Pulmonary - Allergy Drugs Advisory Committee Meeting
This meeting is being convened to discuss whether the use of chlorofluorocarbons (CFCs) as propellants in albuterol metered-dose inhalers (MDIs) is no longer an essential use under the criteria in 21 CFR § 2.125(g).
The ozone layer that is present in the earth’s stratosphere helps protects the environment from ultraviolet (UV-B) radiation. Research conducted in the 1970s indicated that when certain synthetic halogenated hydrocarbons (including CFCs) are released into the environment, they can migrate to the stratosphere, where they contribute to the depletion of the ozone layer. While CFCs are very useful compounds due in part to their relative inertness and stability, these properties also contribute to their long residence in the stratosphere. To the extent depletion occurs due to CFCs and other halogenated hydrocarbons in the stratosphere, penetration of the atmosphere by UV-B radiation increases. Increased exposure to UV-B radiation produces health and environmental damage, including increased incidence of skin cancer and cataracts, suppression of the immune system, damage to crops and aquatic organisms, and increased formation of ground-level ozone. The thinning of the ozone layer has been of considerable consequence to public health due to these effects.
The initial hypothesis linking CFCs to the depletion of the stratospheric ozone layer appeared in a paper by Mario J. Molina and F.S. Rowland in 1974. This research later won them the Nobel Prize. Since 1974, the scientific community has made remarkable advances in understanding atmospheric processes affecting stratospheric ozone and in analyzing data measuring ozone depletion, both over the polar regions and globally. In response to the initial research indicating that CFCs could cause stratospheric ozone depletion and thereby lead to damage to human health and the environment, the Food and Drug Administration (FDA), the Evironmental Protection Agency (EPA) and other government agencies acted on March 1978, to ban the use of CFCs as aerosol propellants in all but "essential applications." The 1978 ban reduced the use of CFCs in aerosols in this country by approximately 95 percent, eliminating nearlyhalf of the total
consumption of these chemicals (including banning the use in all consumer aerosols). In order to define what medical uses would be considered “essential,” the FDA promulgated a regulation (21 CFR 2.125) in that same year listing the general categories of its regulated products that would be considered essential uses of CFCs. These uses were predominantly, but not exclusively, MDIs for the treatment of asthma and COPD. U.S.
In 1990, Congress amended the Clean
Air Act to, among other things, better protect stratospheric ozone and to
complement and be consistent with the
In the latter part of the 1990s, FDA undertook revisions to 21 CFR 2.125 to better reflect our obligations under the Montreal Protocol, the 1990 amendments, and EPA's regulations, and to encourage the development of ozone-friendly alternatives to medical products containing CFCs. Specifically, the rule was amended to allow for removal of listed essential uses as acceptable alternatives became available, and this revision contained the necessary criteria for such a finding of non-essentiality. The rule as finalized provided that to remove an essential-use designation, FDA must find that:
§ At least one non-CFC product with the same active drug is marketed with the same route of administration, for the same indication, and with approximately the same level of convenience of use as the CFC product containing that active moiety (while these alternatives are not required to be MDIs, the presumption is that HFA-MDIs would most easily fit this criteria compared to, for example, dry powder inhalers);
§ Supplies and production capacity for the non-CFC product(s) exist or will exist at levels sufficient to meet patient need;
§ Patients who medically required the CFC product are adequately served by the non-ODS product(s) containing that active moiety and other available products.
To remove the essential-use designation of an active moiety marketed in a CFC product represented by one NDA, there must be at least one acceptable alternative, while for an active moiety marketed in ODS products and represented by two or more NDAs, such as albuterol, there must be at least two acceptable alternatives. (Note: a copy of the final rule for 21 CFR 2.125 as revised is in this briefing document).
Albuterol CFC MDIs have become the short-acting,
“reliever” beta agonist of choice in asthma and also are frequently used in
COPD patients as well for the same purpose of achieving relatively rapid bronchodilation.
Over 50 million albuterol canisters are sold or distributed in the
While for much of the early years of albuterol’s availability in the
FDA approved NDA 20-503 for Proventil
HFA, albuterol sulfate MDI, on
Of note, related to these criteria, branded albuterol products (CFC or HFA) are currently approximately $37 retail, with the CFC generic ranging from $14 - $25. In the preamble to 21 CFR 2.125 when its revisions were finalized, FDA had stated that it would consider costs to patients among its consideration of whether the alternatives adequately serve patient’s needs.
In 2003, the FDA received a “Citizen Petition” from the American Lung Association on behalf of a group of involved patient and professional organizations asking FDA to initiate rule making to remove the essential use designation for albuterol While this advisory committee and public meeting on June 10th is not directly responsive to that petition, this petition and the public comments to the petition are relevant to this meeting and therefore are included in the background materials for this meeting. Particularly, there are submissions from GlaxoSmithKline addressing the criteria for removing an essential use designation, including the issues of affordability and manufacturing capacity.
It is important to also understand the global
context of albuterol (called salbutamol in much of
the rest of the world). Due to the
widespread availability of HFA alternatives, albuterol MDIs are
no longer considered an essential
use of CFCs in many developed countries, including
We thank you in advance for your time and consideration in this important matter. We expect that there will be considerable public input and interest in this meeting and we feel that a full consideration of this input by the PADAC will be of great value to the FDA in deciding on whether to remove the essential use designation for albuterol CFC MDIs.