History of the Montreal Protocol and 21 CFR 2.125

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

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

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

4. General Background • Development of FDA regulations and Montreal Protocol have proceeded in overlapping timeframes, so this talk will overlap the discussions

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 depletion1 • 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. 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)

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

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,…

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)

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)

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

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

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

14. History of the Montreal Protocol and 21 CFR 2.125 • 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

15. History of the Montreal Protocol and 21 CFR 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

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

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

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

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)

20. Trends in Global CFC essential uses: TEAP Report 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 No longer essential; Delisting possible soon

23. Conclusions • 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

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