1. History of the Montreal Protocol and 21 CFR 2.125 Robert J. Meyer, MD Director, ODE II / CDER

2. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 2 General Background The earth’s stratospheric ozone layer provides reductions in ultraviolet radiation (UV-B) reaching the surface Increases in UV-B can cause skin cancers (melanoma and non-melanoma), cataracts, altered immunity as well as other deleterious effects on the environment, as well as to man-made substances like plastics The earth’s stratospheric ozone layer provides reductions in ultraviolet radiation (UV-B) reaching the surface Increases in UV-B can cause skin cancers (melanoma and non-melanoma), cataracts, altered immunity as well as other deleterious effects on the environment, as well as to man-made substances like plastics

3. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 3 General Background Rule Making Procedures: –FDA interprets and implements its authority under the FD&C act and other statutes through regulations –Usual pathway for promulgation of a regulation is via publication of: Proposed Rule − Comment Period − Final Rule –Rulemaking integral to CFC/ODS essentiality determinations Rule Making Procedures: –FDA interprets and implements its authority under the FD&C act and other statutes through regulations –Usual pathway for promulgation of a regulation is via publication of: Proposed Rule − Comment Period − Final Rule –Rulemaking integral to CFC/ODS essentiality determinations

4. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 4 Development of FDA regulations and 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- Publication of work by Molina and Rowland tied stratospheric chlorine from degraded CFCs in the statosphere to ozone depletion 1 At that time, use of CFCs was widespread - refrigerators, A/C, foams, and in consumer and medical aerosol products 1 – Nature, 1974; vol 249:810-812 1974- Publication of work by Molina and Rowland tied stratospheric chlorine from degraded CFCs in the statosphere to ozone depletion 1 At that time, use of CFCs was widespread - refrigerators, A/C, foams, and in 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 US Govt (EPA) 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 US Govt (EPA) 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 (MP) on Substances that Deplete the Ozone Layer” The original protocol now has 184 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 (MP) on Substances that Deplete the Ozone Layer” The original protocol now has 184 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 increasing evidence of growing ozone depletion, espeically over the Antartic (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 increasing evidence of growing ozone depletion, espeically over the Antartic (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 2004, UNEP reviews 2006 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 2004, UNEP reviews 2006 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 - a product centered determination of essentiality that precludes new CFC generics Montreal Protocol has stipulated the following: Decision XII/2 - Any product approved after Dec. 2000 must individually meet IV/25 - a product centered determination of essentiality that precludes new CFC generics

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 the MOP in 2005 if a “plan” has not been submitted by the OEWG the summer of 2005 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 the MOP in 2005 if a “plan” has not been submitted by the OEWG the summer of 2005

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 codified MP into US law Implementing EPA regulations refer to 21 CFR 2.125 for definition of medical essentiality Again, 2.125 was finalized in 1978 CAA amendments of 1990 codified MP into US law Implementing EPA regulations refer to 21 CFR 2.125 for definition of medical essentiality Again, 2.125 was finalized 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 things 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 –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 things 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 –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 In 2002 revisions: 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 In 2002 revisions: 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 –ALBUTEROL is a moiety with more than one product available (2 branded, 3 generics marketed) 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 –ALBUTEROL is a moiety with more than one product available (2 branded, 3 generics marketed)

20. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 20 Trends in Global CFC essential uses: TEAP Report 2004

21. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 21

22. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 22 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

23. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 23 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

24. Pulmonary-Allergy Drugs Advisory Committee June 10 th, 2004 24