CFC Essential Use Status of CFC Essential Use Status of Albuterol:Albuterol:Medical ConsiderationsMedical Considerations

CFC Essential Use Status of CFC Essential Use Status of Albuterol:Albuterol:Medical ConsiderationsMedical Considerations

Pulmonary-Allergy Drugs Advisory Committee Meeting Pulmonary-Allergy Drugs Advisory Committee Meeting June 10, 2004June 10, 2004

Eugene J. Sullivan, MD, FCCPDeputy DirectorDivision of Pulmonary Drug ProductsCDER, FDA

Pulmonary-Allergy Drugs Advisory Committee Meeting Pulmonary-Allergy Drugs Advisory Committee Meeting June 10, 2004June 10, 2004

Eugene J. Sullivan, MD, FCCPDeputy DirectorDivision of Pulmonary Drug ProductsCDER, FDA

Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research

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

OverviewOverviewOverviewOverview

• Background• Currently marketed albuterol MDI products• Essential use criteria• Other issues

• Background• Currently marketed albuterol MDI products• Essential use criteria• Other issues

3Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee June 10, 2004June 10, 2004

BackgroundBackgroundBackgroundBackground

• 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

4Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee June 10, 2004June 10, 2004

Currently Marketed Albuterol MDIsCurrently Marketed Albuterol MDIsCurrently Marketed Albuterol MDIsCurrently 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

5Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee June 10, 2004June 10, 2004

Essential Use Criteria Essential Use Criteria (21 CFR 2.125)(21 CFR 2.125)

Essential Use Criteria Essential Use Criteria (21 CFR 2.125)(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”

6Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee June 10, 2004June 10, 2004

Essential Use Criteria Essential Use Criteria (21 CFR 2.125)(21 CFR 2.125)

Essential Use Criteria Essential Use Criteria (21 CFR 2.125)(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]

7Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee June 10, 2004June 10, 2004

Essential Use Criteria Essential Use Criteria (21 CFR 2.125)(21 CFR 2.125)

Essential Use Criteria Essential Use Criteria (21 CFR 2.125)(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]

8Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee June 10, 2004June 10, 2004

Essential Use Criteria Essential Use Criteria (21 CFR 2.125)(21 CFR 2.125)

Essential Use Criteria Essential Use Criteria (21 CFR 2.125)(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]

9Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee June 10, 2004June 10, 2004

Essential Use Criteria Essential Use Criteria (21 CFR 2.125)(21 CFR 2.125)

Essential Use Criteria Essential Use Criteria (21 CFR 2.125)(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]

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

Essential Use Criteria Essential Use Criteria (21 CFR 2.125)(21 CFR 2.125)

Essential Use Criteria Essential Use Criteria (21 CFR 2.125)(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]

11Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee June 10, 2004June 10, 2004

Essential Use Criteria Essential Use Criteria (21 CFR 2.125)(21 CFR 2.125)

Essential Use Criteria Essential Use Criteria (21 CFR 2.125)(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

12Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee June 10, 2004June 10, 2004

Essential Use Criteria Essential Use Criteria (21 CFR 2.125)(21 CFR 2.125)

Essential Use Criteria Essential Use Criteria (21 CFR 2.125)(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

13Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee June 10, 2004June 10, 2004

Essential Use Criteria Essential Use Criteria (21 CFR 2.125)(21 CFR 2.125)

Essential Use Criteria Essential Use Criteria (21 CFR 2.125)(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

14Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee June 10, 2004June 10, 2004

Essential Use Criteria Essential Use Criteria (21 CFR 2.125)(21 CFR 2.125)

Essential Use Criteria Essential Use Criteria (21 CFR 2.125)(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)

15Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee June 10, 2004June 10, 2004

Essential Use Criteria Essential Use Criteria (21 CFR 2.125)(21 CFR 2.125)

Essential Use Criteria Essential Use Criteria (21 CFR 2.125)(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.

16Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee June 10, 2004June 10, 2004

Other IssuesOther IssuesOther IssuesOther 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]

17Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee June 10, 2004June 10, 2004

Other IssuesOther IssuesOther IssuesOther 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

18Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee June 10, 2004June 10, 2004

Topics for DiscussionTopics for DiscussionTopics for DiscussionTopics for Discussion1. 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.