionals
Type of organisation National: French Programme title Type 1 diabetes mellitus Target Patient and professional Published By Integrascol – It is a website for teachers and teaching professionals welcoming sick or disabled children Website URL http://www.integrascol.fr/fichemaladie.php?id=2 Programme Scope Teaching
Type of organisation National: German Programme title Diabetes mellitus Type 2 (Drug Commission of the German Medical Association) Target Professional Published By AQuMed / AEZQ (DE) - Agency for Quality in Medicine Publication Date 1 January 2002 Primary Contact Rainer Lasek ([email protected]) Website URL http://www.akdae.de/35/85_Diabetes_2002_1Auflage.pdf Programme Scope Management
Type of organisation National: German Programme title Diabetes Target Professional Organisation GBA - Federal Joint Committee, Germany Website URL http://www.g-ba.de/cms/front_content.php?idcatart=214 Type 1 diabetes mellitus Dokumentation Diabetes mellitus Typ 1.pdf Type 2 diabetes mellitus Dokumentation Diabetes mellitus Typ 2.pdf
Type of organisation National: German Programme title Therapeutic Guideline Type 2 Diabetes (Primary Care Guideline Group Hesse) Target Patient and professional Published By AQuMed / AEZQ (DE) - Agency for Quality in Medicine Publication Date 16 June 2004 Primary Contact Ingrid Schubert ([email protected]) Website URL http://www.leitlinien.de/leitlinienanbieter/deutsch/pdf/hessendiabetes Programme Scope Management
Type of organisation National: UK Programme title Type 2 Diabetes Footcare (CG10) Target Patient and professional Published By NICE - National Institute for Clinical Excellence Publication Date 1 January 2004 Primary Contact Fraser Woodward ([email protected]) Website URL http://www.nice.org.uk/cat.asp?c=101518 Programme Scope Prevention / Management
Type of organisation National: UK Programme title Diabetes Type 2 - blood glucose management (PRODIGY Guidance) Target Professional Published By SCHIN (GB) - Sowerby Centre for Health Informatics at Newcastle Publication Date 1 October 2003 Primary Contact Ian Purves ([email protected])
DIABETES MELLITUS – Information to patients 33 / 56 Website URL http://www.prodigy.nhs.uk/guidance.asp?gt=Diabetes-glycaemic control Programme Scope Prevention / Management
Type of organisation National: UK Programme title Diabetes Target Patient and professional Organisation NHS Direct Online Health Encyclopaedia Website URL http://www.nhsdirect.nhs.uk/en.aspx?articleId=128§ionId=6329
Source: http://www.g-i-n.net/index.cfm?fuseaction=membersarea&fusesubaction=docs&documentID=33 • Diagnosis and Classification of diabetes mellitus - Report of a WHO Consultation 1999 The full text and contents of the WHO recommendations on the diagnosis and classification of diabetes mellitus. • Diabetes Task Force. Guidelines for community pharmacists on the care of patients with diabetes. London: Royal Pharmaceutical Society of Great Britain; 1999 • A Desktop Guide to Type 1 ( Insulin-dependent ) diabetes mellitus- European Diabetes Policy Group 1998 - An accessible (but accordingly prescriptive) and up-to-date guideline to most aspects of diabetes care for the insulin-dependent person • Type 2 diabetes. European NIDDM Policy Group - European Union-funded project PRESTIGE Guidelines in Healthcare - A Desktop Guide for the Management of Non-insulin-dependent diabetes mellitus (NIDDM) • National service framework for diabetes: standards – UK Department of Health
Importance : Supplementary BK : Country Further work: Data source / Indicator specification / WEBSITES PROVIDING INFORMATION Outcomes of the Working Group of the Pharmaceutical Forum
Definition Number or number of hits or visits of websites providing medicines and treatment information to patients.
Examples
Type of organisation National: UK Programme title Aspirin treatment in diabetes Target Patient Organisation Diabetes UK Website URL http://www.diabetes.org.uk/infocentre/carerec/aspirin.htm
Type of organisation National: UK Programme title Information for patients: Guidance on the use of long-acting insulin analogues for the treatment of diabetes - insulin glargine Target Patient Organisation NICE - National Institute for Clinical Excellence Website URL http://www.nice.org.uk/page.aspx?o=TA053publicinfo
Type of organisation National: UK Programme title The clinical effectiveness and cost effectiveness of insulin pump therapy Target Patient Organisation NICE - National Institute for Clinical Excellence Website URL http://www.nice.org.uk/page.aspx?o=TA057publicinfo Source: NICE published appraisals (http://www.nice.org.uk/page.aspx?c=153)
Type of organisation National: FI Programme title Medicines information Target Patient Organisation Finnish National Agency for Medicines Website URL http://namweb.nam.fi/namweb/do/haku/view?locale=en
DIABETES MELLITUS – Information to patients 34 / 56
3.1.5 Quality of life
Importance : Core EASE OF USE BK : Country / disease Further work: New data collection / Indicator specification
Definition Qualitative assessment of the ease of standard treatment for priority diseases.
Examples Table: Comparison between antidiabetic treatments Regular insulin Insulin Lispro Humalog is taken during meal, which adds flexibility and convenience to meal planning Insulin pumps Implantable devices and then less worry of possible forgetting
Source: Juvenile Diabetes Research Foundation International - http://www.jdrf.org/index.cfm
Other references US children diary (http://www.jdrf.org/index.cfm) • Insulin injections are not anymore performed with a classical syringe but much easily with syringe pens. • More flexibility with new insulin therapy. • Pump has more freedom and flexibility than taking shots all day, even if it is necessary to put a needle in every three days. Possibility with pump to eat when and what patients want.
DIABETES MELLITUS – Quality of life 35 / 56
C) HIGH LEVEL - Medicines on the market
3.1.6 Medicines effectiveness
Importance : Core INCREMENTAL COST-EFFECTIVENESS RATIO (ICER) BK : Disease / medicines Further work: Indicator specification
Definition Incremental cost-effectiveness ratio (ICER) is the incremental increase in cost for an incremental unit increase in health benefit.
Data extraction For instance, a cost per quality-adjusted life year (QALY) was estimated at £8 400 for Continuous Subcutaneous Insulin Infusion (CSII) or ‘insulin pump therapy' therapy against multiple-dose insulin (MDI) therapy. (Source: http://www.thesaurus-amd.it) A model constructed for the NICE Technology Appraisal suggested that the cost effectiveness of insulin glargine in Type 1 diabetes mellitus patients was around £32 000 per quality- adjusted life year (QALY). (Source: http://www.nice.org.uk/pdf/CG015childrenfullguideline.pdf)
Table: Minimized cost per QALY ratio (2002) Type 1 Type 2 Vial £3 496 £32 508 Cartridge £4 628 £41 236 Pen £43 411 £4 978 Source: • http://www.nice.org.uk/pdf/Final_report_addendum_insulin.pdf • Aventis Submission to the National Institute of Clinical Excellence on the Clinical and Cost-Effectiveness of Insulin Glargine (Lantus) for Type 1 and 2 Diabetes compared with Other Long and Intermediate Acting Insulin Preparations and Insulin Pump Therapy. 2002
Table : Cost effectiveness regarding diabetes mellitus Type 2 (1996) Male Female With diabetes £33 000 £43 000 Without diabetes £15 000 £22 000 Source: An economic model of the long-term health care burden of Type II diabetes. Bagust A, Hopkinson PK, Maier W, Currie CJ. Diabetologia 2001; 44:2140-2155 (http://www.ohe-heed.com/internet.htm)
References: (www.york.ac.uk/inst/crd/crddatabases.htm) • The cost-effectiveness of intensive therapy for diabetes mellitus. Herman WH, Dasbach EJ, Songer TJ, Eastman RC. Endocrinology and Metabolism Clinics of North America 1997; 26(3): 679-695. • The cost-effectiveness of primary prevention for non-insulin dependent diabetes mellitus. Segal L, Dalton A, Richardson J. West Heidelberg, Victoria: Centre for Health Program Evaluation 1996; 1-73. • Comparing estimates of cost effectiveness submitted to the National Institute of Clinical Excellence (NICE) by different organisations: retrospective study. Miners AH, Garau M, Fidan D and Fischer AJ. British Medical Journal 2005; 330:65.
DIABETES MELLITUS – Medicines effectiveness 36 / 56
Importance : Core ASMR BK : Disease / medicines Further work: Methodology review
Definition Improved medical service of the medicine compared to existing and marketed medicines from the same pharmacological class or therapeutic group.
Data extraction Medicines evaluated by The French “Commission de Transparence” receive an ASMR value. The table hereafter presents the number of ASMR evaluations by level regarding diabetes mellitus medicines since 1995 by medicines category.
Table : Number of ASMR evaluations by level regarding diabetes mellitus medicines since 1995 Therapeutic improvement by ASMR level Medicines category Total Insulin Oral antidiabetics I: Major 0 0 0 II: Important 0 0 0 III: Moderate 6 1 7 IV: Minor Both types: 1 Type 1: 0 Type 2: 4 2 7 V: None Both types: 38 Type 1 : 3 13 54 VI : Disapproving notice 0 0 0 Source : http://afssaps-prd.afssaps.fr/html/has/sgt/htm/avis/html/indavis.htm • I, II, III: in terms of therapeutic efficacy and/or reduction of side effects • IV: in terms of therapeutic efficacy and/or usefulness for clinical trial (tolerance, ease of use, observance) • V: No therapeutic improvement but approving notice for inscription • VI: for inscription to collectivity or Social Security • 00: Unable to assess improvement
Importance : Supplementary MARKET WITHDRAWALS BK : Country / medicines Further work: None
Definition Number of medicines withdrawals covering the priority diseases during the last 5 years.
Description Only three medicines have been withdrawn according to EMEA source within the last five years
Table: Information on withdrawn medicines regarding diabetes mellitus Date Products Reasons 18/04/05 EMEA/41035/05 Withdrawal of the Marketing Authorisation for VENVIA (Rosiglitazone) in the EU Commercial reasons 18/04/05 EMEA/41043/05 Withdrawal of the Marketing Authorisation for NYRACTA (Rosiglitazone) in the EU Commercial reasons 26/02/01 EMEA/571/01 Public Statement on LIPROLOG: Withdrawal of the Marketing Authorisation N/A Source: EMEA (http://www.emea.eu.int/htms/human/withdraw/withdraw.htm)
DIABETES MELLITUS – Medicines effectiveness 37 / 56 Case-studies report réf. : Case studies.doc
3.2 Conclusions and recommendations
The table hereafter describes all indicators available and developed for diabetes mellitus. This list is ranked by main objectives and importance.
Table: Indicators: diabetes mellitus summary
Domain Impor- Collected Access Data source Coverage Comments Further work tance DISEASE STATUS Prevalence of disease C Yes P WHO EU-25 Number, percentage Earlier time series availability No R ECHI EU-25 ICD-10 classification Yes P IDF EU-25 2000, 2001 and 2003 Disability Adjusted Life Years C Yes P WHO EU-25 Earlier time series (DALY) availability Therapies availability overview C No R WHO Data source NICE Indicator specification Main active ingredients sales and C No R / OP IMS Health Partial Data source status No P EURO-MED-STAT EU-25 Availability on April or May 2006 Standardised death rates (SDR) S Yes P EUROSTAT EU-25 ICD-10 classification Yes P WHO EU-25 Earlier time series availability Yes R / OP OECD Partial ICD-10 classification Co-morbidity S No R EUDIP Include indicators for each Data source complication Indicator specification No R Literature review No R EuroDiab Partial Diabetes Type 1 only Wrong or misdiagnosis issues S No R Literature review Problem of comparability Data source Indicator specification
ACCESSIBILITY TO MEDICINES Share of reimbursed medicines C No R National organisations Partial Systems very different according Expand to all EU-25 on outpatient market to MS
CONSUMPTION CHAIN Utilisation in DDD/1000 C No P EURO-MED-STAT EU-25 Availability on April or May 2006 inhabitant/day Yes R National organisations FI Expand to all EU-25 Medication errors S No R Literature review Data source
Importance: C=Core / S=Supplementary Access: P=Public / OP=On payment / R=Restrictive Coverage: EU-25 (≥23) / Partial (11 to 22 countries) / Limited (≤10) / EU agg. = EU aggregate only 38 / 56
DIABETES MELLITUS Case-studies report réf. : Case studies.doc
Domain Impor- Collected Access Data source Coverage Comments Further work tance Adverse events S Yes P EMEA EU-25 Only centralised procedures Data source Indicator specification
INFORMATION TO PATIENTS Guidelines from main institutes S Yes P International and Limited Mostly national organisations Data source national organisations Indicator specification Websites providing information S Yes P International and Limited Mostly national organisations Data source national organisations Indicator specification
QUALITY OF LIFE Ease of use C No R Literature review Limited New data collection Indicator specification
MEDICINES EFFECTIVENESS Incremental cost-effectiveness C No R Literature review Limited Indicator specification ratio (ICER) ASMR C Yes P French organisation FR Expand to all EU-25 (HAS) Indicator specification Methodology to review Market withdrawals S Yes P EMEA EU-25 Only central applications Significance of results
Importance: C=Core / S=Supplementary Access: P=Public / OP=On payment / R=Restrictive Coverage: EU-25 (≥23) / Partial (11 to 22 countries) / Limited (≤10) / EU agg. = EU aggregate only 39 / 56
DIABETES MELLITUS Accessibility Data accessibility of indicators is classified as public, restricted and/or on payment. Data collection of a few indicators was not completed for all the Member States when data were too specific, concerned restricted and incidental sources such as for Co- morbidity” and “Wrong or misdiagnosis issues”.
Data sources selection For several indicators such as disease status indicators, a number of data sources were available. For instance regarding standardised death rate, EUROSTAT was recommended data instead of WHO or OECD for geographical and time coverage reasons (see table hereafter).
Table: SDR data sources characteristics EUROSTAT WHO OECD Geographical All EU Member States All WHO Member States 19 EU Member States coverage Time coverage For EU-15 and EFTA (without 2002 1960-2003 (for a few LI) from 1994 onwards (BE, DE: countries only) 1992, IE: 1993). Periodicity Annual Annual Annual Number of causes 65 whose DM 129 whose DM 38 whose DM DM: Diabetes Mellitus
Another example concerns the prevalence of disease indicator for which International Diabetes Federation (IDF) data source was chosen instead of WHO for a wider geographical coverage and availability of data broken down by diabetes mellitus Types 1 and 2.
Table: Prevalence data sources characteristics IDF WHO Geographical coverage All EU Member States Some EU Member States data not available Time coverage 2000, 2001 and 2003 2000, 2001 and 2002 Number of causes 1 (DM only) 200 DM: Diabetes Mellitus
Limitations Data was not always available for both diabetes mellitus Type 1 and 2. Moreover, diabetes mellitus type may be undefined for a few data sources. Thus data comparability is not always good. In our framework, aggregated data were preferred and data by diabetes mellitus type were collected as often as available to ensure comparability.
DIABETES MELLITUS 40 / 56 4 Acute stroke
Stroke is the second leading cause of death at the global level and the third leading cause of disability and death (as DALYs) in EU-25 (DALY = 5.3%)6. Almost a million cases and two hundred thousand deaths due to stroke occur in the European Union every year. Together with cardiovascular diseases (CVD), these cases account for more than a third of all deaths in the European Union7.
The number of indicators broken down by disease and covered for acute stroke is 15 among the 43 non excluded indicators.
4.1 Profile
According to UK National Health Service, cerebrovascular disease is any disease affecting an artery within the brain, or supplying blood to the brain. Whereas a stroke is when the normal blood supply to your brain is cut off. If your brain cells do not get a constant supply of oxygen from the blood, they become damaged or die.
Stroke is classified on the basis of its aetiology as either ischaemic (80%) or haemorrhagic (20%). Ischaemic stroke is produced by occlusion of a cerebral artery [thrombotic or atherosclerotic (50%), embolic (25%) and microartery occlusion, “lacunar stroke”, (25%)]. Haemorrhagic stroke is caused mainly by spontaneous rupture of blood vessels or aneurysms or secondary to trauma8.
More precisely, stroke is defined as abrupt onset of a focal neurological deficit lasting more than 24 hours. It is also called cerebrovascular accident (CVA) or apoplexy. An acute stroke refers to the first 24-hour- period of a stroke. Focal neurological deficit lasting less than 24 hours (usually 5–20 minutes) known as transient ischaemic attack (TIA) is relevant but beyond the scope of this discussion paper.
According to the International Statistical Classification of Diseases and Related Health Problems (ICD-10), cerebrovascular disease can be tackled in 10 classes: • Subarachnoid haemorrhage (I60); • Intracerebral haemorrhage (I61); • Other nontraumatic intracranial haemorrhage (I62); • Cerebral infarction (I63); • Stroke, not specified as haemorrhage or infarction (I64); • Occlusion and stenosis of precerebral arteries, not resulting in cerebral infarction (I65);
6 “Priority Medicines for Europe and the World.” Kaplan W. and Laing R., 2004. WHO 7 The European Stroke Initiative (http://www.eusi-stroke.com/stroke_prevention) 8 WHO (http://mednet3.who.int/prioritymeds/report/background/stroke.doc)
ACUTE STROKE 41 / 56 • Occlusion and stenosis of cerebral arteries, not resulting in cerebral infarction (I66); • Other cerebrovascular diseases (I67); • Cerebrovascular disorders in diseases classified elsewhere (I68); • Sequelae of cerebrovascular disease (I69).
Cerebrovascular disease medicines can be classified according to ATC (see table hereafter).
Table: ATC classification regarding cerebrovascular disease medicines ATC codes Antithrombotic agents B01AA, B01AB, B01AD, B01AE, B01AX Antihemorrhagics B02AA, B02AB, B02BA, B02BD Antianemic preparations B03AA, B03AB, B03AC, B03AE, B03BA, B03BB, B03XA Blood substitutes and perfusion solutions B05 Other haematological agents B06AB Source: World Health Organization Collaborating Centre for Drug Statistics Methodology (http://www.whocc.no/atcddd/)
4.1.1 Disease status
Importance : Supplementary STANDARDISED DEATH RATE (SDR) BK : Country / disease Further work: None
Definition Standardised death rate is the death rate of a population of a standard age distribution.
Data extraction
Table: Cerebrovascular disease - Standardised Death Rate (SDR) per 100 000 inhabitants Country 1999 2001 2003 Country 1999 2001 2003 EU25 93.7 81.1 : MT 96.7 91.6 87.0 CZ 145.6 141.5 143.5 NL 74.3 74.2 67.6 DK 78.5 77.8 : AT 85.7 73.5 80.9 DE 79.7 72.5 67.3 PL 120.9 115.2 107.4 EE 177.2 166.8 158.4 PT 169.9 156.8 146.1 EL 114.7 120.7 116.8 SI 108.6 101.4 104.3 ES 77.7 70.4 66.4 SK 106.2 102.0 : FR 52.7 51.7 50.5 (2) FI 76.0 70.8 68.2 IE 79.6 70.6 60.9 SE 71.5 67.6 64.7 IT 84.6 78.2 76.1 (2) UK 74.0 66.9 (1) : CY : : : BG 220.4 207.2 209.9 LV 229.2 226.4 215.4 RO 240.0 224.0 230.8 LT 125.4 127.5 123.8 IS 65.5 62.4 52.0 LU 80.3 74.2 NO 72.6 64.9 60.3 HU 172.0 152.3 153.5 CH 53.6 49.1 48.0 (2) Note: (1): 2000 data; (2): 2002 data; “:” means not available Source: Eurostat (Data navigation tree: Population and social condition - Health - Public health - Cause of death - National and regional level - Annual data - Cerebrovascular disease (I60-I69)) The causes of death are classified according to the ICD
Importance : Core PREVALENCE OF DISEASE BK : Country / disease Further work: None
Definition The prevalence of a condition means the number of people who currently have the condition.
ACUTE STROKE – Disease status 42 / 56
Data extraction A WHO Euro project (EUROHIS) studied Health Status from seven European countries. For methodological reasons, a pre-test was performed. The Italian pre-test in 2000 revealed that a prevalence of 1.3% (with 301 respondents) is observed with regard to stroke, cerebral haemorrhage. (Source: EUROHIS (WHO): Developing Common Instruments for Health Surveys - A. Nosikov and C. Gudex (Eds.), 2003).
Table: Availability of variables regarding cerebrovascular disease Variable Source Availability status Regularity Stroke prevalence ECHI European Cardiovascular Indicators Surveillance Set project (see Annex) Phase I: 2000-2003 Phase II: 2004-2007 Source: International Compendium of Health Indicators (http://www.healthindicators.org/ICHI/general/ECHI_Hierarchy.htm
As prevalence is the preferred measure for e.g. chronic diseases whereas incidence indicators are used for diseases of shorter duration or with a clear-cut onset (infectious diseases, accidents, cancers), we also collected incidence data for acute stroke. Incidence can be defined as the frequency with which a disease appears in a particular population or area
The incidence of stroke is estimated to be about 150 per 100 000 population per year in industrial countries. It has also decreased by about 20% during the 1980s.
Table: Cerebrovascular diseases incidence per 1000 – WHO (ICD-10: I60-I69) Country 1984 1989 1991 1994 DK : 42 598 46 912 : EE : : : 56 061 EL 24 983 27 536 29 338 : LV : 25 175 26 553 35 125 LT : 18 484 21 336 32 208 NL : 17 343 17 771 : AT : : 63 873 : FI 1 059 : : : SE : 42 706 48 632 45 612 BG : 46 056 : : RO 5 482 11 925 8 349 : Source: European health for all database (HFA-DB) - WHO Regional Office for Europe - http://data.euro.who.int/hfadb Note: “:” means not available
Importance : Core DISABILITY ADJUSTED LIFE YEARS (DALY) BK : Country / disease Further work: None
Definition The Disability Adjusted Life Years (DALY) is a health gap measure, which combines information on the ‘years of life lost’ and ‘years lived with disability’. One DALY can be thought of as one lost year of ‘healthy’ life.
Data extraction Table: Cerebrovascular and stroke DALYs Country Cerebrovascular- 2002 Stroke – 2003 or latest available data Country Cerebrovascular- 2002 Stroke – 2003 or latest available data BE 63 4 MT 2 4 CZ 115 7 NL 86 4 DK 35 4 AT 49 4
ACUTE STROKE – Disease status 43 / 56 DE 514 4 PL 338 7 EE 19 9 PT 146 9 EL 131 6 SI 17 6 ES 220 3 SK 32 5 FR 259 3 FI 36 4 IE 20 4 SE 53 3 IT 386 4 UK 366 4 CY 4 3 BG 165 13 LV 45 12 RO 417 13 LT 34 7 IS 1 3 LU 3 5 NO 25 3 HU 121 8
Source: WHO (http://www.who.int/entity/healthinfo/statistics/bodgbddeathdalyestimates.xls http://www.who.int/cardiovascular_diseases/en/cvd_atlas_29_world_data_table.pdf)
Importance : Supplementary CO-MORBIDITY BK : Country / disease Further work: Data source / Indicator specification
Definition Co-morbidity describes the effect of all other diseases an individual patient might have other than the primary disease of interest. There is currently no accepted way to quantify such co- morbidity. A qualitative indicator on co-morbidity could improve the understanding. Such an indicator could be based on prevalence estimates of the main diabetes mellitus complications.
Data extraction Table: Acute stroke complication rates Complication Doshi et al. (%) Roth et al. (%) Neurological Recurrent stroke 0.0 1.6 Epileptic seizure 0.7 1.5 Infection Urinary tract infections 14.3 30.5 Chest infection 5.0 4.0 Mobility Pressure sore 0.7 4.3 Fall 4.3 10.5 Thromboembolism Deep vein thrombosis 0.7 4.1 Pulmonary embolism 0.0 1.1 Limb pain 8.6 14.2 Psychological Depression 9.3 13.0 Cardiovascular complication 1.4 : Uncontrolled hypertension 2.9 9.0 Acute retention of urine 20.9 4.8 Gastrointestinal Bleeding from the gastrointestinal tract 8.6 3.1 Constipation 22.9 : Drug rash 2.1 : Others 12.4 : Undiagnosed problem 0.7 : Source: • Doshi VS, Say JH, Young SH, Doraisamy P. Complications in stroke patients: a study carried out at the Rehabilitation Medicine Service, Changi General Hospital. Singapore Medical Journal 2003; 44(12): 643-52. The aim of this Singapore study was to analyse stroke complications. A total of 140 case notes were reviewed. The overall complication rate was 54.3%. • Roth EJ, Lovell L, Richard L, Heinemann AW, Semik P, Diaz S. Incidence of and risk factors for medical complications during stroke rehabilitation. Stroke 2001; 32: 523-9.
Importance : Supplementary PREVENTION BK : Country / disease Further work: Indicator specification
Definition Indicator specific to disease since prevention actions or techniques differ from one disease to another.
ACUTE STROKE – Disease status 44 / 56
Data extraction There are two main groups of 'cardio-cerebrovascular' risk factors: • The unmodifiable risk factors are: age, sex, race, family history • The main modifiable risk factors, which must be controlled to decrease the risk of stroke, include hypertension, smoking, high lipids, diabetes and alcohol intoxication.
Diabetes is a prominent risk factor for ischemic but not hemorrhagic stroke (Source: http://www.eusi-stroke.com/stroke_prevention/sp_diabetes.shtml). It is responsible for 7% of deaths in stroke patients. High serum levels of HDL-cholesterol appear to have a protective effect not only for Carotid Artery Disease, but also for ischemic stroke. When the prevalence of smoking and hypertension in the population was taken into consideration and after controlling for age, it was calculated that the two risk factors were responsible for 36% each of all strokes. Moreover, 58% of all strokes could be attributed to one of them or both.
Importance : Core MAIN ACTIVE INGREDIENTS SALES AND STATUS BK : Country / disease / medicines Further work: None
Definition Sales in volume (to avoid price effects) in Defined Daily Dose.
Data extraction Data on utilisation of medicines treating diabetes mellitus are not publicly available yet. If the indicator is selected for the monitoring, availability of public data of EURO-MED-STAT should be confirmed or access to IMS Health on payment data should be considered.
The tables hereafter show medicines and active substances used to treat cerebrovascular disease. These lists come from two distinct sources BNF and WHO which provide two different classifications. It should be confirmed and completed. Sales in volume were not available.
Table: Main medicines and active substances used to treat cerebrovascular disease Disease Category Active substance Ischaemic stroke Drugs used in rheumatic diseases and gout Sulfinpyrazone Acute stroke in evolution Parenteral anticoagulants Heparin Warfarin Myocardial infarction and fibrinolysis Fibrinolytic drugs Alteplase Hypertension and heart failure Vasodilator antihypertensive drugs Sodium Nitroprusside Diazoxide Drugs affecting the renin-angiotensin system Ramipril
Lipid-regulating drugs Statins Atorvastatin Fluvastatin Pravastatin sodium Rosuvastatin Simvastatin Antiplatelet drugs Clopidogrel Dipyridamole modified Source: British National Formulary (http://www.bnf.org)
Table: Main medicines and active substances used to treat cerebrovascular disease Category Sub-category Active substance Drugs to improve blood flow Anti-thrombotic Heparin Low molecular-weight heparin Antiplatelet drugs Aspirin
ACUTE STROKE – Disease status 45 / 56 Abciximab Tirofiban Clopidogrel Fibrinogen-depleting Ancrod Defibrase Improve capillaryflow Pentoxyfilline Thrombolytics Pro-urokinase Streptokinase Tenecteplase Tissue plasminogen activator Urokinase Desmoteplase Drugs to protect brain tissue Calcium-channel blockers Nimodipine Flunarizine Calcium chelator DP-b99 Free radical Ebselen Tirilazad NXY-059 GABA agonists Clomethiazole Glutamate antagonists AMPA antagonists Growth factors Firoblast growth factors Leukocyte adhesion inhibitors Anti-ICAM antibody HU23F2G Nitric oxide inhibitor Lubeluzole Opioid antagonists Naloxone Nalmefene Phosphatidylcholine precursor Citicoline Serotonin agonist Bay x 3072 Sodium channel blockers Fosphenytoin Lubeluzole 619C89 Potassium channel opener BMS-204352 Source: Priority Medicines for Europe and the World “A Public Health Approach to innovation” – Acute stroke (http://mednet3.who.int/prioritymeds/report/background/stroke.doc)
Further work An expert validation is required to complete the list of active substances used to treat acute stroke.
ACUTE STROKE – Disease status 46 / 56 B) WIDER - Medicines for people
4.1.2 Accessibility to medicines
SHARE OF REIMBURSED MEDICINES ON Importance : Core OUTPATIENT MARKET BK : Country / disease / medicines Further work: Data source
Definition Share of active ingredients covering diabetes mellitus eligible for reimbursement.
Data extraction Reimbursement status is described in the table hereafter for a selection of countries. It is different according to medicines name, packaging dosage of medicines, medicine price or patients’ age. These cases vary according to country.
Table: Reimbursement status for main cerebrovascular medicines Country Reimbursement status Market share Independent of medicines Depends on Medicines name or category Packaging dosage Price and patients’ age BE 100% 100% DK 85% - 75% - 50% - 0% : : FR N/A or 65% : : IT N/A or 100% Note: “:” means not available Source : BNF website (http://www.bnf.org/bnf/bnf/current/noframes/4080.htm) Ministero della Salute (http://www.ministerosalute.it/medicinali/bancadati/dettaglioPA.jsp) Banque de données sur les médicaments (www.theriaque.org) Euro Med Stat (http://www.euromedstat.cnr.it)
Further work If the indicator is selected, it should be expanded to remaining EU-25 Member States.
ACUTE STROKE – Accessibility to medicines 47 / 56 4.1.3 Consumption chain
Importance : Core UTILISATION IN DEFINED DAILY DOSES PER 1000 BK : Country / disease / medicines INHABITANTS PER DAY Further work: Expand to remaining EU-25 Member States
Definition It provides a rough estimate of the proportion of the population within a defined area treated daily with certain drugs
Data extraction The National Agency of Medicines of Finland provides data on medicines consumption. These data are not available for all Member States. If the indicator is selected, it should be expanded to remaining EU-25 Member States.
Table: Example of medicines consumption in 2004 in Finland regarding cerebrovascular disease ATC code Subgroup or chemical substance DDD/ 1 000 inhab./ day B01 ANTITHROMBOTIC AGENTS 114.5 B01A ANTITHROMBOTIC AGENTS 114.5 B01AA Vitamin K antagonists 10.1 B01AA03 Warfarin 10.1 B01AB Heparin group 2.9 B01AB01 Heparin 0.2 B01AB02 Antithrombin 0.0 B01AB04 Dalteparin 1.1 B01AB05 Enoxaparin 1.7 B01AB06 Nadroparin : B01AB10 Tinzaparin : B01AC Platelet aggregation inhibitors excl. heparin 101.6 B01AC04 Clopidogrel 2.2 B01AC06 Acetylsalicylic acid 96.2 B01AC07 Dipyridamole 3.1 B01AC11 Iloprost 0.0 B01AC13 Abciximab 0.0 B01AC16 Eptifibatidi 0.0 B01AC17 Tirofiban 0.0 B01AD Enzymes 0.0 B01AE Direct thrombin inhibitors 0.0 B01AX Other antithrombotic agents 0.0 B01AX05 Fondaparinux 0.0 B02 ANTIHEMORRHAGICS 0.3 B02A ANTIFIBRINOLYTICS 0.2 B02AA Amino acids 0.2 B02AA02 Tranexamic acid 0.2 B02AB Proteinase inhibitors 0.0 B02AB01 Aprotinin 0.0 B02B VITAMIN K AND OTHER HEMOSTATICS 0.0 B02BA Vitamin K 0.0 B02BA01 Phytomenadione 0.0 B02BD Blood coagulation factors 0.0 B03 ANTIANEMIC PREPARATIONS 19.4 B03A IRON PREPARATIONS 7.8 B03AA Iron bivalent, oral preparations 7.3 B03AB Iron trivalent, oral preparations 0.4 B03AC Iron trivalent, parenteral preparations 0.0 B03AE Iron in other combinations 0.2 B03B VITAMIN B12 AND FOLIC ACID 11.1 B03BA Vitamin B12 (cyanocobalamin and derivatives) 5.7 B03BA01 Cyanocobalamin 1.1 B03BA02 Cyanocobalamin tannin complex 0.5 B03BA03 Hydroxocobalamin 4.2 B03BB Folic acid, combinations 5.3 B03BB01 Folic acid 5.3 B03X OTHER ANTIANEMIC PREPARATIONS 0.6
ACUTE STROKE - Consumption chain 48 / 56 B03XA Other antianemic preparations 0.6 B03XA01 Erythropoietin 0.3 B03XA02 Darbepoetin alfa 0.3 B05 BLOOD SUBSTITUTES AND PERFUSION SOLUTIONS 0.0 B06 OTHER HEMATOLOGICAL AGENTS 0.0 B06A OTHER HEMATOLOGICAL AGENTS 0.0 B06AB Other hematological products 0.0 Source: National Agencies for Medicines (http://www.nam.fi)
Further work Wait for EURO-MED-STAT database availability.
Importance : Core ADHERENCE TO TREATMENT BK : Country Further work: None
Definition The extent to which a patient acts in accordance with the prescribed interval and dose of and dosing regime.
Data extraction Table: Compliance regarding acute stroke treatment Sappok study Marini study Hillen study Antithrombotic treatment 87.6% 64.0% 76.0% Aspirin 86.0% : : Ticlopidine/Clopidogrel 85.6% : : Phenprocoumon 95.5% : : Note: “:” corresponds to not available Source • Sappok T, Faulstich A, Stuckert E, Kruck H, Marx P, Koennecke HC. Compliance With Secondary Prevention of Ischemic Stroke A Prospective Evaluation. Stroke. 2001;32:1884. • Marini C, Totaro R, Carolei A. Long-term prognosis of cerebral ischemia in young adults. Stroke. 1999; 30: 2320–2325. • Hillen T, Dundas R, Lawrence E, Stewart JA, Rudd A, Wolfe CDA. Antithrombotic and antihypertensive management 3 months after ischemic stroke. Stroke. 2000; 31: 469–475.
Importance : Supplementary BK : Country / disease Further work: Data source / ADVERSE EVENTS Indicator specification
Definition Patient unexpected and undesirable experience occurring following administration of a medicinal product.
Example No medicines regarding acute stroke have been withdrawn or suspended for 5 years according to EMEA source.
ACUTE STROKE - Consumption chain 49 / 56 4.1.4 Information to patients Importance : Supplementary BK : Country / disease Further work: Data source / Indicator specification / GUIDELINES FROM MAIN INSTITUTES Outcomes of the Working Group of the Pharmaceutical Forum
Definition This indicator aims at identifying if there are standard national, European or international guidelines available for priority diseases or if there are any plans or programmes to support guidance implementation for priority diseases.
Examples
Type of organisation National: UK Programme title Management of patients with stroke: rehabilitation, prevention and management of complications, and discharge planning (SIGN CPG 64) Target Patient and professional Organisation Scottish Intercollegiate Guidelines Network Website URL http://www.sign.ac.uk/guidelines/published/numlist.html Programme scope Prevention - Assessment/diagnosis - Management Source http://www.g-i-n.net/membersarea/ dsp_programme_popup.cfm? ProgrammeID=322
Type of organisation National: UK Programme title Intercollegiate Stroke Working Party National Clinical guidelines for stroke 2nd Ed. Target Patient and professional Organisation RCN - Royal College of Nursing Website URL http://www.rcn.org.uk/resources/guidelines.php Programme scope Prevention - Assessment/diagnosis – Management - Rehabilitation Source http://www.g-i-n.net/membersarea/dsp_programme_popup.cfm? ProgrammeID=3918
Type of organisation National: UK Programme title National clinical guidelines for stroke Target Patient and professional Organisation Royal College of Physicians Website URL http://www.rcplondon.ac.uk/pubs/books/stroke/index.htm
Type of organisation National: UK Programme title Clopidogrel and dipyridamole for the prevention of artherosclerotic events Target Patient and professional Organisation NICE – National Institute for Clinical Excellence Publication date May 2005 Professional guidance http://www.nice.org.uk/page.aspx?o=TA090guidance Patient guidance http://www.nice.org.uk/page.aspx?o=TA090publicinfo
Importance : Supplementary BK : Country Further work: Data source / Indicator specification / WEBSITES PROVIDING INFORMATION Outcomes of the Working Group of the Pharmaceutical Forum
Definition Number of hits or visits of websites providing medicines and treatment information to patients
Examples
ACUTE STROKE - Information to patients 50 / 56 Type of organisation National: FI Programme title Medicines information Target Patient Organisation Finnish National Agency for Medicines Website URL http://namweb.nam.fi/namweb/do/haku/view?locale=en
Type of organisation National: UK Programme title Cerebrovascular Accident Target Patient Organisation BIOME Website URL http://nmap.ac.uk/browse/mesh/D020521.html
C) HIGH LEVEL - Medicines on the market
4.1.5 Medicines effectiveness
Importance : Core INCREMENTAL COST-EFFECTIVENESS RATIO (ICER) BK : Disease / medicines Further work: Indicator specification
Definition Incremental Cost-Effectiveness Ratio (ICER) is the incremental increase in cost for an incremental unit increase in health benefit.
Data extraction The table hereafter shows the comparison through ICER between warfarin medicine and aspirin or no treatment. ICER depends on patient low or medium risk category.
Table: ICER comparison regarding Warfarin Aspirin No treatment Low risk patient $370 000 per QALY $14 000 per QALY Medium risk patient $8 000 per QALY positive Source: www.york.ac.uk/inst/crd/crddatabases.htm
Importance : Core ASMR BK : Disease / medicines Further work: Methodology review
Definition Improved medical service of the medicine compared to existing and marketed medicines from the same pharmacological class or therapeutic group.
Medicines evaluated by The French “Commission de Transparence” receive an ASMR value. The table hereafter presents the number of ASMR evaluations by level regarding acute stroke medicines since 1995 by medicines category.
Description Table : Number of ASMR evaluations by level regarding acute stroke medicines since 1995 Therapeutic improvement by ASMR level Number I: Major 5 *
ACUTE STROKE - Medicines effectiveness 51 / 56 II: Important 4 III: Moderate 2 IV: Minor 1 V: None 20 VI : Disapproving notice 1 00 : No assessment 4 Source : http://afssaps-prd.afssaps.fr/html/has/sgt/htm/avis/html/indavis.htm • I, II, III: in terms of therapeutic efficacy and/or reduction of side effects • IV: in terms of therapeutic efficacy and/or usefulness for clinical trial (tolerance, ease of use, observance) • V: No therapeutic improvement but approving notice for inscription • VI: for inscription to collectivity or Social Security • 00: Unable to assess improvement
* Notes : Details on major improvement ASMR levels Active substance Medicine name Commission opinion date Therapeutic improvement Ramipril TRIATEC 1996 Post-myocardial infraction Simvastatin ZOCOR 02/10/1996 and 06/11/1996 Reduction of the mortality of people suffering of coronary disease. Simvastatin ZOCOR 23/07/2003 Effect in secondary prevention for people with acute stroke or pheripherical arteriopathy and in primary prevention for people with diabetes Type 2 and with high cardiovascular risk Simvastatin LODALES 23/07/2003 Simvastatin LODALES 23/07/2003 Reduction of the mortality of people suffering of coronary disease
Further work An expert validation is required to complete the list of active substances used to treat acute stroke.
Limitations These data depend on the list of medicines proposed in the indicator “Main active ingredients sales and status”.
Importance : Supplementary MARKET WITHDRAWALS BK : Country / medicines Further work: None
Definition Number of medicines withdrawals covering the priority diseases during the last 5 years.
Description Only one medicine has been withdrawn according to EMEA source within the last five years.
Table: Information on withdrawn medicines regarding acute stroke Date Product Reasons 05/12/2005 Withdrawal of the Marketing Authorisation for on Tenecteplase Boehringer Ingelheim Pharma GmbH & Co. KG (tenecteplase) in the European Union Commercial reason Source: EMEA (http://www.emea.eu.int/htms/human/withdraw/withdraw.htm)
ACUTE STROKE - Medicines effectiveness 52 / 56 Case-studies report réf. : Case studies.doc
4.2 Conclusions and recommendations
The table hereafter describes all indicators available and developed for acute stroke. This list is ranked by main objectives and importance.
Table: Indicators: acute stroke summary
Domain Impor- Collected Access Data source Coverage Comments Further work tance DISEASE STATUS Prevalence of disease C Yes P WHO Partial Data for Cerebrovascular disease Data not available each year for each country Incidence instead of prevalence No R ECHI EU-25 ICD-10 classification Disability Adjusted Life Years C Yes P WHO EU-25 Data for Cerebrovascular and Earlier time series (DALY) stroke availability Main active ingredients sales and C No R / OP IMS Health Partial Data source status No P EURO-MED-STAT EU-25 Availability on April or May 2006 Standardised death rates (SDR) S Yes P EUROSTAT EU-25 Data for Cerebrovascular disease (ICD-10) Yes P WHO EU-25 Data for Cerebrovascular disease Earlier time series availability Yes R / OP OECD Partial Data for Cerebrovascular disease (ICD-10) Co-morbidity S No R Literature review Limited Data source Indicator specification Prevention S No R / F Literature review Limited Important indicator for stroke Indicator specification
ACCESSIBILITY TO MEDICINES Share of reimbursed medicines C No R National Partial Systems very different according to Expand to all EU-25 on outpatient market organisations MS
CONSUMPTION CHAIN Utilisation in DDD/1000 C No P EURO-MED-STAT EU-25 Availability on April or May 2006 inhabitant/day Yes R National FI Expand to all EU-25 organisations Adherence to treatment C No R Literature review Data source Indicator specification Importance: C=Core / S=Supplementary Access: P=Public / OP=On payment / R=Restrictive Coverage: EU-25 (≥23) / Partial (11 to 22 countries) / Limited (≤10) / EU agg. = EU aggregate only
ACUTE STROKE 53 / 56 Case-studies report réf. : Case studies.doc
Domain Impor- Collected Access Data source Coverage Comments Further work tance Adverse events S Yes P EMEA EU-25 Only centralised procedures Data source Indicator specification
INFORMATION TO PATIENTS Guidelines from main institutes S Yes P International and Limited Mostly national organisations Data source national organisations Indicator specification Websites providing information S Yes P International and Limited Mostly national organisations Data source national organisations Indicator specification
MEDICINES EFFECTIVENESS Incremental cost-effectiveness C No R Literature review Limited Indicator specification ratio (ICER) ASMR C Yes P French organisation FR Expand to all EU-25 (HAS) Indicator specification Methodology to review Market withdrawals S Yes P EMEA EU-25 Only central applications Significance of results
Importance: C=Core / S=Supplementary Access: P=Public / OP=On payment / R=Restrictive Coverage: EU-25 (≥23) / Partial (11 to 22 countries) / Limited (≤10) / EU agg. = EU aggregate only
ACUTE STROKE 54 / 56 Selection of data source For a number of indicators, several data sources are available as for standardised death rate. Indeed, EUROSTAT data was recommended instead of WHO or OECD for geographical and time coverage reasons (see Table hereafter).
Table: SDR data sources characteristics EUROSTAT WHO OECD Geographical All EU Member All WHO Member 19 EU Member coverage States States States Time For EU-15 and EFTA 2002 1960-2003 (for a coverage (without LI) from few countries 1994 onwards (BE, only) DE: 1992, IE: 1993). Periodicity Annual Annual Annual
Number of 65 whose CVA 129 whose CV 38 whose CV causes CV: Cerebrovascular, CVA: Cerebrovascular accident
Limitations The definition of acute stroke is different according to data sources. For some, acute stroke is defined as a cerebrovascular disease as a whole or is defined as an acute stroke so data are not quite comparable.
5 Conclusions
Acute stroke is the third leading cause of disability and death (as DALYs) in EU-25 (DALY = 5.3%) after depression (DALY = 7.8%) and ischemic heart disease (DALY = 7.4%)9. Despite improvements in stroke care, treatment of the long-term effects remains one of the major problems. Diabetes mellitus and its complications have become a major public health problem in all EU-25 countries (DALY = 2.0%)9. It causes significant physical and psychological morbidity, disability and premature mortality among those affected and imposes a heavy financial burden on health services. As these two conditions are most leading conditions in the world and in Europe, it implies that accurate information is available regarding general indicators with regard to disease status. Moreover, this information may come from several data sources. Concerning other priority areas, information increasingly becomes patchy. Only literature reviews or specific surveys are available to provide information on health in Europe, but only regarding a specific population or a specific European region.
However, differences also occur between these two chosen conditions particularly regarding data availability. The main reason is that there is an association collecting data on diabetes mellitus, the International Diabetes Federation which centralises all data on this topic. Even if for all main indicators few organisations contain data, data regarding specific indicators of supplementary objectives are only available on this specific website. Another explanation comes from the disease type, acute or chronic. Approaches to treat these diseases differ. By definition, the perspective to treat a chronic condition implies temporality notions contrary to acute ones. Besides, few
9 “Priority Medicines for Europe and the World.” Kaplan W. and Laing R., 2004. WHO
CONCLUSIONS 55 / 56 indicators are more related to chronic condition than acute ones. For instance, to measure the importance of a disease, prevalence is recommended for chronic conditions, while for acute diseases incidence is more relevant and preferred.
One of the main difficulties was to link the areas identified and find a way to evaluate the impact of medicines use on health. A medical expert validation would be required for a few indicators as for completing the list of active substances used to treat diseases. This expertise will improve the analysis by checking the adequacy between treatments and diseases. Availability of routine data was also a major concern. The main criteria for selecting the indicators once defined according to the needs were to have fairly simple and routinely collectable indicators. The lack of aggregate data which are comparable and valid at national and EU level was a major difficulty. Assessment of data availability could not be made in detail for all indicators, some requiring a great deal of effort at national level and being projects in themselves. Among 43 non excluded indicators, 13 common ones were studied in details in these case-studies, including 17 for diabetes mellitus and 15 for acute stroke (see table hereafter). In each of these three categories, several indicators are ready to be implemented whereas others need further work. This work necessitates identification of data sources, definition of indicators, expansion to all EU-25 Member States, earlier time series or actual data availability. To obtain missing data on specific indicators, a solution would be to set up new data collection either through existing international surveys in adding supplementary questions. For instance, the European Commission gathers several general or specific surveys e.g. EHSS, ECHI or EURODIAB regarding diabetes. In cases where a topic is too different, a second step would be to create new surveys on a regional area.
Table: Number of indicators detailed Common Diabetes Acute
indicators mellitus stroke
Ready to be implemented 5 2 4
Core indicators Further work required 3 7 4
Total 8 9 8
Ready to be implemented 4 3 2
Supplementary Further work required 1 5 5 indicators
Total 5 8 7
Total 13 17 15
CONCLUSIONS 56 / 56 This report was produced by a contractor for Health & Consumer Protection Directorate General and represents the views of the contractor or author. These views have not been adopted or in any way approved by the Commission and do not necessarily represent the view of the Commission or the Directorate General for Health and Consumer Protection. The European Commission does not guarantee the accuracy of the data included in this study, nor does it accept responsibility for any use made thereof.