1. CFC Essential Use Status of Albuterol: Medical Considerations Pulmonary-Allergy Drugs Advisory Committee Meeting June 10, 2004 Eugene J. Sullivan, MD, FCCP Deputy Director Division of Pulmonary Drug Products CDER, FDA Pulmonary-Allergy Drugs Advisory Committee Meeting June 10, 2004 Eugene J. Sullivan, MD, FCCP Deputy Director Division of Pulmonary Drug Products CDER, FDA Center for Drug Evaluation and Research

2. Pulmonary-Allergy Drugs Advisory Committee June 10, 2004 2 OverviewOverview Background Currently marketed albuterol MDI products Essential use criteria Other issues Background Currently marketed albuterol MDI products Essential use criteria Other issues

3. Pulmonary-Allergy Drugs Advisory Committee June 10, 2004 3 BackgroundBackground Dr. Meyer has provided background on the Montreal Protocol, and the FDA regulation concerning the essential use determinations (21 CFR 2.125) The Agency is currently considering whether albuterol has met the criteria for removal from the list of essential uses for CFCs –In keeping with the goals of the Montreal Protocol Phase out of production and importation of ozone- depleting substances (ODSs), including CFCs Approximately ½ of the annual US CFC essential use allocation is for albuterol Two alternative, non-CFC albuterol MDIs are currently marketed in the US –Citizen Petition from “US Stakeholders” group Dr. Meyer has provided background on the Montreal Protocol, and the FDA regulation concerning the essential use determinations (21 CFR 2.125) The Agency is currently considering whether albuterol has met the criteria for removal from the list of essential uses for CFCs –In keeping with the goals of the Montreal Protocol Phase out of production and importation of ozone- depleting substances (ODSs), including CFCs Approximately ½ of the annual US CFC essential use allocation is for albuterol Two alternative, non-CFC albuterol MDIs are currently marketed in the US –Citizen Petition from “US Stakeholders” group

4. Pulmonary-Allergy Drugs Advisory Committee June 10, 2004 4 Currently Marketed Albuterol MDIs CFC MDIs CFCs are Ozone Depleting Substances (ODS) Proventil (Schering-Plough) –approved 1981 –Warrick product also marketed under this NDA Generic versions –Four approved (first approved 1995), three marketed Non-CFC MDIs Non-ODS. HFA-134a does not affect the ozone layer Proventil HFA (3M/Schering-Plough) –Approved and began marketing in 1996 Ventolin HFA (GlaxoSmithKline) –Approved in 2001, and marketed since 2002 CFC MDIs CFCs are Ozone Depleting Substances (ODS) Proventil (Schering-Plough) –approved 1981 –Warrick product also marketed under this NDA Generic versions –Four approved (first approved 1995), three marketed Non-CFC MDIs Non-ODS. HFA-134a does not affect the ozone layer Proventil HFA (3M/Schering-Plough) –Approved and began marketing in 1996 Ventolin HFA (GlaxoSmithKline) –Approved in 2001, and marketed since 2002

5. Pulmonary-Allergy Drugs Advisory Committee June 10, 2004 5 Essential Use Criteria (21 CFR 2.125) 21 CFR 2.125 –“Use of ozone-depleting substances in foods, drugs, devices, or cosmetics” –Lists specific drug moieties for which the use of CFCs is considered “essential” –Sets 4 criteria that must be met in order to remove a drug moiety from the list of “essential uses” 21 CFR 2.125 –“Use of ozone-depleting substances in foods, drugs, devices, or cosmetics” –Lists specific drug moieties for which the use of CFCs is considered “essential” –Sets 4 criteria that must be met in order to remove a drug moiety from the list of “essential uses”

6. Pulmonary-Allergy Drugs Advisory Committee June 10, 2004 6 Essential Use Criteria (21 CFR 2.125) These four criteria are: 1.At least 2 non-ODS products that contain the same active moiety are being marketed with the same route of delivery, for the same indication, and with approximately the same level of convenience of use as the ODS products (For active moieties represented by ≥2 NDAs) [Slide 1 of 2] These four criteria are: 1.At least 2 non-ODS products that contain the same active moiety are being marketed with the same route of delivery, for the same indication, and with approximately the same level of convenience of use as the ODS products (For active moieties represented by ≥2 NDAs) [Slide 1 of 2]

7. Pulmonary-Allergy Drugs Advisory Committee June 10, 2004 7 Essential Use Criteria (21 CFR 2.125) These four criteria are : 2.Supplies and production capacity for the non-ODS products exist or will exist at levels sufficient to meet patient need 3.Adequate US post-marketing use data is available for the non-ODS products 4.Patients who medically require the ODS product are adequately served by the non- ODS products containing the active moiety and other available products [Slide 2 of 2] These four criteria are : 2.Supplies and production capacity for the non-ODS products exist or will exist at levels sufficient to meet patient need 3.Adequate US post-marketing use data is available for the non-ODS products 4.Patients who medically require the ODS product are adequately served by the non- ODS products containing the active moiety and other available products [Slide 2 of 2]

8. Pulmonary-Allergy Drugs Advisory Committee June 10, 2004 8 Essential Use Criteria (21 CFR 2.125) 1.“At least 2 … products … containing the same active moiety, with the same route of delivery, for the same indication, and with approximately the same level of convenience of use…” Same active moiety: albuterol Same route of delivery: oral inhalation Same indication: prevention and relief of bronchospasm in patients 4 [12] years of age and older with reversible obstructive airway disease and the prevention of exercise-induced bronchospasm [Slide 1 of 2] 1.“At least 2 … products … containing the same active moiety, with the same route of delivery, for the same indication, and with approximately the same level of convenience of use…” Same active moiety: albuterol Same route of delivery: oral inhalation Same indication: prevention and relief of bronchospasm in patients 4 [12] years of age and older with reversible obstructive airway disease and the prevention of exercise-induced bronchospasm [Slide 1 of 2]

9. Pulmonary-Allergy Drugs Advisory Committee June 10, 2004 9 Essential Use Criteria (21 CFR 2.125) 1.“At least 2 … products … with the same route of delivery, for the same indication, and with approximately the same level of convenience of use…” Same level of convenience:  Portability  Preparation before use Cleaning of actuator to prevent clogging  Physical effort/ dexterity [Slide 2 of 2] 1.“At least 2 … products … with the same route of delivery, for the same indication, and with approximately the same level of convenience of use…” Same level of convenience:  Portability  Preparation before use Cleaning of actuator to prevent clogging  Physical effort/ dexterity [Slide 2 of 2]

10. Pulmonary-Allergy Drugs Advisory Committee June 10, 2004 10 Essential Use Criteria (21 CFR 2.125) 2.Supplies and production capacity for the non- ODS products exist or will exist at levels sufficient to meet patient need Somewhat difficult because manufacturers (GSK and 3M) would need time to ramp up production GSK has stated that it is “confident that additional internal and external capacity can be installed to ensure adequate supplies and production capacity for Ventolin HFA” and that this could be accomplished within 12-18 months [GSK comment on the Stakeholder’s Citizen Petition, Docket # 2003P-0029/C2] 2.Supplies and production capacity for the non- ODS products exist or will exist at levels sufficient to meet patient need Somewhat difficult because manufacturers (GSK and 3M) would need time to ramp up production GSK has stated that it is “confident that additional internal and external capacity can be installed to ensure adequate supplies and production capacity for Ventolin HFA” and that this could be accomplished within 12-18 months [GSK comment on the Stakeholder’s Citizen Petition, Docket # 2003P-0029/C2]

11. Pulmonary-Allergy Drugs Advisory Committee June 10, 2004 11 Essential Use Criteria (21 CFR 2.125) 3.Adequate US post-marketing use data is available for the non-ODS products Proventil HFA: marketed for 7 years Early reports of actuator clogging No evidence of problems in terms of safety, efficacy, tolerability, patient acceptance Ventolin HFA: marketed for 2 years No evidence of problems in terms of safety, efficacy, tolerability, patient acceptance 3.Adequate US post-marketing use data is available for the non-ODS products Proventil HFA: marketed for 7 years Early reports of actuator clogging No evidence of problems in terms of safety, efficacy, tolerability, patient acceptance Ventolin HFA: marketed for 2 years No evidence of problems in terms of safety, efficacy, tolerability, patient acceptance

12. Pulmonary-Allergy Drugs Advisory Committee June 10, 2004 12 Essential Use Criteria (21 CFR 2.125) 4.Patients who medically required the ODS product are adequately served by the non-ODS products containing the active moiety and other available products “Adequately served” encompasses:  Efficacy/ Safety/ Tolerability √ NDA and post-marketing data  Cost Preamble to 2002 Amendment to 21 CFR 2.125: FDA will consider cost in determining whether alternatives meet patient needs 4.Patients who medically required the ODS product are adequately served by the non-ODS products containing the active moiety and other available products “Adequately served” encompasses:  Efficacy/ Safety/ Tolerability √ NDA and post-marketing data  Cost Preamble to 2002 Amendment to 21 CFR 2.125: FDA will consider cost in determining whether alternatives meet patient needs

13. Pulmonary-Allergy Drugs Advisory Committee June 10, 2004 13 Essential Use Criteria (21 CFR 2.125) “Adequately Served” – the cost issue –Branded CFC products cost more than generics Actual prices vary considerably among payors Retail cost per day*: –$1.44 for Ventolin –$0.69 for CFC generic –Branded HFA products are priced comparably to the branded CFC products “Adequately Served” – the cost issue –Branded CFC products cost more than generics Actual prices vary considerably among payors Retail cost per day*: –$1.44 for Ventolin –$0.69 for CFC generic –Branded HFA products are priced comparably to the branded CFC products *Average National Retail Price; Data from IMS Health, at www.fda.gov/cder/consumerinfo/savingsfromgenerics.htm

14. Pulmonary-Allergy Drugs Advisory Committee June 10, 2004 14 Essential Use Criteria (21 CFR 2.125) “Adequately Served” – The cost issue –Due to existing patents, there are currently no generic HFA products Existing patents will expire in 2010 through 2015 –Given current realities, the removal of the essential use status of albuterol would result in an increase in the price of albuterol MDIs The public health consequences of such an increase are not known and are difficult to predict –Possibly fewer prescriptions filled (albuterol, other) “Adequately Served” – The cost issue –Due to existing patents, there are currently no generic HFA products Existing patents will expire in 2010 through 2015 –Given current realities, the removal of the essential use status of albuterol would result in an increase in the price of albuterol MDIs The public health consequences of such an increase are not known and are difficult to predict –Possibly fewer prescriptions filled (albuterol, other)

15. Pulmonary-Allergy Drugs Advisory Committee June 10, 2004 15 Essential Use Criteria (21 CFR 2.125) “Adequately Served” – The cost issue –Dr. Lutter will discuss the economic aspects in greater detail in the following presentation. This includes descriptions of the various sources of price data, and estimates of how changes in the price of albuterol MDIs might affect utilization. “Adequately Served” – The cost issue –Dr. Lutter will discuss the economic aspects in greater detail in the following presentation. This includes descriptions of the various sources of price data, and estimates of how changes in the price of albuterol MDIs might affect utilization.

16. Pulmonary-Allergy Drugs Advisory Committee June 10, 2004 16 Other Issues Availability of CFCs: Production facilities –Only current source of pharmaceutical grade CFC-11 and CFC-12 for the US is Honeywell’s plant in the Netherlands –The Dutch government has informed Honeywell that CFC production will not be permitted after 2005 –Honeywell states that it will begin production of pharmaceutical grade CFC-11 and CFC-12 at a US plant, and will be able to supply CFCs beyond 2005* Availability of CFCs: Production facilities –Only current source of pharmaceutical grade CFC-11 and CFC-12 for the US is Honeywell’s plant in the Netherlands –The Dutch government has informed Honeywell that CFC production will not be permitted after 2005 –Honeywell states that it will begin production of pharmaceutical grade CFC-11 and CFC-12 at a US plant, and will be able to supply CFCs beyond 2005* [*Docket # 2003P-0029/C9]

17. Pulmonary-Allergy Drugs Advisory Committee June 10, 2004 17 Other Issues Availability of CFCs: Potential actions by the Parties to the Montreal Protocol –CFC “essential use” requests are granted by the Parties annually –Thus far, the Parties have respected the US determination that albuterol is essential, and have granted the CFC volumes requested by the US –However, the Parties have noted the availability of two non-CFC albuterol products in the US, and some have questioned the continued need for CFCs for this purpose –It is not clear how long the Parties will continue to grant CFC requests for use in albuterol MDIs Availability of CFCs: Potential actions by the Parties to the Montreal Protocol –CFC “essential use” requests are granted by the Parties annually –Thus far, the Parties have respected the US determination that albuterol is essential, and have granted the CFC volumes requested by the US –However, the Parties have noted the availability of two non-CFC albuterol products in the US, and some have questioned the continued need for CFCs for this purpose –It is not clear how long the Parties will continue to grant CFC requests for use in albuterol MDIs

18. Pulmonary-Allergy Drugs Advisory Committee June 10, 2004 18 Topics for Discussion 1.Please discuss the extent to which you believe the criteria established in 21 CFR 2.125 for removal of a drug substance from the list of essential uses for CFCs have been met for albuterol. These criteria are: –At least 2 non-ozone depleting substances (non-ODS) that contain the same active moiety are being marketed with the same route of delivery, for the same indication, and with approximately the same level of convenience of use as the ozone-depleting products –Supplies and production capacity for the non-ODS products exist or will exist at levels sufficient to meet patient need –Adequate US post-marketing use data is available for the non-ODS products –Patients who medically require the ODS product are adequately served by the non-ODS products containing the active moiety and other available products 2.Please suggest any additional data or information you believe would be important to consider in making a determination regarding the essential use status of albuterol. 3.Please comment on any additional issues you believe would be important to consider in making a determination regarding the essential use status of albuterol. 1.Please discuss the extent to which you believe the criteria established in 21 CFR 2.125 for removal of a drug substance from the list of essential uses for CFCs have been met for albuterol. These criteria are: –At least 2 non-ozone depleting substances (non-ODS) that contain the same active moiety are being marketed with the same route of delivery, for the same indication, and with approximately the same level of convenience of use as the ozone-depleting products –Supplies and production capacity for the non-ODS products exist or will exist at levels sufficient to meet patient need –Adequate US post-marketing use data is available for the non-ODS products –Patients who medically require the ODS product are adequately served by the non-ODS products containing the active moiety and other available products 2.Please suggest any additional data or information you believe would be important to consider in making a determination regarding the essential use status of albuterol. 3.Please comment on any additional issues you believe would be important to consider in making a determination regarding the essential use status of albuterol.