NATIONAL TRANSITION STRATEGIES FOR MDIs PROPOSED UNITED STATES
Taken from US Government Printing Office Home Pagehttp://www.access.gpo.gov/index.htm, also available at FDA Home Pagehttp://www.fda.cder.gov.
[Federal Register: March 6, 1997 (Volume 62, Number 44)]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
Chlorofluorocarbon Propellants in Self-Pressurised Containers;
Determinations That Uses Are No Longer Essential; Request for Comments
AGENCY: Food and Drug Administration, HHS.
ACTION: Advance notice of proposed rulemaking.
SUMMARY: The Food and Drug Administration (FDA) is seeking publiccomment on the policy it is considering for adoption on making and implementingdeterminations that uses of chlorofluorocarbons (CFC's) currently designatedessential will no longer be deemed essential under the Clean Air Act due to theavailability of safe and effective medical product technology that does not use
CFC's. Essential-use products are exempt from FDA's ban on the use of CFCpropellants in FDA-regulated products and the Environmental ProtectionAgency's (EPA's) ban on the use of CFC's in pressurised dispensers. The agencyis taking this action because it is responsible for determining which productscontaining CFC's or other ozone-depleting substances are an essential use underthe Clean Air Act. FDA is soliciting comments on this policy to assist the agencyin striking an appropriate balance that will best protect the public health, both byensuring the availability of an adequate number of treatment alternatives and bycurtailing the release of ozone-depleting substances.
DATES: Written comments by May 5, 1997.
ADDRESSES: Submit written comments to the Dockets Management Branch(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23,Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT: Wayne H. Mitchell, Center forDrug Evaluation and Research (HFD-7), Food and Drug Administration, 7500Standish Pl., Rockville, MD 20855, 301-594-2041.
Under Sec. 2.125 (21 CFR 2.125), any food, drug, device, or cosmetic in a self-pressurised container that contains a CFC propellant for a nonessential use isadulterated, or misbranded, or both, under the Federal Food, Drug, and CosmeticAct. This prohibition is based on scientific research indicating that CFC's reducethe amount of ozone in the stratosphere and thereby increase the amount ofultraviolet radiation reaching the earth. An increase in ultraviolet radiation willincrease the incidence of skin cancer, and produce other adverse effects ofunknown magnitude on humans, animals, and plants. Section 2.125(d) exemptsfrom the adulteration and misbranding provisions of Sec. 2.125(c) certainproducts containing CFC propellants that FDA determines provide unique healthbenefits that would not be available without the use of a CFC.
These products are referred to in the regulation as essential uses of CFC's and arelisted in Sec. 2.125(e). Under Sec. 2.125(f), any person may petition FDA torequest additions to the list of uses considered essential. To demonstrate that theuse of a CFC is essential, the petition must be supported by an adequate showingthat: (1) There are no technically feasible alternatives to the use of a CFC in theproduct; (2) the product provides a substantial health, environmental, or otherpublic benefit that would not be obtainable without the use of the CFC; and (3)
the use does not involve a significant release of CFC's into the atmosphere or, if itdoes, the release is warranted by the consequence if the use were not permitted.
EPA regulations implementing the provisions of section 610 of the Clean Air Act(42 U.S.C. 7671i) contain a general ban on the use of CFC's in pressuriseddispensers, such as metered-dose inhalers (MDI's) (40 CFR 82.64(c) and82.66(d)). These EPA regulations exempt from the general ban “medical devices”that FDA considers essential and that are listed in Sec. 2.125(e). Section 601(8) ofthe Clean Air Act (42 U.S.C. 7671(8)) defines “medical device” as any device (asdefined in the Federal Food, Drug, and Cosmetic Act), diagnostic product, drug(as defined in the Federal Food, Drug, and Cosmetic Act), and drug deliverysystem, if such device, product, drug, or drug delivery system uses a class I orclass II ozone-depleting substance for which no safe and effective alternative hasbeen developed (and, where necessary, approved by the Commissioner of Foodand Drugs (the Commissioner)); and if such device, product, drug, or drugdelivery system has, after notice and opportunity for public comment, beenapproved and determined to be essential by the Commissioner in consultationwith the Administrator of EPA (the Administrator). Class I substances includeCFC's, halons, carbon tetrachloride, methyl chloroform, methyl bromide, andother chemicals not relevant to this document (see 40 CFR part 82, appendix A tosubpart A). Class II substances include hydrochlorofluorocarbons (HCFC's) (see40 CFR part 82, appendix B to subpart A).
Production of ozone-depleting substances is being phased out world-wide underthe terms of the Montreal Protocol on Substances that Deplete the Ozone Layer(Montreal Protocol), Sept. 16, 1987, S. Treaty Doc. No. 10, 100th Cong., 1stsess., 26 I.L.M. 1541 (1987). In accordance with the provisions of the MontrealProtocol, under authority of Title VI of the Clean Air Act (section 601 et seq.),manufacture of CFC's in the United States was generally banned as of January 1,1996. To receive permission to manufacture CFC's in the United States after thephaseout date, manufacturers must obtain an exemption from the phaseoutrequirements from the Parties to the Montreal Protocol. Procedures for securingan essential-use exemption under the Montreal Protocol are described in the mostrecent request by EPA for applications for exemptions (60 FR 54349, October 23,1995). Firms that wish to use CFC's manufactured after the phaseout date inmedical devices (as defined in section 601(8) of the Clean Air Act) covered undersection 610 of the Clean Air Act must receive exemptions for essential uses underthe Montreal Protocol.
Faced with the statutorily mandated phaseout of the production of CFC's, drugmanufacturers are developing or have developed alternatives to MDI's and otherself-pressurised drug dosage forms that do not contain ozone-depletingsubstances. Examples of these alternative dosage forms are MDI's that use such
non-ozone-depleting substances as propellants and dry-powder inhalers (DPI's). FDA has recently approved the first CFC-free MDI, 3M Pharmaceuticals Inc.'salbuterol sulfate product, Proventil<Register> HFA; although a determination hasnot yet been made on whether this product is a technically feasible alternative tothe use of CFC's, this approval gives the subject matter of this advance notice ofproposed rulemaking (ANPRM) a particular timeliness. The current or futureavailability of “technically feasible alternatives to the use of a [CFC]” may meanthat the existing listing of a use in Sec. 2.125(e) would no longer reflect currentconditions. It is with this situation in mind that FDA is publishing this ANPRMregarding agency determinations that certain uses of ozone-depleting substancesare no longer essential.
FDA has determined that it would be most productive to set out the followingtentative policy on the elimination of essential uses in an ANPRM. The agencybelieves that providing an opportunity for the fullest public participation at theearliest possible stage in the agency decision-making process in this matter isappropriate to assist FDA in striking an appropriate balance that will best protectthe public health, both by ensuring the availability of an adequate number oftreatment alternatives and by curtailing the release of ozone-depleting substances. In striking this balance, FDA intends to assess a number of factors and isinterested in public comment on them. In establishing its policy on the eliminationof essential uses, FDA will assess the potential beneficial effects of reducing CFCemissions from drug products broadly, based on the amount of CFC emissionsthat would be avoided, the stratospheric ozone depletion that would be averted,and the resulting decline in incidence of UV-B-related adverse human healtheffects, including human cancers and cataracts. FDA will also assess thebeneficial public health effects of continued availability of CFC-containing drugproducts broadly, based on the availability, safety, and efficacy of alternatives, infull consideration of differences in patients' medical circumstances, physiologicalsensitivity, and acceptability of use, among others. FDA is specifically solicitingcomments on how it should develop information to assist in striking this balanceand how it should further balance the need for timely action. FDA also believesthat there is adequate time to publish an ANPRM and respond to comments butwill endeavour to complete this rulemaking process in a timely fashion. Becausethe first potential technically feasible alternatives are just now coming on themarket, it will take a significant amount of time for manufacturers to collect andpresent the post-marketing safety and patient acceptance data that the agency willneed to determine if the products are, in fact, technically feasible alternatives (seesection II.B. of this document).
FDA has tentatively determined that certain uses of CFC's, listed in Sec. 2.125(e)as essential, can no longer be considered to be essential. FDA is consideringproposing to remove these uses from the list of essential uses in a rulemaking tobe initiated soon. Uses no longer considered essential are discussed in sectionII.A. of this document. FDA also expects that certain uses still considered to beessential will cease to be considered essential as new technology develops. Section II.B. of this document describes the policy that FDA has tentativelydetermined will be used in making determinations that these uses of CFC's are nolonger essential. FDA has worked closely with EPA in developing the followingpolicy and this ANPRM reflects those discussions. This policy will also be thesubject of a notice of proposed rulemaking to incorporate the policy into FDAregulations. A. Listed Uses That Are No Longer Considered Essential
1. Metered-Dose Steroid Human Drugs for Nasal Inhalation
Steroid human drugs for nasal inhalation are currently available using meteringatomising pumps rather than nasal MDI's. The availability of such products asBeconase® AQ and Vancenase® AQ (beclomethasone dipropionatemonohydrate), Nasarel® and Nasalide® (flunisolide), Flonase® (fluticasonepropionate), and Nasacort® AQ (triamcinolone acetonide), and the widespreadpatient acceptance of these products, indicate to FDA that using CFC's inmetered-dose steroid human drugs for nasal inhalation can no longer beconsidered to be essential and FDA has tentatively determined to remove the usefrom Sec. 2.125(e).
2. Drug Products That Are No Longer Being Marketed
Several of the essential uses listed in Sec. 2.125(e) exempt only a single approveddrug product and, in a few cases, that drug product is no longer being marketed(or is no longer being marketed in a formulation containing CFC's). FDA hastentatively determined that an essential use for which no drug product is currentlybeing marketed should no longer be considered to be essential. The absence of ademand for the product sufficient for even one company to market it is highlyindicative that the use is not essential. Therefore, FDA has tentatively determinedto remove the following uses from Sec. 2.125(e): Polymyxin B sulfate-bacitracinzinc-neomycin sulfate soluble antibiotic powder without excipients, for topicaluse on humans; and contraceptive vaginal foams for human use. B. Criteria for Determination That a Use Is No Longer Essential
In evaluating petitions submitted under Sec. 2.125(f) requesting that a new use belisted as essential, FDA has not required a showing that technically feasible non-CFC alternatives to a product contain the same active ingredient or active moiety1as the drug product that would be the subject of the proposed essential use. Thus,if other drug products, containing other active moieties, are available fortreatment of the same condition, they may be considered technically feasiblealternatives to the proposed essential-use product. Many of the drug productsmarketed under Sec. 2.125 are pharmacologically closely related, are indicated forthe treatment of the same conditions, and may be considered to be treatmentalternatives. In evaluating whether a use remains essential, FDA believes that it isappropriate to evaluate these treatment alternatives together as a therapeutic class. In this regard, FDA has tentatively determined that metered-dose corticosteroidhuman drugs for oral inhalation and metered-dose short-acting adrenergicbronchodilator human drugs for oral inhalation are appropriate therapeutic classesfor essential-use determinations. The determination of whether drug products thatare not members of either therapeutic class represent essential uses of CFC's willbe made under the criteria set out in section II.B.2. of this document.
FDA has tentatively determined that all drugs currently marketed under Sec. 2.125(e)(2) should be considered to be members of the therapeutic class“metered-dose corticosteroid2 human drugs for oral inhalation.” These drugscontain the following active moieties:
1 21 CFR 314.108(a) defines active moiety as meaning “the molecule or ion, excluding thoseappended portions of the molecule that cause the drug to be an ester, salt (including a salt withhydrogen or coordination bonds), or other noncovalent derivative (such as a complex, chelate, orclathrate) of the molecule, responsible for the physiological or pharmacological action of the drugsubstance.”2 The active ingredients in all drug products currently marketed under the essential use formetered-dose steroid human drugs for oral inhalation are members of the subclass of substancesknown as corticosteroids. FDA has tentatively determined that it would be more accurate to usethe more specific term corticosteroids rather than the more general term steroids to describe thetherapeutic class.
FDA has tentatively determined that drugs containing the following activemoieties currently marketed under Sec. 2.125(e)(3) should be considered to bemembers of the therapeutic class “metered-dose short- acting adrenergicbronchodilator human drugs for oral inhalation”:
Adrenergic bronchodilator drug products containing the active moiety salmeterolare not included in the therapeutic class because of the longer duration of actionand different indication of usage of salmeterol as compared to metered-doseshort-acting adrenergic bronchodilator human drugs for oral inhalation. Adrenergic bronchodilator drug products containing the active moiety epinephrineare also not included in the class because epinephrine is the only active moietyused in drug products sold over-the-counter (OTC). These OTC drug products areavailable to patients who may not have access to prescription drugs. Therefore,FDA has tentatively determined that prescription drug products should not beconsidered as alternatives to drug products containing epinephrine. Thedetermination of whether a drug product containing salmeterol or epinephrineconstitutes an essential use would be considered under the criteria for anindividual active moiety discussed in section II.B.2. of this document.
The use of CFC's in any drug product that is a member of a therapeutic classdescribed above would no longer be considered essential if, for each therapeuticclass:
1. Three distinct alternative products, representing at least two different activemoieties, are being marketed, with the same route of delivery, for the sameindication, and with approximately the same level of convenience of use as theproducts containing CFC's. At least two of the three alternative products must beMDI's.
2. Adequate supplies and production capacity exist for the alternative products tomeet the needs of the population indicated for the therapeutic class.
3. At least 1 year of post-marketing use data for each product are available. Thereshould be persuasive evidence of patient acceptance in the United States of eachof the alternative products.
4. There is no persuasive evidence to rebut a presumption that all significantpatient sub-populations are served by the alternative products.
FDA believes that making essential-use determinations for an entire class ofclosely related drug products will expedite the elimination of drug products thatrelease ozone-depleting substances. FDA recognises that there may be limitedincentives to develop alternative products containing every active moietycurrently marketed under essential-use exemptions. By eliminating the essentialuse by therapeutic class, FDA will ensure that these drugs do not remain on themarket longer than necessary.
FDA also hopes that the knowledge that the essential use covering a givenproduct may be eliminated, even though no alternative product exists containingthe same active moiety as that product, may provide added incentive for themanufacturer of that product to develop an alternative product containing thesame active moiety. In addition, the agency believes that requiring multiplealternative drug products containing multiple active moieties should ensure thatall significant patient populations have safe and effective alternatives to CFC-containing drug products.
A discussion of the application of these criteria can be found in section II.B.3 ofthis document.
Under the proposed policy being considered for elimination of the essential-usestatus of the therapeutic classes, the essential-use status for individual members ofa therapeutic class would only be eliminated when the essential-use status for thetherapeutic class as a whole is eliminated. FDA recognises that this approach mayallow the essential-use status of an individual member of a therapeutic class to beretained despite the marketing of one or more technically feasible alternativescontaining the same active moiety, pending elimination of the essential-use statusfor the therapeutic class as a whole. In addition to the policy FDA is consideringfor elimination of the essential-use status of the therapeutic classes describedabove, FDA is considering a policy for elimination of the essential-use status ofindividual members of a therapeutic class in advance of elimination of theessential-use status for the therapeutic class as a whole. Under this proposedpolicy, the essential-use status of an active moiety within a therapeutic classwould be eliminated when one alternative product that contains the same activemoiety is being marketed. All other elements of the policy regarding therapeuticclasses would apply, including: The alternative product is delivered by the sameroute of administration, for the same indication, and with approximately the same
level of convenience of use; there are adequate supplies and production capacity;at least 1 year of post-marketing use data are available; and there is no persuasiveevidence to rebut a presumption that all significant patient sub-populations usingthat active moiety are served by the alternative product. Therapeutic classeswould still be evaluated under the proposed therapeutic class policy, andalternative products used in the evaluation of the essential-use status of a memberof the therapeutic class under the proposed additional policy would also be usedin the evaluation of the class as a whole. FDA requests public comment on theseapproaches, and other possible approaches, for the elimination of the essential-usestatus of individual members of the therapeutic classes and the therapeutic classesas a whole.
In examining the essential-use status of drug products when FDA has not alreadymade a tentative determination that a currently listed essential use can no longerbe considered to be essential, or when the drug is not a member of one of thetherapeutic classes described in section II.B.1. of this document, FDA will look atother drug products containing the same active moiety as possible technicallyfeasible alternatives. The use of CFC's in any drug product that is not a memberof a therapeutic class described in section II.B.1. of this document would nolonger be considered essential if:
1. One alternative product containing the same active moiety is being marketed,delivered by the same route of administration, for the same indication, and withapproximately the same level of convenience of use compared to the productcontaining CFC's.
2. Adequate supplies and production capacity exist to meet the needs of thepopulation indicated for the alternative drug product containing the active moiety.
3. At least 1 year of post-marketing use data for the product are available. Thereshould be persuasive evidence of patient acceptance in the United States of thealternative product.
4. There is no persuasive evidence to rebut a presumption that all significantpatient sub-populations are served by the alternative product.
A discussion of the application of these criteria can be found in section II.B.3. ofthis document.
Drug products marketed under the following current essential uses wouldgenerally be evaluated under the above “individual active moieties” criteria:
Metered-dose ergotamine tartrate drug products administered by oralinhalation for use in humans.
Intrarectal hydrocortisone acetate for human use.
Anesthetic drugs for topical use on accessible mucous membranes ofhumans where a cannula is used for application.
Metered-dose nitroglycerin human drugs administered to the oral cavity.
Metered-dose cromolyn sodium human drugs administered by oralinhalation.
Metered-dose ipratropium bromide for oral inhalation.
Metered-dose atropine sulfate aerosol human drugs administered by oralinhalation.3
Metered-dose nedocromil sodium human drugs administered by oralinhalation.
Metered-dose ipratropium bromide and albuterol sulfate, in combination,administered by oral inhalation for human use.
Sterile aerosol talc administered intrapleurally by thoracoscopy for humanuse.
As discussed in section II.B.1. of this document, the essential-use status of drugscontaining the active moieties epinephrine and salmeterol will also be evaluatedunder the “individual active moieties” criteria.
FDA requests public comment on the appropriateness of potentially eliminatingsuch essential uses and criteria outlined here.
In arriving at the tentative criteria for evaluating the essential- use status of thetwo therapeutic classes, FDA has kept in mind that the MDI is the most widelyaccepted delivery system for administering drugs by oral inhalation for thetreatment of asthma and chronic obstructive pulmonary disease. Physicians andpatients value an MDI's compact size and ease of use. Because these factors are
3 The evaluation of the essential use status of drug products containing atropine sulfate may be anexception to the application of the criteria set out in section II.B. of this document. Drug productscontaining atropine sulfate were never commercially marketed under Sec. 2.125, but weremanufactured for the U.S. Army for use by armed services personnel. The unique status of this usemay require that other criteria be applied to it.
important and help ensure that patients receive appropriate medical treatment,FDA would require that at least two of the alternative products be available as anMDI. FDA is also aware that not all patients may tolerate a given drug product. Accordingly, FDA has reached the tentative conclusion that there must beproducts representing at least two different active moieties before FDA willconsider that there are technically feasible alternatives to the therapeutic class. FDA is proposing that there be three distinct drug products. FDA wishes to ensurethat there are substantial differences among the alternative products in order togive patients a wide variety of therapeutic options. Therefore, a drug product anda second generic drug product that refers to the first drug product to gainapproval, under section 505(j) of the Federal Food, Drug, and Cosmetic Act (21U.S.C. 355(j)), would not generally be considered to be two distinct drug productsfor purposes of evaluating the essential-use status of the drug.
For most of the essential uses that would be evaluated under the “individual activemoieties” criteria, there is only one product being marketed under each essentialuse. Therefore, requiring the availability of more than one alternative wouldappear to be inadvisable.
Because of their larger size and relative lack of convenience of use, FDA does notconsider currently available nebulisers to be technically feasible alternatives toMDI's. Currently available delivery systems that FDA considers to be technicallyfeasible alternatives to MDI's using CFC's are multiple-dose DPI's4 and MDI'sthat do not contain CFC's. Continuing changes in technology may give FDAreason to revisit this tentative determination.
In evaluating whether adequate supplies and production capacity exist for thealternative product or products to meet the needs of the patient populationindicated for drug products covered by an essential use, FDA's analyses will beflexible, but with one overarching principle: To ensure that there are nosignificant shortages of drug product that could harm the public health of theUnited States. Factors such as multiple production sites, to secure a steady supplyif there is an interruption at one site, would be considered favourably in thisregard.
In evaluating post-marketing use data and evidence of patient acceptance underthe third criterion, FDA anticipates that it may be useful for sponsors ofalternative products to conduct large post-marketing studies, preferably in the
4 Single-dose DPI's that are currently marketed in the United States would not be consideredtechnically feasible alternatives to MDI's using CFC's. The agency has tentatively determined thatthese single-dose DPI's do not approximate the convenience of MDI's because patients must carryboth the single-dose DPI device and a supply of the drug. The patient must also load the deviceprior to each use. The comparative inconvenience of single-dose DPI's does not warrant theirbeing considered technically feasible alternatives. The agency also believes that these single-doseDPI's have not shown adequate levels of patient acceptance.
U.S. clinical practice setting, directly comparing their product which does notcontain CFC's to the CFC-containing product for which it would be considered analternative. It may also be possible for several sponsors to jointly commission alarge post-marketing clinical study of their common products. In addition to theformal studies described above, manufacturers of alternative products, or otherpersons requesting the elimination of an essential use, may wish to submit to FDAa review of post-marketing surveillance data from FDA's MEDWATCHprogramme, the spontaneous reporting systems of other countries, and all otheravailable post-marketing data after a potential alternative product has beenmarketed in the United States for a period of 1 year. FDA has tentativelyconcluded that foreign data would not be considered acceptable as the soleevidence of patient acceptance, but these data will be considered in addition toU.S. post-marketing use data in cases where U.S. formulations and foreignformulations have been shown to be the same or substantially similar. The term“patient acceptance” here assumes that the alternative products have adequatesafety, tolerability, effectiveness, and compliance. Because information regardingpatient acceptance is not routinely captured by post-marketing surveillance, suchassessments should be incorporated into the proposed formal clinical studies.
In evaluating the last criterion, that there is no persuasive evidence to rebut apresumption that all significant patient sub-populations are served by thealternative product, FDA believes that there should be a strong presumption that,if the first three criteria are met, then all relevant sub-populations will beadequately served by alternative products. If FDA is not already in possession ofevidence indicating the presence of a sub-population served only by a productcontaining CFC's, then the burden of producing compelling scientific evidencethat there is a sub-population served only by a product containing CFC's would beplaced on anyone opposing the determination that a use is no longer essential.
FDA currently intends to publish a notice of proposed rulemaking after thecomment period for this ANPRM closes. That proposed rule would eliminateessential uses for steroid human drugs for nasal inhalation and for drugs that areno longer marketed. The proposed rule would also codify the criteria forelimination of essential uses discussed in section II.B. of this document. FDAintends to use the preamble of the proposed rule to respond to comments on thisANPRM.
As the criteria for eliminating essential uses are met, FDA will proposeelimination of essential uses for the appropriate therapeutic classes or individualactive moieties. FDA intends that such proposals will be published and finalisedin an expeditious manner.
FDA is aware that the proposed policy contained in this ANPRM is, to a certaindegree, predicated on the assumption that drug manufacturers are aggressivelydeveloping alternatives to products containing CFC's. If this assumption is lessthan fully met, FDA recognises that it may have to take an even more active rolein encouraging the development of technically feasible alternatives. Furthermore,FDA contemplates re-examining the effectiveness of the policy set out in thisANPRM 1 to 3 years after the publication of the first final rule implementing thepolicy set out in this ANPRM. If this re-examination reveals that alternatives toCFC's are not being aggressively developed, FDA will consider eliminatingessential uses where manufacturers of drug products covered by those uses havenot demonstrated due diligence in developing alternative products.
FDA is required to examine the impacts of its proposed rules under ExecutiveOrder 12866 and the Regulatory Flexibility Act (5 U.S.C. 601- 612). ExecutiveOrder 12866 directs agencies to assess all costs and benefits of availableregulatory alternatives and, when regulation is necessary, to select regulatoryapproaches that maximise net benefits (including potential economic,environmental, public health and safety, and other advantages; distributiveimpacts; and equity). The Regulatory Flexibility Act requires agencies to analyseregulatory options if the proposed rule is expected to have a significant impact ona substantial number of small entities. FDA is soliciting information and data tohelp it examine the impacts that a proposed rule based on this advance noticewould have. In order to help the agency prepare these analysis, FDA requestscomments on the following impact questions:
1. Are the incentives discussed in the ANPRM adequate to spur the neededmarket innovation? Are there alternative means of introducing appropriate marketincentives?
2. Assuming that an alternative product is approved for marketing, what is theestimated cost of obtaining post-marketing data supporting the new product as atechnologically feasible alternative? How much time would be necessary? Whatother costs should the agency consider?
3. How much would it cost to obtain the data including the post-marketing studydiscussed in the ANPRM? How much would it cost to obtain the data excludingsuch a post-marketing study? What are the components of this estimate (e.g.,person-hours, contract dollars, etc.)?
4. How much time should be allowed for phasing out a CFC-containing productno longer considered essential?
5. Are there other alternative policies that the agency should consider that wouldachieve the stated goals and be less burdensome to patients that use these productsand/or to the industry that provides the products?
III. Other Rulemaking Proceedings Regarding CFC's
In the very near future, FDA intends to propose a rule regarding criteria to beapplied in agency determinations to add new essential uses to Sec. 2.125(e). Theagency is not soliciting comments on this separate rulemaking proceeding, and isonly mentioning the matter here to provide a more complete picture of FDA'scurrent plans regarding the regulation of CFC-containing drug products. FDAdoes not intend to respond to any comments regarding this issue at this time; thosepersons wishing to comment on this issue should wait until the proposed rule ispublished.
Consistent with the phaseout provisions of the Clean Air Act, the proposed ruleregarding the addition of new essential uses will provide new and substantiallymore stringent criteria for determining that a use is essential. Specific criteria willbe proposed for both investigational drugs and commercially marketed drugs.
FDA currently intends that this proposed rule will provide a restructuring of Sec. 2.125(e) to eliminate essential uses that cover an entire class of drugs, such ascurrent Sec. 2.125(e)(3) “metered- dose adrenergic bronchodilator human drugsfor oral inhalation.” In their place, FDA will propose to list the use of every activemoiety currently marketed under the current class essential use. This will meanthat an individual wishing to market, for example, an adrenergic bronchodilatorwhere the active moiety is not listed will need to petition FDA to amend Sec. 2.125(e) to add the use of the active moiety.
The proposed rule would also eliminate out-of-date transitional provisions, andmake other similar non-substantive housekeeping changes.
The agency has determined to go directly to a proposed rule on these provisionsof the agency's policy, rather than requesting comment on them in this or anotherANPRM, in order to accelerate consideration of the new more stringent criteriafor determining when new uses are essential. FDA believes that as the agency willsoon be eliminating essential uses, it would be a waste of scarce agency resources,as well as inconsistent with the general policy favouring the phase out of ozone-depleting substances, to create new essential uses unless an extraordinary showingof public benefit can be made.
Interested persons may, on or before May 5, 1997, submit to the DocketsManagement Branch (address above) written comments regarding this ANPRM. Two copies of any comments are to be submitted, except that individuals may
submit one copy. Comments are to be identified with the docket number found inbrackets in the heading of this document. Received comments may be seen in theoffice above between 9 a.m. and 4 p.m., Monday through Friday.
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