1. History of the Montreal Protocol, FDA regulation of CFCs and Background to Meeting Robert J. Meyer, MD Director, ODE II / CDER

2. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 2 General Background The earth’s ozone layer is a region of relatively higher ozone concentrations in the stratosphere The earth’s ozone layer is a region of relatively higher ozone concentrations in the stratosphere

3. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 3 General Background This “layer” reduces the amount of ultraviolet radiation (UV-B) reaching the surface from sunlight As a result of ozone loss, the increased UV-B leads to increases in skin cancers (melanoma and non-melanoma), cataracts, impaired immunity Other deleterious effects on the environment also result, as do effects on man-made substances (like plastics) This “layer” reduces the amount of ultraviolet radiation (UV-B) reaching the surface from sunlight As a result of ozone loss, the increased UV-B leads to increases in skin cancers (melanoma and non-melanoma), cataracts, impaired immunity Other deleterious effects on the environment also result, as do effects on man-made substances (like plastics)

4. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 4 Development of US law, FDA regulations, and the Montreal Protocol have proceeded in overlapping timeframes, so this talk will overlap the discussions General Background

5. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 5 History of the Montreal Protocol and 21 CFR 2.125 1974- Work by Molina and Rowland published tying ozone depletion to stratospheric chlorine from degraded CFCs 1 At that time, use of CFCs was widespread in the US –Refrigerators, A/C, foams, and in many consumer and medical aerosol products 1 – Nature, 1974; vol 249:810-812 1974- Work by Molina and Rowland published tying ozone depletion to stratospheric chlorine from degraded CFCs 1 At that time, use of CFCs was widespread in the US –Refrigerators, A/C, foams, and in many consumer and medical aerosol products 1 – Nature, 1974; vol 249:810-812

6. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 6 History of the Montreal Protocol and 21 CFR 2.125 1978 – In response to growing evidence of CFCs harming the ozone layer, CFCs were generally banned in spray can/aerosols by U.S. Govt (EPA) – e.g. hairsprays, spray paint… FDA published 21 CFR 2.125 banning use of CFCs in FDA regulated products (with essential exemptions) 1978 – In response to growing evidence of CFCs harming the ozone layer, CFCs were generally banned in spray can/aerosols by U.S. Govt (EPA) – e.g. hairsprays, spray paint… FDA published 21 CFR 2.125 banning use of CFCs in FDA regulated products (with essential exemptions)

7. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 7 History of the Montreal Protocol and 21 CFR 2.125 1987 - 27 nations (including U.S.) initiate a global ozone treaty in Montreal, known as the “Montreal Protocol on Substances that Deplete the Ozone Layer” hereafter referred to as the “MP” The original protocol now has over 180 signatory Parties (countries) and is regarded as the model for successful, global environmental treaties 1987 - 27 nations (including U.S.) initiate a global ozone treaty in Montreal, known as the “Montreal Protocol on Substances that Deplete the Ozone Layer” hereafter referred to as the “MP” The original protocol now has over 180 signatory Parties (countries) and is regarded as the model for successful, global environmental treaties

8. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 8 History of the Montreal Protocol and 21 CFR 2.125 Original phase-out of CFCs slated for 2000 (London - 1990) Phase-out of CFCs is moved up to end of 1995 (Copenhagen - 1992) due to evidence of increasing ozone depletion, especially over the Antarctic (ozone “hole”) While depletion is most prominent over southern hemisphere, the depletion is global MP controls many ozone depleting substances (ODS): CFCs, Halons, HCFCs, methyl bromide, carbon tetrachloride,… Original phase-out of CFCs slated for 2000 (London - 1990) Phase-out of CFCs is moved up to end of 1995 (Copenhagen - 1992) due to evidence of increasing ozone depletion, especially over the Antarctic (ozone “hole”) While depletion is most prominent over southern hemisphere, the depletion is global MP controls many ozone depleting substances (ODS): CFCs, Halons, HCFCs, methyl bromide, carbon tetrachloride,…

9. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 9 History of the Montreal Protocol and 21 CFR 2.125 As of January 1st, 1996, all use of CFCs banned in industrial countries; rest of the world in 2010 MDIs for asthma and COPD currently exempted under essential use process Nominations for essential uses reviewed annually (e.g., in 2005, the Parties ordinarily review 2007 nominations) As of January 1st, 1996, all use of CFCs banned in industrial countries; rest of the world in 2010 MDIs for asthma and COPD currently exempted under essential use process Nominations for essential uses reviewed annually (e.g., in 2005, the Parties ordinarily review 2007 nominations)

10. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 10 History of the Montreal Protocol and 21 CFR 2.125 Montreal Protocol has stipulated the following: Decision IV/25 - All essential uses of CFCs based on products necessary for public health without adequate alternatives (technically & economically) - ‘macroscopic’ determination of essentiality (i.e., use of CFCs in MDIs for asthma and COPD) Montreal Protocol has stipulated the following: Decision IV/25 - All essential uses of CFCs based on products necessary for public health without adequate alternatives (technically & economically) - ‘macroscopic’ determination of essentiality (i.e., use of CFCs in MDIs for asthma and COPD)

11. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 11 History of the Montreal Protocol and 21 CFR 2.125 Montreal Protocol has stipulated the following: Decision XII/2 - Any product approved after Dec. 2000 must individually meet IV/25 –Product-centered determination of essentiality that essentially precludes new CFC generics or other new CFC products unless the new product individually exceeds the high hurdle of IV/25 Montreal Protocol has stipulated the following: Decision XII/2 - Any product approved after Dec. 2000 must individually meet IV/25 –Product-centered determination of essentiality that essentially precludes new CFC generics or other new CFC products unless the new product individually exceeds the high hurdle of IV/25

12. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 12 History of the Montreal Protocol and 21 CFR 2.125 Montreal Protocol has stipulated the following: Decision XV/5: –Essential use nominations are now use specific (e.g., XX tonnes for albuterol) –No quantity of essential use CFCs will be authorized for albuterol beginning with this year’s MOP if a “plan” for albuterol phase-out has not been submitted by the OEWG the summer of 2005 »FDA final rule published in March 2005 on phase- out of albuterol meets this stipulation for US Montreal Protocol has stipulated the following: Decision XV/5: –Essential use nominations are now use specific (e.g., XX tonnes for albuterol) –No quantity of essential use CFCs will be authorized for albuterol beginning with this year’s MOP if a “plan” for albuterol phase-out has not been submitted by the OEWG the summer of 2005 »FDA final rule published in March 2005 on phase- out of albuterol meets this stipulation for US

13. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 13 History of the Montreal Protocol and 21 CFR 2.125 CAA amendments of 1990, in part, codified MP into US law Implementing EPA regulations refer to HHS/ FDA through 21 CFR 2.125 for definition of medical essentiality Again, 2.125 was originally published in as a final rule in 1978 CAA amendments of 1990, in part, codified MP into US law Implementing EPA regulations refer to HHS/ FDA through 21 CFR 2.125 for definition of medical essentiality Again, 2.125 was originally published in as a final rule in 1978

14. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 14 1978 Federal Regulation (21 CFR 2.125) was promulgated stating that CFC containing regulated products were misbranded/adulterated unless deemed essential “Essential” based on: No technically feasible alternatives Provides substantial (health, public, or environmental) benefit Release of CFC small, or justified given benefit 1978 Federal Regulation (21 CFR 2.125) was promulgated stating that CFC containing regulated products were misbranded/adulterated unless deemed essential “Essential” based on: No technically feasible alternatives Provides substantial (health, public, or environmental) benefit Release of CFC small, or justified given benefit History of the Montreal Protocol and 21 CFR 2.125

15. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 15 1978 FDA rule had no mechanism to determine when uses are no longer essential and to delist them (only mechanims to add new classes/drugs to the list) Many important drugs not listed separately, but in broad classes –e.g., “Adrenergic bronchodilators for human use….” 1996, FDA publishes an Advanced Notice of Proposed Rulemaking (ANPR) proposing revisions to 2.125 1978 FDA rule had no mechanism to determine when uses are no longer essential and to delist them (only mechanims to add new classes/drugs to the list) Many important drugs not listed separately, but in broad classes –e.g., “Adrenergic bronchodilators for human use….” 1996, FDA publishes an Advanced Notice of Proposed Rulemaking (ANPR) proposing revisions to 2.125 History of the Montreal Protocol and 21 CFR 2.125

16. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 16 History of the Montreal Protocol and 21 CFR 2.125 Close to 10,000 comments received, many sparked by lobbying efforts NPR published in 1999 with fewer resulting substantive comments and little controversy FR amending 2.125 published on July 24, 2002 FR went into effect January 2003 Close to 10,000 comments received, many sparked by lobbying efforts NPR published in 1999 with fewer resulting substantive comments and little controversy FR amending 2.125 published on July 24, 2002 FR went into effect January 2003

17. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 17 History of the Montreal Protocol and 21 CFR 2.125 2002 revisions to 2.125: Listed individual moieties as essential uses of ozone depleting substances (ODS) in 2.125 (e) rather than classes (e.g., albuterol is listed, rather than all adrenergic bronchodilators) Added a higher hurdle for IND use of ODSs and to raise the bar for new listings of essential uses Lists criteria for determining individual uses are no longer essential 2002 revisions to 2.125: Listed individual moieties as essential uses of ozone depleting substances (ODS) in 2.125 (e) rather than classes (e.g., albuterol is listed, rather than all adrenergic bronchodilators) Added a higher hurdle for IND use of ODSs and to raise the bar for new listings of essential uses Lists criteria for determining individual uses are no longer essential

18. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 18 History of the Montreal Protocol and 21 CFR 2.125 Non-essentiality Criteria: –At least one non-ODS product with the same active moiety*, the same indication, route of administration, about the same level of convenience –At least 1 year of post-marketing data is available for the non-ODS product –Production capabilities and supplies are adequate –Patients who require the CFC product are adequately served * For products with only one marketed brand or strength Non-essentiality Criteria: –At least one non-ODS product with the same active moiety*, the same indication, route of administration, about the same level of convenience –At least 1 year of post-marketing data is available for the non-ODS product –Production capabilities and supplies are adequate –Patients who require the CFC product are adequately served * For products with only one marketed brand or strength

19. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 19 History of the Montreal Protocol and 21 CFR 2.125 Non-essentiality Criteria (continued): –For Moieties with more than one available product/strength: –At least two non-ODS product with the same active moiety, the same indication, route of administration, about the same level of convenience –Other criteria the same Non-essentiality Criteria (continued): –For Moieties with more than one available product/strength: –At least two non-ODS product with the same active moiety, the same indication, route of administration, about the same level of convenience –Other criteria the same

20. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 20 History of the Montreal Protocol and 21 CFR 2.125 Since a moiety-by-moiety approach does not effectively address drugs not being reformulated, rewrite of 2.125 stated that: [FDA] has therefore revised § 2.125(g)(2) to permit the agency to undertake an evaluation of all ODS products after January 1, 2005, not just those products without a non-ODS replacement.

21. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 21 Beginning in 2005, FDA may convene public meetings (i.e., PADAC meetings) to discuss those products still listed as essential to determine if changes in the medical practice and availability of alternatives render these products as no longer essential “Essential” based on: No technically feasible alternatives Provides substantial (health, public, or environmental) benefit Release of CFC small, or justified given benefit Beginning in 2005, FDA may convene public meetings (i.e., PADAC meetings) to discuss those products still listed as essential to determine if changes in the medical practice and availability of alternatives render these products as no longer essential “Essential” based on: No technically feasible alternatives Provides substantial (health, public, or environmental) benefit Release of CFC small, or justified given benefit History of the Montreal Protocol and 21 CFR 2.125

22. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 22 History of the Montreal Protocol and 21 CFR 2.125 Note that if PADAC recommends that DRUG X is no longer essential, there is a process that plays out from here For FDA to follow the advice, FDA would need to publish a NPR stating that we had preliminarily determined DRUG X to no longer be an essential use Public comments would be sought and considered prior to final regulatory action (i.e., a final rule) Note that if PADAC recommends that DRUG X is no longer essential, there is a process that plays out from here For FDA to follow the advice, FDA would need to publish a NPR stating that we had preliminarily determined DRUG X to no longer be an essential use Public comments would be sought and considered prior to final regulatory action (i.e., a final rule)

23. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 23 CFC essential Use - then and now Beta-agonists: isoethrane, isoprot., albuterol, epineph, metaprot., pirbuterol, bitoterol, salmeterol ICS: fluticasone, flunisolide, TAA, BDP, Dexamethsone Nasal Steroids Cromones: Cromolyn, Nedocromil Anticholinergics: Ipratropium, atropine Albuterol/Ipratropium, Talc, Contraceptive Foams, Rectal CS foams, Ergotamine MDIs, Polymyxin, anesthetic drugs, NTG Beta-agonists: isoethrane, isoprot., albuterol, epineph, metaprot., pirbuterol, bitoterol, salmeterol ICS: fluticasone, flunisolide, TAA, BDP, Dexamethsone Nasal Steroids Cromones: Cromolyn, Nedocromil Anticholinergics: Ipratropium, atropine Albuterol/Ipratropium, Talc, Contraceptive Foams, Rectal CS foams, Ergotamine MDIs, Polymyxin, anesthetic drugs, NTG No longer essential; Delisting possible soon

24. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 24 Approved Non-CFC Inhaled Respiratory Medications* 1. Beta-agonists: –albuterol (Proventil HFA, Ventolin HFA, IVAX’s albuterol sulfate HFA – all MDIs) –levalbuterol (Xopenex HFA - MDI) –salmeterol (Serevent Diskus – MDPI (multidose dry powder inhaler)) –formoterol (Foradil Aerolizer – DPI (dry powder inhaler)) 2. Inhaled Corticosteroids : –Budesonide (Pulmicort Turbuhaler – MDPI) –fluticasone (Flovent Diskus - MDPI and Flovent HFA - MDI) –mometasone (Asmanex – MDPI) –beclomethasone (QVAR - MDI) 1. Beta-agonists: –albuterol (Proventil HFA, Ventolin HFA, IVAX’s albuterol sulfate HFA – all MDIs) –levalbuterol (Xopenex HFA - MDI) –salmeterol (Serevent Diskus – MDPI (multidose dry powder inhaler)) –formoterol (Foradil Aerolizer – DPI (dry powder inhaler)) 2. Inhaled Corticosteroids : –Budesonide (Pulmicort Turbuhaler – MDPI) –fluticasone (Flovent Diskus - MDPI and Flovent HFA - MDI) –mometasone (Asmanex – MDPI) –beclomethasone (QVAR - MDI) * Products for nebulization excluded

25. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 25 3. Cromones: –none 4. Anticholinergics: –ipratropium (Atrovent HFA - MDI) –tiotropium (Spiriva - DPI) 5. Corticosteroid/LABA combination: –salmeterol/fluticasone (Advair Diskus - MDPI) 3. Cromones: –none 4. Anticholinergics: –ipratropium (Atrovent HFA - MDI) –tiotropium (Spiriva - DPI) 5. Corticosteroid/LABA combination: –salmeterol/fluticasone (Advair Diskus - MDPI) Non-CFC Inhaled Respiratory Medications* * Products for nebulization excluded

26. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 26 Moieties currently listed as essential for which no current reformulated or direct alternative product exists: 1. Beta-agonists* –metaproterenol (Alupent) –pirbuterol (Maxair) 2. Inhaled Corticosteroids –flunisolide (Aerobid), –triamcinolone (Azmacort) 3. Cromones –Cromolyn (Intal) –Nedocromil (Tilade) 4. Beta agonist/Anticholinergic combination –Albuterol/Ipratropium (Combivent) 1. Beta-agonists* –metaproterenol (Alupent) –pirbuterol (Maxair) 2. Inhaled Corticosteroids –flunisolide (Aerobid), –triamcinolone (Azmacort) 3. Cromones –Cromolyn (Intal) –Nedocromil (Tilade) 4. Beta agonist/Anticholinergic combination –Albuterol/Ipratropium (Combivent) *epinephrine excluded

27. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 27 Trends in Global CFC essential uses: TEAP Report 2004

28. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 28 ConclusionsConclusions US Govt. moved proactively to address issue of ozone depletion and has had a key role in the Montreal Protocol MP is a successful treaty, leading to important reductions in CFCs and other ODS MP is increasingly moving towards control in specific essential uses, notably albuterol US Govt. moved proactively to address issue of ozone depletion and has had a key role in the Montreal Protocol MP is a successful treaty, leading to important reductions in CFCs and other ODS MP is increasingly moving towards control in specific essential uses, notably albuterol

29. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 29 US is progressing in CFC transition, with many non-CFC products available, many CFC products no longer marketed Some CFC products/moieties remain on the market with no current alternatives Do these product remain essential? US is progressing in CFC transition, with many non-CFC products available, many CFC products no longer marketed Some CFC products/moieties remain on the market with no current alternatives Do these product remain essential? ConclusionsConclusions

30. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 30 Charge to the PADAC As per the revisions to 2.125, FDA is convening its first PADAC meeting to discuss those products listed as essential to determine if changes in the medical practice and availability of alternatives render these products as no longer essential “Essential” based on: No technically feasible alternatives Provides substantial (health, public, or environmental) benefit Release of CFC small, or justified given benefit As per the revisions to 2.125, FDA is convening its first PADAC meeting to discuss those products listed as essential to determine if changes in the medical practice and availability of alternatives render these products as no longer essential “Essential” based on: No technically feasible alternatives Provides substantial (health, public, or environmental) benefit Release of CFC small, or justified given benefit

31. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 31