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

History of the Montreal History of the Montreal Protocol and 21 CFR 2.125Protocol and 21 CFR 2.125


Robert J. Meyer, MDRobert J. Meyer, MD

Director, ODE II / CDERDirector, ODE II / CDER

2Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee June 10June 10thth, 2004, 2004

General BackgroundGeneral BackgroundGeneral BackgroundGeneral 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



• 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


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

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



History of the Montreal Protocol History of the Montreal Protocol and 21 CFR 2.125and 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

• 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




• 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)




• 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




• 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,…




• 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)




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)


• 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)





• 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


• 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





• 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


• 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




• 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


• 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




• 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






• 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




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




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




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)


Trends in Global CFC essential Trends in Global CFC essential uses: TEAP Report 2004uses: TEAP Report 2004

Trends in Global CFC essential Trends in Global CFC essential uses: TEAP Report 2004uses: TEAP Report 2004

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CFCs used for MDIs in the Montreal Protocol: Aggregate allocation, use and nomination data

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CFC essential Use - then and nowCFC essential Use - then and nowCFC essential Use - then and nowCFC 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


ConclusionsConclusionsConclusionsConclusions

• 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


Documents

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