CFC Essential Use Status of Albuterol: Medical Considerations

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CFC Essential Use Status of AlbuterolMedical
Considerations

• 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
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Overview

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

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Background

• 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

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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

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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

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Essential Use Criteria (21 CFR 2.125)

• These four criteria are
• 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

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Essential Use Criteria (21 CFR 2.125)

• These four criteria are
  
• 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
• 
  
  Slide 2 of 2

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Essential Use Criteria (21 CFR 2.125)

• 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

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Essential Use Criteria (21 CFR 2.125)

• 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

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Essential Use Criteria (21 CFR 2.125)

• 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 Stakeholders Citizen
  Petition, Docket 2003P-0029/C2

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Essential Use Criteria (21 CFR 2.125)

• 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

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Essential Use Criteria (21 CFR 2.125)

• 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 v
• 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

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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

Average National Retail Price Data from IMS
Health, at www.fda.gov/cder/consumerinfo/savingsfr
omgenerics.htm
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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)

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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.

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Other Issues

• Availability of CFCs Production facilities
• Only current source of pharmaceutical grade
  CFC-11 and CFC-12 for the US is Honeywells 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
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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

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Topics for Discussion

• 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
• 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.
• Please comment on any additional issues you
  believe would be important to consider in making
  a determination regarding the essential use
  status of albuterol.