Metered-dose inhaler formulations of bronchodilators and corticosteroids that contain chlorofluorocarbons could be banned once "three distinct" non-CFC products are available, FDA said in an advance notice of proposed rulemaking published March 6.

The agency is tentatively proposing that metered-dose corticosteroid inhalers and metered-dose short-acting bronchodilator inhalers would lose their "essential use" exemption from the ban on CFC-containing products when three alternative products are available, provided those products represent "at least two different active moieties...with the same route of delivery, for the same indication, and with approximately the same level of convenience of use as the products containing CFCs." In addition, FDA proposes, at least two of the three products would have to be MDIs.

FDA lists three caveats to determining that a product represents a genuine alternative: (1) "Adequate supplies and production capacity exist for the alternative products to meet the needs of the population indicated for the therapeutic class"; (2) "At least one year of postmarketing use data for each product are available...[providing] persuasive evidence of patient acceptance in the U.S. of each of the alternative products"; and (3) "There is no persuasive evidence to rebut a presumption that all significant patient subpopulations are served by the alternative products."

Products covered by the two therapeutic classes identified in the notice include the inhaled corticosteroids beclomethasone, dexamethasone, flunisolide, fluticasone and triamcinolone; and the inhaled bronchodilators albuterol, bitolterol, isoetharine, isoproterenol, metaproterenol, pirbuterol and terbutaline.

"FDA recognizes that there may be limited incentives to develop alternative products containing every active moiety currently marketed under essential-use exemptions," the notice states. "By eliminating essential use by therapeutic class, FDA will ensure that these drugs do not remain on the market longer than necessary." FDA "also hopes that the knowledge that the essential use covering a given product may be eliminated, even though no alternative product exists containing the same active moiety as that product, may provide added incentive for the manufacturer of that product to develop an alternative product containing the same active moiety," the notice states.

Two bronchodilators, epinephrine and salmeterol, are not included in the class for purposes of the CFC rule. FDA explains that salmeterol (Glaxo Wellcome's Serevent) has "a longer duration of action and different indication" than other bronchodilators, while epinephrine is available over-the-counter to "patients who may not have access to prescription drugs."

The FDA notice includes a separate list of "individual active moieties" to cover agents not included in the two therapeutic classes. In addition to salmeterol and epinephrine, the list includes metered-dose versions of ergotamine, nitroglycerin, cromolyn sodium, nedocromil sodium, ipratropium, atropine, and ipratropium/ albuterol, as well as intrapleural aerosol talc, intrarectal hydrocortisone and topical anesthetic sprays.

For "individual" products, FDA is proposing to remove the essential use exemption when "one alternative product containing the same active moiety is being marketed, delivered by the same route of administration, for the same indication, and with approximately the same level of convenience of use."

FDA again adds the caveat that adequate supply must be available, there must be at least one year of post-marketing experience with evidence of patient acceptance in the U.S., and there must be no "persuasive evidence" that specific subgroups need the CFC-containing product. Individual members of the corticosteroid and bronchodilator classes could be removed on the same grounds, the notice states.

The agency is tentatively proposing that two groups of products would lose their essential use exemption right away: CFC-containing nasal steroid inhalers and products that are no longer being marketed.

"Because of their larger size and relative lack of convenience of use, FDA does not consider currently available nebulizers to be technically feasible alternatives to MDIs," the notice declares. "Currently available delivery systems that FDA considers to be technically feasible alternatives to MDIs using CFCs are multiple-dose [dry-powder inhalers] and MDIs that do not contain CFCs."

FDA has "tentatively determined" that single-dose DPIs are not feasible alternatives because they "do not approximate the convenience of MDIs" since "patients must carry both the single-dose DPI device and a supply of the drug." The "agency also believes that these single-dose DPIs have not shown adequate levels of patient acceptance," the notice declares. "Continuing changes in technology may give FDA reason to revisit" its tentative determination about feasible substitutes, the notice adds.

FDA points out that the first CFC-free metered dose inhaler, Schering-Plough/3M's Proventil HFA, recently entered the market. "Although a determination has not yet been made on whether this product is a technically feasible alternative to the use of CFCs, this approval gives the subject matter of this advance notice of proposed rulemaking a particular timeliness," the notice states.

If the agency's final policy takes the form of the March 6 proposal, the continued availability of CFC-containing albuterol MDIs would appear to hinge on Schering's ability to demonstrate patient acceptance of Proventil HFA. Schering has indicated that it may consider withdrawing its CFC-containing albuterol line once HFA is established ("The Pink Sheet" Oct. 28, T&G-2).

"FDA anticipates that it may be useful for sponsors of alternative products to conduct large postmarketing studies, preferably in the U.S. clinical practice setting, directly comparing their product which does not contain CFCs to the CFC-containing product for which it would be considered an alternative," the notice states. "It may also be possible for several sponsors to jointly commission a large postmarketing clinical study of their common products."

"Because information regarding patient acceptance is not routinely captured by postmarketing surveillance, such assessments should be incorporated into the proposed formal clinical studies," the notice states. "FDA has tentatively concluded that foreign data would not be considered acceptable as the sole evidence of patient acceptance, but these data will be considered in addition to U.S. postmarketing use data in cases where U.S. formulations and foreign formulations have been shown to be the same or substantially similar."

"In evaluating whether adequate supplies and production capacity exist for the alternative product or products to meet the needs of the patient population...FDA's analyses will be flexible, but with one overarching principle: To ensure that there are no significant shortages of drug product that could harm the public health," the notice declares. "Factors such as multiple production sites, to secure a steady supply if there is an interruption at one site, would be considered favorably in this regard."

FDA is asking for comments on the proposal within 60 days. Specific topics FDA would like addressed include the cost of obtaining postmarketing data to demonstrate that a non-CFC product is a feasible alternative and the amount of time to allow for phasing out of CFC-containing products no longer considered essential.

CFC-CONTAINING ASTHMA MDIs COULD BE BANNED WHEN "THREE DISTINCT ALTERNATIVES" ARE AVAILABLE; ONE YEAR MARKETING OF NON-CFC ALTERNATIVES REQUIRED -- FDA

More from Archive

More from Pink Sheet