SUMMARY THE EUROPEAN COMMUNITY STRATEGY

SUMMARY THE EUROPEAN COMMUNITY STRATEGY FOR THE PHASEOUT OF CFCS IN MDIS 1. The Eurpean Cmmunity s transitin strategy fr the phaseut f CFCs in metered-dse inhalers (MDIs) was submitted t the Parties t the Mntreal Prtcl in accrdance with Decisin IX/19. The purpse f the strategy is t describe hw the phaseut f CFC-cntaining MDIs and their replacement by CFC-free MDIs is t be managed in the Cmmunity. Full dcument f the Eurpean Cmmunity s transitin strategy fr the phaseut f CFCs in MDIs can be btained frm web link http://zne.unep.rg/exemptin_infrmatin/essential_use_nminatins/mdi_submissins/mditra nsitin-ec.pdf 2. It is imprtant t nte that this dcument has been published in 1998 and reflects the situatin at that mment. Given that the current situatin with regard t CFC-MDI is nw quite different frm thse at the time f publishing the strategy. It is essential fr readers t nte that sme f the elements in this strategy are utdated. A. CFC MDI Transitin Strategy 3. CFCs are still currently available in Eurpe fr the manufacture f MDIs thrugh the essential uses exemptin. This permits the cntinued prductin and use f CFCs fr agreed essential uses where technical and ecnmically feasible alternatives are nt available. Under the rules f the essential uses exemptin, CFCs will n lnger be authrised fr prducts where acceptable alternatives are available. 4. The fllwing principles have been agreed t guide the phase-ut f CFC in MDIs: Principle 1: That all thse invlved will prmte the transitin t nn-cfc alternatives; Principle 2: That the health and safety f patients during the transitin will be safeguarded Principle 3: That the nminatin, apprvals and licensing systems will be perated with efficiency, cnsistency and transparency. B. MDIs and Alternatives t CFC MDIs and their Develpment 5. There was internatinal (WHO/GINA) cnsensus that the primary treatment f asthma and COPD shuld be by the inhaled rute. The predminant frm f inhaled therapy in mst f the Eurpe was the MDI (80% f prescribed inhalers). The remaining 20% were mainly DPIs and much smaller prprtin f nebulised drugs. Alternatives t CFC-cntaining MDIs were becming available thrughut the Eurpean Cmmunity. 6. DPIs and Nebulisers: Althugh the Eurpean market fr inhaled therapy was traditinally dminated by MDIs, almst f the active substances are als available in DPI frmulatin including the multi-dse system. In sme parts f the Eurpean Cmmunity (Scandinavia and the Netherlands), a majrity f patients were already treated with DPIs rather than MDIs. Althugh DPIs were nt suitable fr all patients, the wide range f available DPIs prvided a safety back-up during the transitin t CFC-free MDIs and prvided additinal ptins fr patients. The nebulisers were generally reserved fr patients with special needs and were currently expensive. The new devices may make this mre viable ptin in the future. 1

7. CFC-free MDIs: As DPIs and nebulisers were nt interchangeable with MDIs fr all patients. It was therefre vital t develp CFC-free MDIs with the same advantages fr patients. HFC-134a and HFC-227 had been identified as the nly real alternatives t CFCs fr MDI use. As a result f a majr research and develpment effrt, pharmaceutical cmpanies had made gd prgress in develping CFC-free MDIs. In general, each cmpany had fcus its frmulatin effrts n the MDI prducts which were the mst cmmnly prescribed and which use the mist CFCs. The fllwing steps were undertaken t identify alternatives t CFCs in MDI use. Research t identify prpellants as substitutes t CFCs; Txiclgy testing f prpellants fr pharmaceutical usage; Refrmulate MDIs using the identified prpellants in accrdance with the EC guidelines n replacement f CFCs in medical prducts. Intensive research and testing t identify and develp new frmulatin; Redevelp cmpnent f the primary packaging (metal can, valves, elastmers, actuatrs); Txiclgical studies n the final frmulatin befre r in parallel with stability testing; Clinical studies n the new prduct, ver a treatment perid f up t ne year 8. Naming, Packing and Identifying the Alternatives: Accrding t Decisin VIII/10 (3) that CFC and Nn-CFC prducts must be differentiated, the Directive 92/27/EEC sets ut the nrmal prcedure whereby the prpsed labeling fr medicinal prducts is submitted t the apprpriate regulatry authrities with the applicatin fr marketing authrisatin. Pharmaceutical cmpanies will decide whether they wish t retain the existing brand name and adapt its existing labeling, including the additin f the term CFC-free r t intrduce a cmpletely new brand name fr the nn-cfc MDI. CFC-free prducts shuld als include a leaflet t explain abut the new prpellant and the reasns fr change. This differentiatin is vital t pst-marketing safety mnitring s that any reprted adverse effects can crrectly be attributed t the type f prduct cncerned. C. Apprval f New Prducts and Pst-authrizatin Surveillance 9. Cperatin between Member States: Befre CFC-free MDIs can be prescribed t patients, they need t receive marketing authrisatin frm the cmpetent authrities. Such authrisatin is nly granted when the cmpetent authrity is satisfied that the prpsed alternative prduct is safe and effective. Obtaining marketing authrisatin fr CFC-free MDIs acrss the entire Eurpean Cmmunity is currently a lengthy prcess, because each Member State cnducts its wn review and authrisatin prcedures. The transitin t CFC-free alternatives shuld als be managed n a Cmmunity-wide basis. Cmpetent authrities shuld n lnger give marketing authrisatin fr new CFC-cntaining inhalers. 10. T streamline the apprval prcedures, it was in the general interest f Member States t cperate and share the wrklad f review. Prcedures fr reviewing replacements fr existing CFC prducts and apprving new CFC-free prducts shuld include at least the fllwing elements: that cmpanies shuld submit applicatins acrss the whle f the Cmmunity simultaneusly; that cmpetent authrities shuld c-perate in sharing ut the wrk and its results; that CFC-free prducts shuld be authrised fr use withut delays and, as far as pssible, simultaneusly acrss the Member States; Member States shuld ensure that their prcedures fr agreeing pricing and reimbursement d nt cause unnecessary delays t the availability f CFC-free medical inhalers n the Eurpean market. 2

11. Pst Authrisatin Surveillance and Safety Audit: When new prducts are marketed, an intensive pst-authrisatin surveillance is critical t cnfirm the safety f new CFC-free prducts. Dctrs and pharmacists can als play a useful rle in evaluating the success and safety f CFC-free inhalers. 12. Phase-ut Time f CFC-Cntaining Prducts: Nrmally, the CFC prduct culd remain available in the market fr up t twelve mnths fllwing launch f the replacement prduct. Any safety issues with the CFC-free prducts will need t be rapidly identified, evaluated and acted n s that they are reslved befre the equivalent CFC-cntaining prduct is finally withdrawn. D. Phasing-ut CFCs in MDIs in the EC 13. The strategy was based n phasing ut CFCs as far as pssible categry by categry while taking int accunt f knwn limitatins t substitutin within categries f active substance, the need t ensure that all patients cntinue t have access t the medicines they require and the different circumstances perating in different Member States. Prducts fr the treatment f asthma and COPD are classified int the fllwing 6 categries: A Shrt acting beta agnist brnchdilatrs e.g. salbutaml terbutaline, fenterl B Inhaled Sterids e.g. beclmethasne, budesnide, fluticasne, C Nn Steridal anti-inflammatries e.g. crmglycate, nedcrmil D Antichlinergic brnchdilatrs e.g. ipratrpium brmide, xytrpium brmide E Lng acting beta agnists brnchdilatrs e.g. salmeterl, frmterl F Cmbinatin drugs 14. Criteria fr Determining when Sufficient Alternatives are Available: The criteria fall int tw grups: thse fr determining when the use f CFCs wuld n lnger be cnsidered essential fr individual prducts, and thse fr determining when the use f CFCs wuld n lnger be cnsidered essential fr a whle categry. These tw systems wuld perate in parallel. 15. Hwever, t reflect the different circumstances f Member States, CFCs may have t be apprved fr a particular prduct in a particular Member State even after the criteria fr transitin have been met. Any dergatin alng these lines wuld have t be temprary and wuld nt delay the transitin elsewhere in the Cmmunity. 16. The fllwing cnditins will als need t be met befre it is cnsidered that there are sufficient technical and feasible alternatives available fr CFCs t be withdrawn: Adequate prductin and distributin capacity f the CFC-free MDIs t meet the needs f all patients cvered by the prduct r categry cncerned; An adequate range f dses and strengths t cver distinct patient subgrups; Efficacy f the alternative prducts and treatments generally cmparable t the CFC prduct they are replacing (persnnel preference f sme patients cannt be used); Sufficient pst marketing surveillance f the refrmulated prducts and n safety prblems identified 17. Stckpile f CFCs and CFC MDIs: Careful mnitring f prductin and stckpiles, imprt cntrls and making CFCs available nly fr thse prducts still met the essential uses criteria is essential fr successful CFC MDI phase-ut. Once the essential use exemptin be withdrawn fr a particular CFC prduct r categry f prducts, n mre CFCs will be available fr the manufacture f thse CFC prducts. 3

18. Cmpanies may still be able t sell stckpiled MDIs which have already been manufactured, as there is n bligatin t withdraw marketing authrisatin. It is pssible t envisage a perid f 12 mnths during which the CFC prduct and its CFC free alternative are bth available, particularly t assist pst-marketing surveillance. After that time, hwever, the cntinued presence f CFC prducts n the market will be unnecessary, and might cnfuse dctrs and patients invlved in the transitin. Cmpanies shuld prepare plans t withdraw their CFC prducts within the suggested timeframe and in accrdance with their dctr and patient educatin prgrams. 19. New CFC MDIs: As part f the strategy frm 1 January 1998, (i) cmpetent authrities shuld nt give marketing authrisatin t any new CFC cntaining inhalers, (ii) the Eurpean Cmmissin will nt apprve the allcatin f CFCs fr the manufacture f any new MDI prduct, and (iii) cmpanies shuld cease develping and prmting CFC-cntaining MDIs. E. Awareness Raising 20. Patients are at the centre f the transitin and need t be fully aware f the issues invlved. Infrmatin needs t be crdinated t ensure that dctrs, ther health prfessinals and asthma patients assciatins prvide accurate, cherent and useful infrmatin t patients befre, during and after transitin. Wherever pssible, new patients shuld be started n CFC free inhalers, and manufacturers shuld n lnger develp and market new inhalers cntaining CFCs. 21. Awareness raising activities culd be dne at (i) the gvernment level health department, (ii) prfessinal and patient assciatin level thrugh treatment guideline, medical sympsia, prmtinal material, media cverage etc. and (iii) at industry level t help in educating the medical prfessinal thrugh educatinal material, medical sympsia, and reprints f pertinent articles and reprts. This educatinal activity shuld invlve increasing awareness f DPIs as well as the refrmulated MDI prducts. As mre alternatives becme available it is essential that a mre active patient strategy is develped t prevent cnfusin. F. Exprt f MDIs frm the EC 22. The Eurpean Cmmunity was a majr exprter f CFC-cntaining MDIs t bth develped and develping cuntries. These exprts wuld need t cntinue even after the transitin has been accmplished in the Cmmunity in rder t ensure that patients, especially in develping cuntries, are nt deprived f essential medicines. MDI manufacturers based in the Eurpean Cmmunity are expected t help prmte the transitin away frm CFC-cntaining MDIs in their exprt markets. They shuld ensure that, wherever pssible, patients relying n MDIs prduced in Eurpe are given access t CFC-free inhalers and thereby benefit frm the experience f transitin in Eurpe. G. CFC Prductin Issues 23. CFCs fr use in the prductin f MDIs were manufactured in the EC by 4 prducers. These were (i) AlliedSignal (The Netherlands), (ii) Ausimnt (Italy), (iii) Elf-Atchem (Spain), and (iv) Rhne Pulenc (UK). These prducers als prduced CFCs fr the manufacture f MDIs in a number f develped and develping cuntries. CFC prducers within the EC prduced mainly CFC 11 and CFC 12 fr use in MDI manufactures within the EC and wrldwide and fr the basic dmestic needs f A5 cuntries. 24. Prductin f CFCs fr MDI fr Exprt t Develping Cuntries: There was a cncern that nce CFC MDIs have been phased ut in the EC, pharmaceutical-grade CFCs culd becme in shrt supply fr the cntinued manufacture f MDIs within the EC fr exprt t develping cuntries where the transitin t nn-cfc prducts will prceed mre slwly 25. One ptin wuld be prductin campaigns t prduce a sufficient stckpile f CFCs t supply MDI manufacture fr exprt. A perid f 2 years might be required t establish an adequate stckpile f CFCs thrugh 'campaign prductin. Hwever, its disadvantage were the difficulty f accurately assessing future demand fr CFCs and n assurances that CFCs will nt degrade, nr that 4

the MDIs ultimately prduced with these stckpiled CFCs wuld nt deterirate faster than MDIs prduced with freshly-prduced CFCs. 26. A secnd pssible surce f CFCs fr MDI prducers wuld be frm prductin facilities lcated in develping cuntries. This was nt currently thught t be a realistic ptin. Prductin facilities wuld need t be registered and the CFCs btained apprved by the cmpetent Regulatry Authrities, including thse in the cuntry f MDI manufacture. The CFC prductin wuld have t cmply with stringent Gd Manufacturing Practice (GMP). 27. Given the cntinued prductin f CFCs within the EC t supply the basic dmestic needs f Develping Parties, it was mst unlikely that, ver the perid f the EC transitin, there wuld be a shrtage f pharmaceutical grade CFCs fr the manufacture f MDIs in the EC, whether fr use in the Cmmunity r fr exprt. 5