Denied - FDA Lawyers Blog

DEPARTMENT OF HEALTH &. HUMAN SERVICES
Edward John AHera
Buchanan Ingersoll & Rooney PC
1700 K Street, N. W., Suite 300
Washington, DC 20006-3807
MAR
1 2011
Food and Drug Administration
Rockville MD 20857
Re: Docket No. FDA-2008-P-0219
Dear Mr. AHera:
This letter responds to the citizen petition that you submitted on behalf of the Tannates
Working Group, an unincorporated association of manufacturers, suppliers, and
distributors of tannate-containing products (the Tannates Working Group), which was
received b(' the Food and Drug Administration (FDA or the Agency) on January 3, 2008
(Petition). The Petition requests that FDA:
1. recognize and confirm that FDA has a history of regulating cough/cold products
on an active therapeutic moiety basis;
2. recognize and confirm that the long history of safe and effective use of many
cough/cold active therapeutic moieties 2 ~ regardless of the particular salt form
- has rendered these moieties generally recognized as safe and effective
(GRASfE) which requires rulemaking for any changes in the regulation of these
drugs;
3. recognize and confirm that the regulation of active pharmaceutical ingredients
(APIs)3 such as chlorpheniramine, dexchlorpheniramine, brompheniramine,
dexbrompheniramine, pheniramine, pyrilamine, phenindamine, pseudoephedrine,
and dextromethorphan in their tannate salt form is no different from the regulation
of the cough/cold APIs in other salt forms such as maleates, sulfates,
hydrobromides, or hydrochlorides;
I
This citizen petition was originally assigned docket number 2008P-OO IOICP 1. The number was changed
to FDA-2008-P-02l9 as a result of FDA's transition to its new docketing system (Regulations.gov) in
January 2008.
2 The term active therapeutic moiety as used in the Petition is considered synonymous with the term active
moiety which is defined in 2) CFR 314.108 to mean "the molecule or ion, excluding those appended
portions of the molecule that cause the drug to be an ester, salt, ..., or other noncovalent derivative ... of
the molecule, responsible for the physiological or pharmacological action of the drug substance."
3 The term API as used in this instance in the Petition is considered to mean the active moiety present in the
drug product (see note 2). In this response, the term drug product is used to mean "a fin ished dosage form,
for example, tablet, capsule, or solution, that comains a drug substance, generally, but not necessarily, in
association with one or more other ingredients" as defined in 21 CFR 314.3; the term drug substance
means an "active ingredient that is intended to furnish pharmacological activity or other direct effect in the
diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of
the human body .... ," also as defined in § 314.3. The term active moiety is used refer to as defined in 2 J
CFR 314.108. Thus, for instance, a carbetapentane tannate tablet would be a drug product; carbetapentane
tannate would be the drug substance (or active ingredient); and carbetapentane would be the active moiety
(or API as used in this instance in the Petition).
4. recognize and confirm that certain coughcold drug products containing tanates
are legally peritted to remain on the market based on history of
use, FDA's
"rush-to-market" regulation, and the professional labeling for the coughcold
monograph;
5. recognize and confirm that there is no legal impediment to the same API being
simultaneously marketed in both prescription and over-the-counter (OTC) drugs
in light of the fact that the OTC coughcold monograph provides for professional
labeling of aTe drugs, thus creating a "meaningful difference" between the
products;
6. recognze and confirm that FDA has regulated this area by rulemaking for almost
40 years and any change in regulation must be made via the rulemaking process;
and
7. review the issues and data set forth in your Petition and refrain from takng any
categorical enforcement action against coughcold drug products containing
tanates.
FDA has carefully considered the information submitted in your Petition and other
relevant data available to the Agency. Based on our review of these materials and for the
reasons described below, your Petition is denied.
I. BACKGROUND
As your Petition touches on several areas of
food and drug law, it is important to consider
the statutory and regulatory framework of the relevant provisions of the law in our
response. Accordingly, the following subjects are discussed below: (A) the generally
recognized as safe and effective (GRAS/E) standard; (B) the Drg Efficacy Study
Implementation (DESI) review; and (C) the over-the-counter (OTC) drug review for
coughcold products. The background section ends with section D on tanate products
specifically. The Agency's analysis of
to the relief
these topic areas and their application
requested follows in the discussion section.
A. The Generally Recognized As Safe And Effective (GRASIE) Standard
Under the Federal Food, Drug, and Cosmetic Act (the Act), a drug can be lawfully
marketed without an application only ifit is not a new drug, or if
it satisfies one of
two
"grandfather" clauses.
Under section 201(P) of
the Act (21 U.S.C. 321(P)), the term new drug means:
(I) Any drg . . . the composition of which is such that such drg is not generally
recognzed, among experts qualified by scientific traing and experience to
4 Your Petition has not raised the question of whether taate products might be grandfathered under either
the 1938 or 1962 grandfather clauses. See 21 U.S.C. 321(P)(l); Pub. L. 87-781, section 107 (reprited
following 21 V.S.C.A. 321)). Thus, ths response will not address the issue of grandfathered drgs.
2
evaluate the safety and effectiveness of drgs, as safe and effective for use under
the condition prescribed, recommended, or suggested in the labeling thereof. . . ;
or (emphasis added)
(2) Any drug. . . the composition of
which is such that such drg, as a result of
investigations to determine its safety and effectiveness for use under such
conditions, has become so recognized, but which has not, otherwise than in such
investigations, been used to a material extent or for a material time under such
conditions.
the Act, a drug is a new drug ifits "composition" is such
that the drug "is not generally recognzed, among experts qualified by scientific training
and experence to evaluate the safety and effectiveness of drugs, as safe and effective for
use under the conditions prescribed, recommended, or suggested in the labeling thereof'
Thus, under section 201(P) of
(not GRAS/E). Further under section 201(P) a drug that is so recognzed is stil a new
drug if it has not "been used to a materal extent (i.e., long use) or for a material time
under such conditions."
This definition includes two separate criteria, either of which is suffcient to make a
product a new drug: (1) lack of general recognition of safety and effectiveness and (2)
insufficient duration and extent of
use: In other words, evidence of
use for a material
time and to a materal extent alone is insuffcient to render a product not a new drug; it
must also be GRAS/E. Conversely, a GRAS/E drug that has not been used for a material
time and to a material extent wil be considered a new drug.
The legal standard for determining whether a drug product is GRAS/E within the
meaning of
section 201(P) of
the Act is well-established in case law and requires that a
drug product satisfy three criteria.5 First, the particular drug product must have been
subjected to adequate and well-controlled clinical investigations establishing that the
product is safe and effective.6 Second, those investigations must have been published in
the scientific literatue so that they are available to qualified expers.7 Third, experts
must generally agree, based on those published studies, that the product is safe and
5 See Weinberger v. Bentex Pharms., Inc., 412 U.S. 645, 652-653 (1973) (establishig standad); Premo
Pharm. Labs., Inc. v. United States, 629 F.2d 795,803-804 (2d Cir. 1980) (same).
6 See Weinberger v. Bentex Pharms., 412 U.S. 645 at 652-653 ; Weinberger v. Hynson, Westcott &
Dunning, 412 U.S. 609, 629-630 (1973); United States v. 50 Boxes, 721 F. Supp. 1462, 1465-1466 (D.
Mass. 1989), afd. United States v. 50 Boxes. 909 F.2d 24 (ltCir.Mass. 1990); United States v. 225
Drug, 826 F.2d 564 (7th Cir. Il.
1987); United States v. Articles of Drug, 745 F.2d. 105, 118-119 (1 sl Cir. P. R. 1984); see also 21 CFR
314.200(e)(I).
Cartons, 871 F.2d 409,413 (3rd Cir. N.J. 1989); United States v. Articles of
7 See Weinberger v. Bentex Pharms., 412 U.S. 645 at 652; United States v. An Article of Drug Consisting of
4,680 Pails, 725 F.2d 976, 987 (5th Cir. Tex. 1984); Premo Pharm. Labs., 629 F.2d 795 at 803; United
States v. Seven Cardboard Cases, 716 F. Supp. 1221, 1223-1224 (E.D. Mo. 1989); United States v. 118/100
Tablet Bottles (Margesic), 662 F. Supp. 511,513 (W. D. La. 1987).
3
effective for its intended uses.s A product's general recognition as safe and effective
must be evidenced by at least the same quality and ~uantity of data as are necessar to
support approval of a new drug application (NDA).
adequate and wellcontrolled clinical investigations. To be adequate and well-controlled, a study must, for
example, enroll a sufficiently large number of adequately characterized study
FDA's regulation at 21 CFR 314.126 describes the characteristics of
paricipants; have at least one control group; minimize bias (usually through random
assignents of study participants to control and treatment groups and through the
participants and investigators to those assignents); and analyze the results of
blinding of
the study adequately to assess the effects ofthe treatment. 10 One ofthe purposes of
requiring rigorously controlled investigations is to ensure that the drug products taken by
I
I
patients have been shown to be safe and effective based on accepted scientific methods.
Rigorously controlled clinical investigations help distinguish the effect of a drug from
other influences, such as spontaneous change in the course of the disease, placebo effect,
b. db' 12
or iase 0 servation.
eourts have noted that the issue in a "new drug" inquiry is not whether a drug is safe and
effective but whether there is general scientific recognition of
the drug's safety and
effectiveness.13 Hence the requirement that studies used to establish that a drug is
the studies are not publicly available to scientists, there
can be no scientific basis for general recognition.
GRAS/E must be published - if
It is also well-established that anecdotal data, such as the clinical experence of practicing
use, cannot be the basis for finding that it is
GRAS/E. Only substantial evidence as defined by the Act wil suffice to establish that a
drug is not a new drug.I4 The requirement that GRAS/E status be based on the same
physicians, or a drug's long history of
8 See
Premo Pharm. Labs., 629 F.2d 795 at 802-803; Seven Cardboard Cases, 716 F. Supp. 1221 at 1223;
118/100 Tablet Bottles (Margesic), 662 F. Supp. 511 at 514.
9 See Weinberger v. Hynson, Westcott & Dunning, 412 U.S. 609, 629-30 (1973); 50 Boxes, 721 F. Supp.
1462 at 1465-1466, affd. United States v. 50 Boxes, 909 F.2d 24 OSI Cir. 1990); 225 Cartons, 871 F.2d 409
Drug, 826 F.2d 564;
Articles of
Drug, 745 F. 2d. 105 at 118-119; see also FDA
regulations at 21 CFR 314.200(e)(1).
at 413; Articles of
lO 21 CFR 314.126
II Id.
12Id.
13 United States v. Undetermined Quaritities of
Various Articles of
Drug . . ., 675 F.2d 994,1000 (8th Cir.
Mo. 1982); Premo Pharm. Labs., 629 F.2d 795 at 803-804.
14 See Weinberger v. Hynson, Westcott & Dunning, 412 U.S. 609 at 619; 50 Boxes, 909 F.2d 24 at 27-28;
225 Cartons, 871 F.2d409 at 418-419; An Article of
Drug Consisting of 4,680 Pails, 725 F.2d 976 at 987;
50 Boxes, 721 F. Supp. 1462 at 1465-1467, affd. United States v. 50 Boxes, 909 F.2d 24; Seven Cardboard
Drug. . . Hormonin, 498 F. Supp. 424, 431-
Cases, 716 F. Supp. 1221 at 1223; United States v. Articles of
432 (D. N. J. 1980).
4
quantity and quality of evidence that would support approval of an NDA is also reflected.
in FDA regulations at 21 CFR 314.200(e)(1). 15
Finally, because the Supreme Court has held that the word "drug" in the "new drug"
definition refers to the entire finished product, including excipients, and not just to the
active ingredient,16 cours generally have not been receptive when firms seek to rely on
studies of one drug product to support a claim that their similar or identical drug product
is GRASIE. 17 The case law is clear that having the same active ingredient as an approved
or otherwise safe and effective drug product does not establish that a drug product is
GRASIE; therefore, GRASIE status canot be confered on one drug product because it
has the same active ingredient as another drug product that is GRAS/E. In short,
GRAS/E status is not and cannot be established by similanty to another drug product. 18
Each drug product must independently be shown to be safe and effective in adequate and
well-controlled clinical investigations.
B. The DESI Review
In i 962, Congress amended the Act to require that new drugs be proven effective, as well
as safe, for their labeled indications to obtain FDA approval (the Kefauver-Hars
Amendments, Public Law 87-781 (1962)). This amendment also required FDA to
conduct a retrospective evaluation of the effectiveness of the drug products that FDA had
approved as safe between 1938 and 1962. FDA contracted with the National Academy of
ScienceslNational Research eouncil (NASINRC) to make an initial evaluation ofthe
effectiveness ofthese drg products. The NASINRC created panels to conduct the
15 We recognze that the tannate products referenced in your Petition are not curently the subject of an
adminstrative hearig, and the reference to 21 CFR 314.200, which pertins to that context, is not meant to
suggest either that they are or that such a hearg would be required. However, the amount and tye of
the
documentation necessar to demonstrate that a drg product is GRAS/E is the same regardless of
. context.
16 United States v. Generix Drug Corp., 460 U.S. 453 (1983).
17225 Cartons, 871 F.2d 409 at 417-418; United States v. Atropine Sulfate, 843 F.2d 860 (5th Cir. 1988);
Drug, 745 F. 2d. 105 at 117-118; Seven Cardboard Cases, 716 F. Supp. 1221 at 1224-1225. A
few cour that have faced most directly the issue of the applicabilty of studies of another drg to the drug
Articles of
at issue have suggested that they might permt use of
those studies if
there was evidence that the drg at
issue was bioequivalent to the studied drug (225 Cartons, 871 F.2d 409 at 417-418; United States v.
Article of
Drug, 709 F. Supp. 511 (D. N. J. 1987)). To date, no court has
Undetermined Quantities of
actully found a drg to be GRAS/E based on adequate and well-controlled studies of another drg and
evidence ofbioequivalence.
18 Likewise, passage of
the Hatch-Waxman Amendments to the Act in 1984 provides evidence of
congressional intent to subject drgs that share very similar characteristics to the application requirement.
Under the Hatch-Waxman Amendments, drgs that are bioequivalent to drugs with approved NDAs stil
need approved abbreviated new drg applications (ANAs). This requirement enables FDA to evaluate
active ingredients, inactive ingredients, labeling, chemical, manufactug, and controls, and other factors,
in addition to bioequivalence, tht combine to determne the safety and effectiveness of a finished drg
product.
5
19 The NASINRC reports
review, which was broken down into specific drug categories.
for these drug products were submitted to FDA, which reviewed and re-evaluated the
findings. FDA then published its findings in Federal Register notices.2o FDA's
administrative implementation of
the NASINRC reports was called the Drug Effcacy
Study Implementation (DESi).21
The Federal Register notices FDA published under DESI set forth the Agency's
conclusions and assessments of whether, and under what circumstances, the reviewed
drug products were considered "effective" for use as required by the Act. 22 The Agency
assessed the drg products as either effective, probably effective, possibly effective, lacks
substantial evidence of effectiveness (i.e., ineffective), and ineffective as a fixed
combination.23 For drug products that lacked sufficient evidence on which to base a
determination as to effectiveness, FDA also deterined whether additional time was
warranted to further study the drug product.24 The Federal Register notices identified by
name and NDA number each drg specifically
reviewed in a proceeding.25
I had pre-1962 applications, they were
Because all drug products reviewed under DES
the ultimate effectiveness
classification - contained a finding that the covered drug products were new drugs and
that they required an application approved for both safety and effectiveness to be legally
marketed.26 If a drug product was determined to be effective for one or more indications,
the applicant was required to submit a supplement seeking approval of amended labeling
consistent with the DESI findings.27 If the drug product was found to lack substantial
considered new drugs, and all DES
I notices - regardless of
" -
evidence of effectiveness for all labeled indications, its application was withdrawn.28
19 Drug Effcacy Review, Final Report to the Commissioner of
Food and Drugs, FDA, from the Division of
Sciences, Washington, DC, 1969 (The
Medical Sciences, National Research Council, National Academy of
DESI Final Report).
20 Guidance for FDA staff and industr, Marketed Unapproved Drugs - Compliance Policy Guide
History ofFDA Marketing Approval Requirements
Drugs That Lack Required FDA Approval, at 8.
(Marketed Unapproved Drugs, CPG), Appendix: Brief
and Categories of
21Id.
22Id.
23 The DESI Final Report, at 7.
24 Conditions for Marketing New Drugs Evaluated in Drug Effcacy Study, 35 FR 11273 (July 14, 1970).
25 21 CFR 310.6.
26 Marketed Unapproved Drugs CPG at 9.
27Id.
28Id.
6
Between 1938 and 1962, if
a drug obtained approval, FDA considered drugs that were
identical, related, or similar (IRS) to the approved drug tobe covered by that approval,
and allowed those IRS drugs to be marketed without independent approval. DESI
covered the products specifically reviewed by the NASINRC panels as well as those IRS
products that had entered the market without PDA approval. 29 When FDA implemented
I review, the Agency realized that it would be both inequitable and inconsistent
the DES
with the purpose of
the Kefauver-Hars Amendments to require drugs that had been
approved between 1938 and 1962 to prove their effectiveness while exempting from the
same burden those drugs that were IRS to the drug approved as safe under an NDA. 30
Consequently, in 1972, FDA issued a regulation stating that unapproved drugs that were
I notice could also be covered by
the NDAs reviewed and thus were subject to the DES
I notice evaluating the approved
product, including with respect to new drug status and with respect to findings of
effectiveness (or lack thereof).31 That Agency regulation, currently found at 21 CPR
310.6, states that:
IRS to a drug with an approved NDA named in a DES
Even though these (IRS) products are not listed in the notices, they are covered
by the new drug applications reviewed and thus are subject to these notices. All
persons with an interest in a product that is identical, related, or similar to a drg
listed in a drug effcacy notice (effectiveness notice) or a notice of opportnity
for a hearg wil be given the same opportty as the applicant to submit data
and information, to request a hearng, and to participate in any hearg. It is not
feasible for the Food and Drug Admnistration to list all products which are
covered by an NDA and thus subject to each notice. However, it is essential that
the findigs and conclusions that a drug product is a "new drg" or that there is a
lack of evidence to show that a drg product is safe or effective be applied to all
identical, related, and similar drg products to which they are reasonably
applicable.
Ths regulation is often referred to as the "IRS Rule." The IRS Rule also states that an
"identical, related, or similar drug includes other brands, potencies, dosage forms, salts,
and esters of the same drug moiety as well as of any drug moiety related in chemical
strctue or known pharacological properties" (§ 31O.6(b)(l)). .In promulgating this
regulation, the Agency stated that "it was necessary thtit the definition of (IRS drug) be
broad so that manufacturers are alerted to the possibilty of their products being affected"
and thus included specific examples of what would constitute an IRS drug to which the
drug efficacy findings (effectiveness findings) would apply.32
The Agency also recognized that there would be drugs for which the applicabilty of drg
effectiveness findings would not be as clear, and for which the judgment of experts
29 Marketed Unapproved Drugs CPG at 8.
30 Marketed Unapproved Drugs CPG at 8.
3137 FR 23185 (October 31,1972).
3237 FR 23185 (October 31, 1972).
7
would be necessar to determine the applicability of the effectiveness findings.33 Thus,
§ 310.6(b)(2) provides that:
Where experts qualified by scientific training and experience to evaluate the
safety and effectiveness of drgs would conclude that the findings and
conclusions, stated in a drg effcacy notice or notice of opportity for hearing,
that a drg product is a "new drg" or that there is a lack of evidence to show that
a drug product is safe or effective are applicable to an identical, related, or
similar drg product, such product is affected by the notice. A combination drug
product containng a drg that is identical, related, or similar to a drg named in a
notice may also be subject to the findings and conclusions in a notice that a drg
product is a "new drg" or that there is a lack of evidence to show that a drg
product is safe or effective.
Accordingly, DESI notices include language regarding their applicability to IRS drugs.
Thus, rather than eliminating the need for an approved application, the finding that a
product is IRS to a DES
I drug in fact subjects that IRS product (including an IRS product
that is a different saltester of a reviewed drug) to the Agency determinations made under
DESI, both with respect to new drug status and effectiveness. Accordingly, if a DESI
proceeding concludes that the drugs named in that proceeding are effective for at least
one indication, the IRS drugs, far from being determined to be GRAS/E, are themselves
new drgs that are required to obtain approved applications to be legally marketed.34
C. The OTC Drug Review for CoughCold Products
The OTC drug review is a three-stage public rulemaking process. The process involves
evaluation of the safety and effectiveness of the active ingredients in a drug product
category by an advisory panel of scientific experts, which is published in the Federal
Register (proposed monograph); publication of
FDA's proposed regulation (tentative
final monograph); and publication of
the final regulation (final
monograph) (21 CFR
330.1O(a)(6), (a)(7), and (a)(9)).
September 9, 1976, FDA published an advance notice of
proposed rulemakng (ANPRM) to establish a monograph under § 330.1O(a)(6) for OTC
In the Federal Register of
33Id.
34 Undetermined Quantities of
Various
Articles of
Drug . . .,675 F.2d 994 at 1001; Premo Pharm. Labs.,
FDA's approach, the conclusions
reached durg the DESI review about a drg product containg, for example, dexbrompheniamine
maleate, pseudoephedre sulfate, or dextromethorpha hydrobromide should also apply to the taate salts
of these same active therapeutic moieties as well" (Petition at 14). Indeed, the DESI notices addressing
629 F.2d 795 at 805. In your Petition, you assert that "(aJs a result of
products containng these ingredients concluded that they, and drgs IRS to them, are new drgs requirng
approved applications (47 FR 47085 (October 22, 1982); 47 FR 20856 (May 14, 1982); 42 FR 44275
(September 2, 1977); 38 FR 7265 (March 19, 1973); 36 FR 11758 (June 18, 1971); 36 FR 9339 (May 22,
1971)).
8
cold, cough, allergy, bronchodilator, and antiasthmatic drug products.35 The monograph,
recommended by the Advisory Review Panel on OTC Cold, Cough, Allergy,
Bronchodilator, and Antiasthmatic Drug Products (the Cougheold Panel) in a report
submitted to the agency on March 3, 1976, established conditions under which OTC cold,
cough, allergy, bronchodilator and antiasthmatic drugs are GRAS/E and not
misbranded.36 The APls were classified for paricular indications based on whether they
were GRAS/E and not misbranded (Category I), or not GRAS/E and misbranded
(Category 11).37 The CoughCold Panel also classified products under a third category
(eategory III) if sufficient data were unavailable to permit final classification under either
of the prior categories.38 In addition, the CoughCold Panel provided its
recommendations on a varety of coughcold drug issues, such as fixed dose
combinations (e.g., acceptable numbers and appropriate pharacological combinations of
APIs), Category III testing procedures, and the symptoms for which coughcold products
are marketed.
The final monograph includes GRAS/E active ingredients in five separate categories:
antihistamines, decongestants, antitussives, bronchodilators, and expectorants, and is
available at 21 CFR par 341.39
D. Tannates
Tanate-containing cough, cold, and allergy products were originally developed in the
late 1950s by the Research Laboratories ofIrwin, Nessler, and eompany (Decatur,
Ilinois) (Irin, Nessler & Co.). These products were designed to provide sustained-
3541 FR 38312, 38337-38338 (September 9, 1976).
36Id. The report also provided the Cough-Cold Panel's findings regarding the safety and effectiveness of
individual APIs (and API combinations) in then-marketed drug products that were submitted to the CoughCold Panel for review. .
37 21 CFR 330.1 0(a)(5)(i)-(ii)
3821 CFR 330.10(a)(5)(iii)
39 The FDA issued the tentative final monograph for single ingredient QTC cold, cough, allergy,
bronchodilator, and antiasthmatic drg products in segments, over a 3-year penod. The fist segment, on
anticholinergic drug product and expectorant drg products, was published in the Federal Register of July
9, 1982 (47 FR 30002). The second segment, on
bronchodilator drg products, was published in the
Federal Register of
October 26, 1982 (47 FR 47520). The thd segment, on antitussive drg products, was
published in the Federal Register of
October 19, 1983 (48 FR 48576). The fourt and fifth segments, on
nasal decongestat drg products and antihstaine drg products, were published in the Federal Register
of January 15, 1985 (50 FR 2200 and 50 FR 2220 respectively). The Agency's tentative final monograph
for OTC cough-cold combintion drug products was published in the Federal Register of August 12, 1988
(53 FR 30522). Final monographs for these OTC drug products also were published in segments between
1985 and 1994: Anticholinergic (50 FR 46582 (November 8, 1985)); bronchodilator (51 FR 35326
(October 2, 1986)); antitussive (52 FR 30042 (August 12, 1987)); expectorant (54 FR 8494 (February 28,
1989)); antihstamine (57 FR 58356 (December 9, 1992)); nasal decongestat (59 FR43386 (August 23,
1994)); and combination products (67 FR 78158 (December 23, 2002)).
9
release, long-acting, stable formulations of
many then-marketed active ingredients.4o The
stability of these products stems from the ability of organic amines (such as
chlorpheniramine, pyrlamine, and phenylephrne bases) to combine with tanic acid to
form stable tanate salts having limited solubilty in water.41 Given their stabilty and
limited solubilty, tanate salts release gradually in the presence of aqueous solutions of
electrolytes (such as those found in the gastrointestinal lumen) and thus provide a
sustained level of action as well as an extended period of response. 42
Excessively rapid solubilzation of the amines in the low pH aqueous environment of the
stomach can also be prevented by the addition of polygalacturonic acid to the tanate
salts of organic amines.43 Irwin, Nessler & Co. commercialized an extended-release,
tanate-based drug delivery system based on this premise, callng this delivery system
"Durabond" (or the "Durabond Principle"). The company's tanate cough, cold, and
allergy product line based on the Durabond Principle was marketed under the trade name
"Rynatan." The product line originally included prophenpyrdamine maleate
(pheniramine maleate), phenylephrne tanate, and pyrlamine tannate, but was
subsequently reformulated to include ch10rpheniramine tanate, phenylephrine tanate,
and pyrlamine tannate.44 Rynatan, although marketed as a prescription product, was
never the subject of an approved NDA. Accordingly, Rynatan was not specifically
reviewed in
the DESI program.45
Clinical studies on formulations ofRynatan were conducted to evaluate the effectiveness
and safety of tanate cough, cold, and allergy products shortly after they were originally
marketed, and some of these studies provided some suggestion that the products were
these studies were published in recognized medical
effective.46 Although some of
40 Cavallito, C. J, and Jewell, R., Modification of
Rates of
Gastrointestinal Absorption of
Drugs. i. Amines,
J. Am. Pharm. Assoc., 47(3 Par 1):165-168, 1958; see also Cavallto, C. J. et al Some Studies ofa
Sustained Release Principle, J. Pharm. Sci., 52:259-263, 1963.
41Id.
42Id.
43Id. In their 1958 study, Cavallto and Jewell reported that the rate of
release ofprophenpyrdamine
maleate, prophenpyrdamine tannate, morphine sulfate, and morphine tannate increased with decreasing
pH.
44 Kaplan, H. et at., Evaluation of a Long-Acting Oral Antihistainc Decongestant (Ryntan~)for Nasal
Allergies, Ann. Allergy 21 :41-47, 1963; Lawler, E. G., Limperis, N. M., A New Long-Acting Antihistamine
for Pediatrc Use, Clin. Med., 5:1669-1672,1958, Vilanyi, L., Clinical Note: Evaluation ofRynatan, Eye,
Ear, Nose and Throat Monthly, 38:650-651,1959; Simon, D. L., A Long-Acting Oral Decongestant
Suspension for Children, Clin. Med., 7:1761-1770, 1960; Editorial, Med. Sci., 3:376-377, 1958.
45 The DESI program is discussed in section I.B of
ths response.
46 Most of
these studies involved the Durabond product Rynatan. Two studies, one by Kaplan and the other
by Lawler and Limperis, evaluated effectiveness based on patients' assessments of duration of relief of
relief) to none (no relief) (Kaplan et at. 1963; Lawler et
symptoms, ranging from excellent (8-12 hours of
at. 1958). These open label and uncontrolled studies used a patient-assessed, subjective assessment of
10
of
these studies meets the standard for an adequate and well-controlled
clinical trial under section 505(d) ofthe Act (21 U.S.C. 355(d)) (and under 21 CFR
314.126), and none would be considered adequate by current standards to support the
journals, none
effectiveness and safety of the products.
All of these clinical studies, however, refer to the claim that the Durabond Principle
the active ingredients (a
combination of antihistamine and decongestant). Contemporary to these clinical studies,
a review of in vivo evaluations of delayed-release formulations also referred to tannate
products as an example of sustained-release preparations.47 Indeed, the corresponding
provides long-acting activity due to the sustained release of
tanate salts of drug products containing coughcold APls reviewed as par. ofthe OTC
drug review (for example, brompheniramine, chlorpheniramine, dexbrompheniramine,
dexchlorpheniramine, dextromethorphan, diphenhydramine, ephedrine, phenylephrne,
pseudoephedrine, pyrlamine, and triprolidine) all provide a sustained release of
the
APi.48
The eoughCold Panel did not review any tanate forms of any active moieties as par of
its review that lead to the establishment of the OTC coughcold monograph. Moreover,
no tanate salts ofthe active ingredients addressed in the aTe Drug Review are
mentioned in any advanced notice of proposed rulemaking, tentative final monograph, or
final monograph (including the preambles) associated with the aTe coughcold
monograph. Simply put, no tannate containing coughcold products are covered by the
OTC coughcold monograph.
Some firms also marketed tanate forms of APls not reviewed under the aTe drug
review. These included carbetapentane, carbinoxamine, and hydrocodone among others.
For instance, cough lozenges containing carbetapentane tanate were marketed under the
trade names Retlexol and Candette by the firms Isodine Pharacal and Pfizer, Inc.,
respectively. These firms obtained pre-1962 NDAs for the products. DESI proceedings
on these
drugs rated them as possibly effective and gave the NDA holders 6 months to
effectiveness, and thus were not adequate and well-controlled (Id.). Another study by Vilanyi and
Stilwater also used a parent-assessed, subjective assessment of effectiveness in children (Vilanyi et al.
1959). One study on children treated with Rynata for various allergic and nonallergic conditions showed
present for 8 hour or more in about 77 percent of
the patients (Simon 1960).
beneficial effects that were
However, ths study was also an open label and uncontrolled study, and provides rio information on
whether the parents or the investigator assessed effectiveness of
the product. In another open label and
patients with various prutic dermtoses were shown to have had a good
uncontrolled study, 47 percent of
response to treatment (Kile, R. L., Oral Treatment of
Prutic Dermatoses With a New Antihistamic
Compound, Antibiotic Med., CUn., Ther., 5(9):578-581, 1958). This study suffers not only from subjective
reporting, but provides no clarification on whether the patients or the investigator assessed effectiveness of
the product.
47 Beckett, A. H., Delayed Release Formulation: In vivo Evaluation, Pharm. J., 201:425-432, 1968.
48 As a comparson, the tannate salts of
these cough-cold APIs are often dosed at intervals from
approximately 8 hours to every 12 hours, whereas the dosing intervals for the corresponding salts reviewed
the OTC monograph range from every 4 to 8 hours.
as par of
11
submit substantial evidence of effectiveness via a supplemental NDA.49 No data were
submitted for either product, and neither Reflexol nor Candette was ever approved under
an NDA for effectiveness as well as for safety. The NDA for Reflexol was subsequently
withdrawn at the request of the applicant/o approval of the NDA for Candette ultimately
was withdrawn on grounds of safety. 51
Any marketed tanate forms of carbinoxamine and hydrocodone are subject to the notices
issued by the Agency in 2006 and 2007 regarding such products. Those notices state that
other salt or ester
products containing carbinoxamine and hydrocodöne bitarrate (or any
of
hydro
codon
e) are new drugs that require an approved application to be lawfully
52 Under the terms of
marketed.
those notices
firms should already have ceased
manufacturing and marketing drug products containing these ingredients.
II. DISCUSSION
A. FDA Does Nòt Regulate Cough/Cold Products on an Active
Therapeutic Moiety Basis
regulating coughcold
You state that FDA has a long, almost half-centu history of
products on an active therapeutic moiety basis (Petition at 3, 13) and that the long history
of safe and effective use of many coughcold active therapeutic moieties - regardless of
their particular salt form - has rendered the moieties generally recognized as safe and
these
effective (GRAS/E), which requires rulemaking for any changes in the regulation of
drugs (Petition at 3, 14). Moreover, you assert that FDA has taken this active therapeutic
moiety approach to regulating drug products during the DESI review process, the OTC
Drug Review process, and in other regulatory contexts (for example, determinations of
new drug exclusivity and orphan drug product regulation) (Petition at 13-18).
Your claim that FDA regulates drug products, whether for coughcold indications or
other uses, on an active therapeutic moiety basis is a gross overstatement, and your claim
that "there is no legal or scientific reason to regulate tanates any differently than other
salts such as maleates, sulfates, hydrobromides, or hydrochlorides" (Petition at 13) is
without merit. While there are some regulatory contexts in which the active moiety is the
relevant regulatory entity, the active moiety is not the relevant regulatory entity when
FDA considers, without submission of any supporting data to the Agency, whether a drug
is safe and effective. The Agency has adopted an active-moiety-based approach with
respect to the 5-year period of data exclusivity granted to NDAs for products containing
chemical entities never previously approved by FDA either alone or in combination, and
witl respect to the Agency's grant of orphan drug designation. With respect to the
4936 FR 3532 (February 26, 1971).
5037 FR 2851 (Febru
8, 1972).
5137 FR 25249 (November 29, 1972).
52 See Federal Register notices at 71 FR 33462 (June 9, 2006) and 72 FR 55780 (October 1, 2007) for
carbinoxame and hydrocodone respectively.
12
approval ofNDAs or the determination of GRAS/E status, it is the drug product (i.e., the
particular formulation of active and inactive ingredients) that is the relevant regulated
entity, and not the active moiety. FDA does not consider a drug to be GRAS/E because
another drug with the same active moiety has been found to. be safe and effective. Each
of
your arguments is addressed below.
1. DESI Review
I review
process supports your assertion that the Agency regulates drug products based on the
You state in your Petition that FDA's regulation of drug products durng the DES
active therapeutic moiety, regardless of
the salt form of
the drug (Petition at 13-14).
Specifically, you state that "the review panels and the Agency recognized the difficulty of
publishing a list of all products subject to a particular finding, and instead stated (in
individual DESI Federal Register notices and in regulation) that the review findings
apply to (IRS) drug products as well" (Petition at 13). You assert that the Agency's
DES
I findings to IRS products "reflects the Agency's conscious decision
application of
to extend the findings for a particular API to other salts without enumerating each and
every salt that is chemically and pharmacologically possible" (Petition at 13-14) and that
FDA's approach "supports the proposition that the active therapeutic moiety is the most
the API" (Petition at 14). You further claim that "FDA's historical and
fuctional par of
contemporary approach to addressing varous salt forms of an active therapeutic moiety.
. . provides strong support for the continued marketing of tanate-containing drugs in
general, and coughcold products in particular" (Petition at 18).
I review, FDA conducted effectiveness evaluations of
We disagree. Under the DES
specific drug products approved as safe between 1938 and 1962. The effectiveness
evaluations were not conducted on the basis of the active moiety of the drug product, but
rather on the specific product that had been approved as safe. As discussed above in
section I.B, the Agency did find that it was in the public interest for effectiveness
deterinations under DESI to apply to drug products that were either identical or
53 The
"reasonably related and similar" to the drug products listed in the DESI notices.
Agency
deterined that the effectiveness findings could be applicable to other brands of
the same active moiety, as well as
identical drugs, as well as different salts and esters of
54
any drug moiety related in chemical strctue or known pharmacological properties.
However, the Agency recognized that in some circumstances slight differences in drugs,
such as a salt or an ester, could in fact produce very different effects. S5 To this end, FDA
stated that it was "reasonable to conclude that the. . . I effectiveness) study conclusions"
were applicable to related or similar products, unless the sponsor of such a product
provided data showing that its similar or related drug did in fact have different actions or
the DESI-reviewed product,56
effects than that of
S3 37 FR 23185 at 23185 (October 31,1972).
S4Id.
SS Id.
S6Id.
13
Thus, the Agency did not conclude that DESI findings of effectiveness categorically
apply to all salts of
the DESI-reviewed product, and its approach to IRS products does
not imply, as stated in your Petition, that the Agency regulates salts of the same active
moiety based on the active moiety alone. Rather, the Agency's approach to IRS products
under DESI solely indicates that "the findings and conclusions that a drug product is a
'new drug' or that there is a lack of evidence to
show that a drug product is safe or
effective (wil be) applied to all identical, related, and similar drug products to which
(those conclusions) are reasonably applicable.,,57
this response, the DESI process, including the IRS Rule,
does not involve findings that products are GRAS/E or otherwise authorize the marketing
of any drugs without approved applications; on the contrary, all DES
I proceedings
As described in section I.B of
contain a finding that covered products are new drugs and - regardless of whether the
products are found effective or ineffective - require approved applications to be legally
marketed. Thus, to the extent that firms are marketing tannate drug products that are IRS
to a product in a closed DESI proceeding, such firms have been on legal notice since the
relevant DESI proceeding was finalized that their drg products are ilegally marketed
without an approved application. To the extent that firms are marketing tanate drug
products that are IRS to a product in a DESI proceeding that is stil pending, the failure to
submit a notice of paricipation and request a hearing in that proceeding or to raise any
contentions that their products are not new drugs constitutes a waiver of any contentions
58
not raised.
2. aTe Drug Review
You cite the OTC Drug Review in support of your
claim regarding regulation by active
moiety (Petition at 14-15), but in fact the coughcold monograph and preambles
associated with the regulation show that FDA regulates OTC monograph coughcold
products on the basis of the drug product, not merely the active moiety.
59 The
monograph identifies specific salt forms, or the specific free base, of active ingredients as
GRAS/E provided the other monograph conditions are met,60 For instance, the
monograph identifies specific forms of antihistamines as brompheniramine maleate,
chlorpheniramine maleate, dexbrompheniramine maleate, dexchlorpheniramine maleate,
diphenhydramine citrate, diphenhydramine hydrochloride, pyrlamine maleate, and
trprolidine hydrochloride.6 Similarly, permitted antitussives include dextromethorphan
5721 CFR 310.6(a).
5821 CFR 314.200(e).
59 21 CFR par 341.
60Id.
6121 CFR 341.2.
14
and dextromethorphan hydrobromide;62 permitted bronchodilators include ephedrine,
ephedrine hydrochloride, and ephedrine sulfate;63 and permitted oral nasal decongestants
include pseudoephedrine hydrochloride, pseudoephedrine sulfate, phenylephrne
64
hydrochloride, and phenylephrne bitartrate (effervescent dosage form only).
The monograph's specificity in identifying the permitted salt or free-base forms ofthe
drug indicates that unidentified salts are not acceptable under the monograph. If any salt
form were acceptable, the monograph could simply identify as the active ingredient the
active moiety - such as, chlorpheniramine, diphenhydramine, dextromethorphan, or
pseudoephedrie - without reference to any appended salt. The coughcold monograph
does not do this.
Furthermore, an active ingredient included in an OTC monograph must be recognized in
an official United States Pharacopeia (USP) monograph that sets standards for the
the ingredient (§§ 330)0(a)(2) and 330.
14(i)). A
identity, strengt, quality, and purity of
USP monograph establishes specific standards and test methods for a specific active
ingredient, including, for instance, chemical formula, molecular weight, melting range,
and identification testing. Such standards are not and could not be interchangeable for
the same active moiety. In other words, USP
the free-base and/or different salt form of
monographs are specific to the salt or free-base form, not merely the active therapeutic
moiety. In addition, there are no USP monographs for the tanate forms of any active
moiety.
Last, the statement from the CoughCold Panel report that you cite on page i 5 of your
Petition ilustrates that the OTC Drug Review does not regulate drugs in the review based
on active moiety alone and dòes not treat all salt forms as equivalent. The Panel
concluded that "provided that there are suitable data to establish bioequivalence and
safety, salts, esters and complexes of ingredients discussed in the monograph would be
acceptable."65 When the Agency did add additional salt forms to the OTC monograph,
additional data demonstrating bioequivalence and safety were required.66 Nothing in the
coughcold monograph preamble describes safety and bioequivalence data for tanate
salts.
3. Exclusivity Provisions
6221 CFR 341.4.
6321 CFR 341.6.
64 21 CFR 314.20.
65 41 FR 38312, at 38337-38338 (September 9, 1976).
66 Id. See also 57 FR 58,356, 58,359 (December 9,1992) (recognzing information in a comment and
citizen petition suggesting diphenhydramine citrate was equivalent to dipherlydramine hydrochloride); 69
FR 63482, 63483-63484 (November 2, 2004) (recognzing studies described in a citizen petition that
established phenylephre bitartate as equivalent to phenylephre hydrochloride).
15
You state that FDA has taken an "active therapeutic moiety-based approach" with respect
to deterinations regarding new drug exclusivity to support your assertion that a drug
product is most appropriately regulated on the basis ofthe active therapeutic moiety
portion of the molecule and not on the particular salt form of that active therapeutic
moiety (Petition at 4, 17). Your reliance on the exclusivity provisions (new chemical
entity (NCE) and orphan drug exclusivity) within the Act to support the regulation of
coughcold products solely on the basis of active moiety is, however, unsupported. NCE
exclusivity was created by the Drug Price Competition and Patent Term Restoration Act
of 1984 (also known as the "Hatch-Waxman Amendments" to the Act)67 as a 5-year
perod of marketing exclusivity to certain pioneer drugs to protect these drugs from
generic competition for the specified terms by preventing the submission of abbreviated
the Act (21
applications that refer to them.68 At issue here is section 505(j)(5)(F)(ii) of
(j)(5)(F)(ii))69 that states:
(i)f an application submitted under subsection (b) of this section for a drg, no
which
has been approved in any other application under subsection (b) of this section, is
approved after September 24, 1984, no application may be submitted under this
subsection which refers to the drg before the expiration of five years from the
date of the approval.
active ingredient (including any ester or salt ofthe active ingredient) of
FDA's regulations implementing these provisions gave 5 years of exclusivity for each
"drug product that contains a new chemical entity.,,7o The regulations define a "new
chemical entity" as "a drug that contains no active moiety that has been approved by
FDA in any other" new drug application.,,71 "Active moiety" is fuher defined as "the
molecule or ion, excluding those appended portions of the molecule that cause the drug to
be an ester, salt (including a salt with hydrogen or coordination bonds), or other
noncovalent derivative. .. of the molecule, res~onsible for the physiological or
the drug substance.,,7 Thus, to qualify for 5-year exclusivity,
pharacological action of
an approved drug must contain no previously approved active moieties.
FDA based its interpretation of the statutory language on the classification scheme for
negotiation of
the Hatch-Waxman
Amendments to effect congressional intent not to confer signficant perods of exclusivity
previously approved compounds.73 The exclusivity scheme also
on minor varations of
"new molecular entities" that existed at the time of
67 Pub. L. No. 98-417,98 Stat. 1585.
68 Actavis Elizabeth LLC v. FDA, 625 F.3d 760, 761, n.4(D.C. Cir. 2010).
69 See also section 505(c)(3)(E)(ii) of
the Act (21 U.S.C. 355(c)(3)(E)(ii)).
70 21 CFR 314.108(b )(2).
71 21 CFR 314.
108
(a).
72 Id.
7354 FR 28872, 28898 (July 10, 1989); see also 59 FR 50338,50835 (October 3, 1994).
16
reflects congressional intent to balance the need for financial incentives to support
development of
innovative drugs with the need for lower cost generic drug products.74
These policies are distinct from those underlying the statutory requirement of safety and
effectiveness for finished drug products, and have not been applied in that context. As
courts have noted, the definition of active ingredient in the "new chemical entity" context
is different from the definition of active ingredient that is applied in other parts of the
statute, including in the context of approving ANDAs.75
Your reference to the "orphan drg" exclusivity is similarly misplaced. Section 527(a) of
the Act (21 U.S.C. 360cc(a)) provides a 7-year exclusivity perod for approved products
designated as orphan drugs during which no approval wil be given to a subsequent
applicant's marketing application for the same drug for the same indication unless the
subsequent product is shown by the applicant to be clinically superior. "Same drug" for
small molecule orphan drug products is defined in FDA regulations as "a drug that
contains the same active moiety as a previously approved drug and is intended for the
same use as the previously approved drug, even if the paricular ester or salt (including a
salt with hydrogen or coordination bonds) . . . has not been previously approved." In
promulgating this regulation, the Agency explicitly noted this definition of sameness was
"for the purposes of consideration of exclusive marketing under the Orphan Drug Act,"
and that the definition was different from that used in evaluating an application for
market approval. 76 Thus, neither of these exclusivity provisions supports your request
that FDA take an "active therapeutic moiety" approach towards active ingredients in the
context of drug safety and effectiveness.
B. Tannate CoughCold Drug Products Do Not Meet Established
GRAS/E Standards and Are New Drugs
You state that tanate-containing drugs have been on the market for decades with few, if
any, safety or effectiveness issues (Petition at 8, 20). You state that FDA has reviewed
tanate-containing drugs for the treatment of diabetes insipidus and anemia (among other
the DESI review, and that while some ofthese drugs were removed
indications) as par of
from the market and/or their applications have been withdrawn, it does not appear that
these actions were taken because ofthe tanate form ofthe drug (Petition at 20-21). You
also cite the finding made under the DESI review that a number of
products containing
carbetapentane tanate were "possibly effective" for the temporar relief of cough
74 See discussions in 57 FR 62076,62077 (December 29,1992),56 FR'3338, 3338 (January 29,1991), and
54 FR 28872,28881.
75 Actavis Elîzabeth LLC v. FDA, 625 F.3d 760 at764, n.6, citing 54 FR 28872, 28881. Moreover, in
addition to the 5-year period of exclusivity, the Hatch-Waxman Amendments grant 3-year exclusivity to
the application for the drug "contain
report of new clinical investigations . . . essential to the approval of the application and conducted or
sponsored by the applicant. . . ." (section 505(j)(5)(F)(iii) of
the Act; 21 U.S.C. 355(j)(5)(F)(iii)).
drg products that include previously approved active ingredients if
7656 FR 3338,3341 (January 29, 1991).
17
You state that while some of
these products were withdrawn at the behest ofthe NDA holder, there is no evidence that
the withdrawals were in any way linked to the presence of tannates (Petition at 22).
(Petition at 22, citing 36 FR 3532 (February 26, 1972)).
The evidence cited in your Petition for the safety and effectiveness oftannate coughcold
products is at best anecdotal and certainly not the robust scientific evidence that the
statute, Agency regulations, and three decades of case law require to demonstrate the
safety and effectiveness of a drug product and support a determination that a product is
GRAS/E.
As stated in section LA of this response, for a drug product to be considered GRAS/E, the
particular drug product must have been subjected to adequate and well-controlled clinical
investigations establishing that the product is safe and effective; the investigations must
have been published in the scientific literature so that they are available to qualified
experts; and experts must generally agree, based on those published studies, that the
product is safe and effective for its intended uses.77 Moreover, a product's general
recognition as GRAS/E must be evidenced by at least the same quality and quantity of
data as are necessary to support approval of an NDA.78
A review ofthe published scientific literature relevant to tannate drugs products for
cough, cold, and related indications does not indicate the existence of any adequate and
well-controlled studies regarding any tanate product. 79 In fact, there is a dearth of
17 See note 6.
78 See note 7.
79 FDA reviewed the studies described in the following articles: Weiler, J. M. et aI, Randomized, DoubleBlind, Parallel Groups, Placebo-Controlled Study of Efficacy and Safety of Rynata in the Treatment of
Allergic Rhnitis Using an Acute ModeL, Ann. Allergy, 64:63, 1990; Vilanyi, L. et aI. 1959; Simon, D. L.
1960; Lawler and Limperis 1958; Kaplan, H. 1963;., Double Blind, Placebo Controlled Study of
and Safety of
Effcacy
Rynatan to Treat Allergic Rhtis, J. Allergy and Clin. Immun., 81:176 (1988); Kaplan et aI.,
Clinical Impression and Subsequent Double Blind Study of an Antitussive Preparation, Ann. Allergy,
23: 111 (February 1965); Knutson, D., and Braun, C., Diagnosis and Management of Acute Bronchitis,
Amer. Fam. Phys., 65:2039 (May 15,2002); and Bogner, R. L., and Walsh, J. M., Sustained-Release
Priciple inHuman Subjects Utilzing Radioactive Technques, J. Pharm. Sci., 53:617 (June 1964). In
addition, although a search of the published literatue is sufficient for purposes of determing whether
there are adequate and well-controlled clinical studies to support a finding that a product is GRAS/E, FDA
also reviewed the followig information, including that submitted in support of
your Petition: Kastrp,
Erwn K. ed., FACTS AN COMPARSON (1973), Facts and Comparisons, Inc. (St. Louis, MO) and
DRUG FACTS AN COMPARSONS, 2008, Wolters Kluwer Health (St. Louis, MO); Weiler, J. M. et al;
Life Sciences Research Office, Federation of American Societies for Experimental Biology, Evaluation of
Tanc Acid as a Food Ingredient (1977), available from U.S. Department of
the Health Aspects of
Commerce, National Technical Information Service, at 4; Informatics, Inc., Scientific Literatue Reviews
on Generally Recognzed as Safe (GRAS/E) Food Ingredients - Tannc Acid (July 1973), available from
U.S. Deparent of
Commerce, National Technical Information Service; OTC ingredient list (Petition note
FDA 71-56, Tannc Acid in Mice and
32); Food and Drug Research Labs, Inc., Teratologic Evaluation of
Commerce,
Rats (January 31,1975), available from U.S. Deparent of
Service; Litton Bionectis, Inc., Mutagenic Evaluation of
1975), available from U.S. Departent of
National Techncal Informtion
Compound FDA 73-56, Tannc Acid (March 21,
Commerce, National Techncal Information Service; de Vries, J.,
Food Safety and Toxicity (New York: CRC Press, 1997), 11-12; USP Material Safety Data Sheet, Tanc
18
reliable clinical data, as no adequate and well-controlled clinical studies have been
perormed on such tanate products. Moreover, published chemical, manufacturing, and
controls (CMC) data and clinical pharmacology data regarding tannates are scarce, and
any existing data were often obtained with small studies and now obsolete methods.8o
the legal
Therefore, coughcold tanate products fail the first two requirements of
standard for GRAS/E status: there are no adequate and well-controlled clinical
investigations published in the scientific literature establishing that any such product is
safe and effective. Therefore, no tanate product is generally recognized as safe and
effective.
1. Tannate Products Are Not Covered by the OTC Drug Review and
Are Therefore Not GRAS/E Based on the OTe Drug Review
The OTC Drug Review is the only arena in which GRAS/E status is based on evidence of
the safety and effectiveness of active ingredients rather than complete, finished products,
products. Under the
and the GRAS/E status applies only to a specific, limited class of
aTC Drug Review, the Agency examines data related to active ingredients in products
long marketed as OTC drugs.8l Based on review of
these data, the Agency establishes a
set of conditions (active ingredients, dosage, route of administration, indications,
warnings, etc.) for OTC drug products in paricular therapeutic categories and publishes
\
them in monographs.82 Products containing active ingredients
identified in a final
monograph and meeting the specified conditions are considered GRAS/E and may be
marketed without applications.83
Monographs do not, however, cover prescription drug products. In fact, after reviewing
and evaluating the applicability of an OTC monograph model (in which applicants would
only need to satisfy the standards established in the monograph) to prescription drugs,
FDA concluded that it would be scientifically infeasible to regulate prescription drugs
under a monograph system.84 In its scientific expertise, FDA concluded that prescription
drug products have characteristics that, when taken together, do not lend themselves to
Acid (Petition note 92).
80 In vivo data included studies of
urnary excretion of chlorpheniamine in four subjects, which was
measured with absorption spectrophotometr after administration of chlorpheniamine maleate and
chlorpheniamine tannate (Cavallto and Jewell
1963). Because the study showed that excretion of
both salts, the authors concluded that urar
chlorpheniamine was iregular after admiistration of
excretion is an unreliable reflection of
the rate of oral absorption.
81 Marketed Unapproved Drugs CPG at 11.
82Id.
83Id.
84 Congressional Report: Feasibilty and Cost of a New Monograph System for Marketed Unapproved
Dntgs House Report 108 -193 and Senate Report 108 -107, Food and Drug Adminstration (July 2004)
(Monograph Feasibility Report).
19
marketing under monographs developed for classes of drugs without an applicationspecific review.85
The OTC coughcold monograph, like other aTe monographs, does not encompass
prescription drug products. Moreover, the scope ofthe coughcold monograph is defined
by specific conditions. As stated in the monograph at § 341.1:
An over-the-counter cold, cough, allergy, bronchodilator, or antiasthmatic drug
product in a form suitable for oral, inhalant, or topical administration is generally
recognized as safe and effective (GRAS/E) and is not misbranded if
it meets each
of the conditions in this part and each of the general conditions established in
§ 330.1. .
the OTC coughcold monograph. First,
tanates are not marketed as aTe products; they are marketed as prescription products
Tanates do not, however, meet the conditions of
and therefore the monograph does not apply to them. Furthermore, even iftannates were
marketed as OTC products, permitted active ingredients in the monograph are saltspecific. No active ingredients identified in the monograph are tannate salts. In addition,
even ifthe monograph specified ingredients on an active moiety basis rather than an
active ingredient basis (as your Petition contends), other deviations oftannates from the
use would render them not GRAS/E under the monograph. As
noted in note 48 in the response, marketed tannate products generally have longer dosing
monograph conditions of
intervals than the dosing intervals specified in the coughcold monograph.86 Moreover,
many of these products are combinations that include ingredients not peritted in the
monograph (such as carbetapentane tannate and methscopolamine nitrate) and most bear
labeling with indications that are not permitted under the monograph.87 Accordingly, the
tanate products are not GRAS/E under the OTC coughcold monograph.
85 The Agency stated that in contrast to OTC drgs, prescription products, by statutory definition, are not
safe for use except under the supervision ofa practitioner (21 U.S.C. 353(b)(1 )(a)), are tyically used to
treat diseases that canot be self-diagnosed, and have detailed practitioner-directed labeling (Monograph
Feasibilty Report, at 3). Thus, developing a label suitable to a class of drgs or maintainig a label
appropriate to all products containng a single drg ingredient would be very difficult (Id.). Moreover, a
risk-benefit profie for prescription drgs must be established individually, especially for those drgs that
pose unque and greater safety risks than other drgs (e.g., narow therapeutic index drgs) (Id.). Finlly,
prescription drugs are critical to their safe and effective use and must be
evaluated for each individual product because differences in how products are manufactured can have
major effects on their risks and benefits (Monograph Feasibilty Report, at 4).
chemistr and bioavailabilty of
86 For instance, products attbuting a 12-hour dosing to the tannate salt include among others Anaplex
DMX Suspension, C-Phed Tanate Suspension, BromTann Suspension" Tanafed Suspension, Brovex AT
Suspension, Lodrne D Suspension, Lodrane XR Suspension, P-Tex Suspension, and TanaCof-XR.
87 Such indications include the following: (1) "antihistaminc amelioration of allergic reactions
(chlorpheniamine taate marketed as AHIST by Magna Pharmaceuticals, Inc., and Provident
Pharmaceuticals, LLC (Provident)); (2) "temporar relief of nasal congestion associated with the common
cold, bronchial asthma, acute and chronic bronchitis, and other upper respiratory tract conditions"
(combination ofbrompheniamine taate and phenylephrne tannate marketed as J-Tan D Chewable
Tablets by JA YMAC Pharaceuticals, LLC and Provident; and Tanabid Chewable Tablets marketed by
Portl Pharmaceuticals, Inc., and Provident); (3) "temporarly relieves nasal congestion and pressure, ruy
nose, sneezing, itchig of
the nose and throat, and itchy watery eyes due to the common cold, sinusitis, hay
20.
FDA has adopted procedures whereby, with submission of appropriate supporting data,
drugs currently not marketed under an OTC monograph may be considered by the OTC
Drug Review, determined to be GRAS/E, and added to the monograph, which would
make marketing them without an application lawful (§§ 330.1O(a)(l2) and 330.14).
These products, however, would have to be marketed over the counter.
2. Tannate Products Are Not Rendered GRAS/E by Their History of
Use
You also assert that the history of safe and effective use of many coughcold active
therapeutic moieties has rendered them GRAS/E, regardless of their particular salt form
(Petition at 3,20-30). For two reasons, this claim is inconsistent with both the statutory
definition of a new drug and over 30 years of judicial interretation of this definition as
discussed above. First, the cours have consistently rejected the claim that a product can
be GRAS/E based on it long history ofuse.88 Substantial evidence is required: GRAS/E
status can only be based on published studies of suffcient quality and quantity to justify
approval of an NDA. 89 As stated above, FDA has not identified any adequate and wellcontrolled studies of any tanate coughcold product in the published scientific literature.
Second, because the word "drug" in the new drug definition refers to the finished product
- an issue settled by the Supreme eour in its Generix decision - GRAS/E status is not
and cannot be established by similarity to, or based on data regarding, another drug, even
one with the same active ingredient.
fever, or other respiratory allergies (cWoipheniramine tannate marketed as Ed-CWor- Tan by Edwards
Pharmaceuticals, Inc., and Provident).
88 United States v. 50 Boxes, 909 F.2d 24 at 27-28 (151 eir. Mass. 1990) (rejecting the fi's argument that
"a long history of safe and effective use (plus other scientific information) indicate both safety and
effectiveness" and can substitute for substantial evidence of effectiveness for puroses of GRAS/E
inquir); 225 Cartons, 871 F.2d 409 at 418-419 ("Neither Bentex nor Entrol-C can be read as supporting
Sandoz's contention that the body of experience from long-standing market acceptance, without the
controlled research required under the FDA regulation, can support a claim of general recogntion."); 4,680
Pails, 725 F.2d 976 at 987, n.26 ("Pfier argues that. . . it may show general recognition based upon
herds and flocks of animals. . . .
expert' experience and observations over long periods in thousands of
We do not agree. . . . the tye of evidence upon which Pfizer attempts to rely is the very tye of anecdotal
evidence that the rule established in Hynson was meant to replace."); 50 Boxes, 721 F. Supp. 1462 at 14651467 ("Essentially, Sandoz's experts argue that while there may not be the scientific studies conventionally
required to obtain FDA approval of a new drg, less rigorous information concernng CPB Suppository and
its long use should be suffcient to earn it
a judicial exemption as 'generally recognied' by experts as safe
and effective. As indicated earlier, however, ths argument is incorrect as a matter oflaw."); Articles of
Drug. . . Hormonin, Hormonin, 498 F. Supp. 424 at 431-432 ('''Anecdotal evidence,' i.e., testimony
of
physicians unsupported by controlled investigation or scientific publication, does not constitute 'substantial
evidence'. . . . The mere fact that a drg product has been marketed for an extended period does not
preclude a fiding of 'new drg' status.")
89 See note 10.
21
this response, the DESI process, including the IRS Rule,
does not involve findings that products are GRAS/E or otherwise authorize the marketing
of any drugs without approved applications. Thus, your references to the DESI review of
certain tanate
products described on pages 20-21 of
your Petition to support a finding of
GRAS/E for coughcold tannates are misplaced. In fact, two of these drugs were
As stated above in section I.B of
injectable drugs, not oral drugs like the coughcold tanate products. 90 The fact that
under the DESI review, FDA may have found that some tanate products, for certain
indications and in specific dosage forms, were effective is not relevant with respect to
whether other tannate products, in some cases in different dosage forms, are effective for
completely different indications. Firms that marketed the only coughcold tanate
products reviewed under DESI, which contained carbetapentane tanate, never submitted
any evidence of effectiveness in support of these products and discontinued marketing
them (see section I.D of this response).
Tannic Acid as a Food Substance Is Irrelevant
3. The GRAS Status of
to the GRAS/E Status of Drug Products Containing Tannates
You state that "FDA codified tannic acid as a GRAS direct human food ingredient in
1985, based upon several scientific evaluations, a scientific literature review, and a report
issued by the Select Committee on GRAS substances" (Petition at 9). You state "(t)hese
conclusions, based on decades of
historical use (of
tannic acid) and many scientific
studies, support safe use in humans" (Petition at 9). You thus conclude that "as extracts
and reaction products of tanic acid, tanates are GRAS providing further historical
evidence of safe use" (Petition at 8), and that because "distilates, isolates, extracts,
concentration of extracts, and reaction products of GRAS substances may also be
considered GRAS, . . . (t)anates, therefore, may be considered GRAS themselves"
(Petition at 9-10, also generally at 25-29).
FDA's regulations for food and human consumption list tanic acid as GRAS within
specific categories of food, levels of use, and functional uses (21 CFR 184.1097). That
tannic acid is GRAS for certain uses in food does not address the safety of a drug product
-in tannate form or the effectiveness of
tanic
such a drug product. The GRAS status of
the Act (21 U.S.C. 348), these specific
acid merely indicates that under section 409 of
uses of tanic acid in food are exempt from premarket approval requirements. It has no
tannate-containing drug products under section
bearing on the GRAS/E status of
201(P)(1) of
the Act.
c. There Is No "Ingredient Equivalence Policy" for Different Tannate
Forms
You state that "under FDA's ingredient equivalence policy, the regulation of
such active
pharaceutical ingredients (APls) as chlorpheniramine, dexchlorpheniramine,
brompheniramine, dexbrompheniramine, pheniramine, pyrlamine, phenindamine,
pseudoephedrine, and dextromethorphan in their tannate salt form is no different from the
90 You refer to tannate products used to treat diabetes insipidus, hypertension, and anemias. Two of
drugs were injectable drgs, not oral drgs like the cough/cold taate products.
22
these
regulation ofthe coughcold APIs in other salt forms such as maleates, sulfates,
hydrobromides, or hydrochlorides" (Petition at 3, 13-19).
There exists no
FDA "ingredient equivalence policy" as described by you such that the
varous salt forms of an active moiety are recognized as equally safe and effective
without appropriate data specific to the full API (Petition at 14-15). Such a policy, were
itIo exist, would be inconsistent with Agency regulations, policies, and practices in areas
directly related to determinations of drug safety and effectiveness. For example, FDA
has determined that different salts öf the same active moiety are different active
ingredients for the purposes of ANDA approval under section 505(j) of the Act. FDA
also has determined that "active ingredient" in this context refers to "the active ingredient
in the finished drug product prior to its administration.,,91 Accordingly, FDA does not
permit firms to substitute a different salt or ester form of an active ingredient for the form
used in the reference listed drug, except in liIlited circumstances not relevant to tannate
drug products.92 In addition, FDA does not accept suitabilty petitions requesting the
substitution of a different salt or ester for non-combination products.93
Adopting a "ingredient equivalence policy" also would contradict case law on the
definition of
new drug, including the Supreme Cour's Generix case, which states that the
GRAS/E status of a product is assessed by reference to the complete finished product, not
merely the active ingredient.
In addition, as a scientific matter the Agency rejects your view that tanate salts should
be treated no differently than any other salt form of the same active moiety. The salt
form of an active moiety may affect both the effectiveness and safety of the finished drug
product. For example, the salt form may influence the drug's bioavailabilty. Increased
the active
bioavailabilty could result in toxicity due to increased systemic exposure of
moiety. A salt also could decrease the effectiveness ofthe active moiety by decreasing
may
systemic exposure. Furthermore, the salt itself
be toxic.94
9121 CFR 314.94(a)(5); 54 FR 28872,28881 ("if
the proposed drug product contained a different salt or
the active ingredient in the listed drug, the active ingredient in the proposed drg product would not
be identical to the active ingredient in the listed drg, and, therefore, could not be approved in an ANA").
ester of
9221 CFR 314.93(d)(3) (permtting one different active ingredient in a combination product under certin
the
conditions including demonstration that different ingredient is not a new drg under section 201(P) of
Act); 21 CFR 314.94(a)(5)(ii)(A).
9321 CFR 314.93(a); 54 FR 28872,28878 (July 10, 1989) ("FDA considers the salt or ester of
an active
ingredient to be an active ingredient, and wil not approve petitions that seek permssion to submit an
ANA for drg product which substitutes a different salt or ester of an active ingredient from that of a
listed drg" in non-combination drug products).
94 Chlorpheniamine cyanide would be as lethal as any cyanide compound. A metabisulfite salt of an active
moiety would expose consumers with sulfite sensitivity to the risk of acute astha, anaphylaxis, or
angioedema.
23
Thus, as a scientific matter, the different salts of an active moiety are not interchangeable
and they cannot be presumed to have the same safety and effectiveness profies.95 Your
Petition proposed a policy that would have different salt forms of an active moiety
presumed identical in safety and effectiveness. Such
a policy would be irrational on its
face and at odds with the core premise of the Act's approval requirement - namely, that
the burden is on firms marketing a product to demonstrate with credible scientific data
the safety and effectiveness of their drug product prior to marketing it.
D. Neither FDA's "Rush-to-Market" Policies Nor the Professional
Labelig for the Cough/Cold Monograph Permit the Marketing of
Unapproved Tannate Products
You state that "(t)he tanate-containing APIs also fit within FDA's historical 'rush-tomarket' regulation (21 eFR 330.13), pursuant to which aTe products marketed on
cerain dates were permitted to remain on the market, with the recognition that the non-
final monograph could change before finalization," and if"a change were to occur, then
the product may need to be modified to meet the new requirements" (Petition at 22). You
state that under this rubric, "a product marketed after the publication of a proposed
monograph but before the effective date of a final monograph was allowed to be
marketed under that proposed monograph" (Petition at 22). You assert that because
"( c )oughco1d drug products containing the tannate salt form of varous active therapeutic
moieties were. . . marketed before (the date of a final monograph), . . . any tannatecontaining products marketed under this legal rubric are stil appropriately marketed
pursuant to this regulation today" (Petition at 23).96
Your Petition, however, mischaracterizes the "rush-to-market" regulation. The
circumstances described by the regulation under which products can be marketed without
applications do not apply to tanate coughcold products.
the OTC Drug Review.97 As an
initial step in the review, advisory panels covering varous OTC therapeutic classes
assessed data submitted in support of drgs marketed over the counter before the
inception of
the review in 1972, and then reported the results of
the assessment and
recommendations to FDA. Periodically, these panels would also discuss drugs offered
for indications within their purview that contained active ingredients marketed only by
prescription, or active ingredients marketed OTC at a lower dose and by prescription at a
The rush-to-market regulation was adopted as par of
higher dose. Sometimes the panel would conclude that products containing such a
9S As the Agency stated in the context of
the DESI review of
drgs: "The Commissioner recognzes that
apparent slight differences in drgs such as a salt, an ester, an isomer, and others, may produce very
different effects" (37 FR 23185 (October 31,1972)).
96 You state that, for example, a number of products containing taates were being marketed as of 1973
(e.g., Rynata Tablets, Rynatan Pediatrc Suspension, Rynatuss Pediatrc Suspension, Rynatuss Tablets).
97 21 CFR 330.13. For background on this regulation see the proposed and fmal rules at 40 FR 56675
(December 5, 1975) and 41 FR 32580 (August 4, 1976), respectively.
24
prescription active ingredient or at the higher, prescription dose, should be marketed
OTC.
Some firms began marketing products containing these prescription-only dosage levels or
ingredients as OTC products based on the panel discussions and recommendations, but
from FDA that it agreed with the paneL. FDA thus adopted the rush
to market regulation at § 330.13 to prevent this premature OTC marketing of drugs
previously marketed by prescription only. Section 330.13 clarified that prior to Agency
publication of a panel's recommendations regarding OTC marketing of these prescription
products in a proposed or tentative final monograph, such products when marketed OTC
are considered new drugs and subject to regulatory action. Once a non-final monograph
is published, this regulation permits firms to market products in accordance with it,
before any comment
subject to the risk that FDA, in the final monograph or otherise, may disagree with the
panel's recommendation and adopt a different position requiring relabeling, recall, or
98
other regulatory action.
The rush-to-market regulation is not, however, relevant to the marketing of the tanate
coughcold products and certainly does not serve as a basis for marketing without
application of any tannate product. First, no tanate products are marketed OTC, and this
regulation only pertains to drugs previously marketed by prescription that firms switched
to OTC status. Second, even if some tannates were marketed OTC, the tannate salts were
never discussed by the advisory panels as appropriate for OTC marketing nor were they
included in any proposed or tentative monograph, so the regulation simply does not
apply; no tanate product is marketed in accord with the conditions of a non-final
monograph. Lastly, the coughcold monograph is final; the proposed versions no longer
have any legal effect. The monograph components covering various coughcold
pharacological classes (antihistamines, antitussives, nasal decongestants, etc.) were
issued in final form between 1986 and 1994; the component covering permitted
combinations of these ingredients was published in final in 2002. The final monograph
governs the marketing of
aTe coughcold products marketed without applications,
and
as discussed, the tanate products are not in compliance with it.
E. Professional Labelig of OTC Drugs Has No Legal Bearing on the
Prohibition Against Marketing of OTC or Prescription CoughCold
Tannate Products
With regard to professional labeling, you state that "(a)s long as a lroduct meets the
monograph conditions, including the use of professional labeling9 . . ., FDA canot
98 21 CFR 330.13(b )(2).
99 Professional
labeling is defied by FDA as information that only a health care professional, and not the
general public, receives about a product. Professional labeling gives the physician information about
dosages or paricular indications that the physician may use, in his or her medical judgment, when deciding
whether to prescribe a paricular OTe medicine for a patient. This information is often dissemited via
the medical literatue, drug company samples for physicians, advertisements in professional publications,
and publication in such references as the Physician~' Desk Reference for prescription drgs (51 FR 35326,
35337 (October 2, 1986)).
25
force manufactrers to obtain NDAs for these products nor can the Agency require the
wholesale removal of these products from the market" (Petition at 31 ). You assert that
"(n)umerous OTC monographs, including the coughcold monograph, also include
special provisions pertaining to the optional use of professional labeling for certain
patient populations" (Petition at 32).
The provision in some OTC monographs for professional labeling is irrelevant to the
question of
whether tannate coughcold products are lawfully marketed without
applications. Professional labeling permits firms marketing monograph-compliant OTC
products to provide directly to health care professionals special labeling that is not
provided to consumers.IOO This practitioner-directed labeling gives the health care
professional directions for how to use the product in certain populations or for conditions
that require supervision of a licensed practitioner under section 503(b) of the Act (21 U.
S. C. 353(b)). When a monograph includes professional labeling, a product marketed
OTC has two sets of labeling: one directed at and provided to consumers that provides
adequate directions for safe
and effective use by a layperson, and one provided only to
health care professionals detailing uses that must be managed by a practitioner for the
professional labeling avoids the
product to be used safely and effectively. The use of
having the same drug product marketed both with and without
the Rx (prescription) only legend.
marketplace confusion of
Thus, the professional labeling provisions apply only to products marketed OTC and
would not apply to tannates as they are marketed only as prescription products.
Furherore, as described above, tanate coughcold products do not comply with the
OTC monographs in their active ingredients or conditions of
use. In other words, if
your
Petition is suggesting that tanate coughcold products are simply monograph-compliant
drugs marketed as prescription products with practitioner-directed labeling that reflects
both the aTe and prescription uses authorized by the monograph, this asserion is not
borne out by the labeling. Indeed, it is notable that many tanate products have labeling
for use in pediatrc populations much younger than even the monograph professional
labeling would permit, despite the lack of any studies showing that these products are
safe and effective in this pediatrc population, or identifyng the safe and effective dose.
F. The Fact that Products May Be Legally Marketed Both Rx and OTC
Has No Bearing on the Marketig Status of Tannate Products
In addition, you state that "there is no legal prohibition against the simultaneous
marketing of
the same API in both prescription and OTC products" (Petition at 12). You
state that "(a)ccording to FDA's interpretation of
the (Act), an API can be marketed both
in aTe and prescription products at the same time so long as there is a 'meanngful
difference' between the two products (e.g., a difference in indication, strength, route of
administration, or dosage form)" (Petition, at 12, citing 70 FR 52050 (September 1,
2005)). You claim that the Agency's decision regarding the simultaneous marketing of
100 Id.
26
Plan BtI TabletslOI both as an OTC and a prescription drug based solely on a difference
in patient age is precedent for allowing the simultaneous marketing of a coughcold
tanate product as both an aTe and a prescription drug (Petition at 12).
To be marketed under the coughcold monograph, tannate coughcold products would
have to be marketed OTC. The Agency, however, is not aware of any tanate coughcold
product that is marketed OTC; tanates are marketed as prescription products.
Whether a product as labeled meets the criteria under section 503(b) of
the Act to be
marketed as a prescription product is an entirely different question than whether the
product is lawfully marketed without an application. As noted above, FDA has not
identified any published literature, for any tannate product, of sufficient quality to
establish the product as GRAS/E, and these products do not comply with the coughcold
monograph; therefore, as a legal matter, approved applications are required. Given the
varation in dosages, labeled indications, intended patient population, and other
use among marketed tannate coughcold products, it is impossible to
generalize about whether these products could be properly marketed as prescription
products. Should a firm seek approval to market a tannate product, FDA would assess, as
part of
the application and for the paricular product, whether the product would need to
be limited to prescription status under section 503(b) and labeled accordingly.
conditions of
G. Your Petition That the Agency Refrain From Takig Enforcement
Action Against Unapproved CoughCold Tannate Products Is Denied
on Procedural Grounds
In your Petition, which you fied as a citizen petition under 21 CFR 10.30, you request
that the Agency refrain from taking any "categorical" enforcement action against tanate
coughcold products. Your request is denied on procedural grounds. Specifically, we
deny your request that the Agency refrain from taking any enforcement action relating to
such products because the relief you request canot be sought under § 10.30.102
As stated in § i 0.30(k), § 10.30 does not apply to "referral of a matter to a United States
attorney for the initiation of court enforcement action and related correspondence. . . ."
Agency decisions to take, or refraÍn from taking, enforcement actions are decisions
related to referral of a matter to a United States attorney for the initiation of court
enforcement action for violations of
the Act. Therefore, your request that the Agency
101 Plan B(ß (leyonorgestrel) is a contraceptive drg, oftn referred to as emergency contraception.
102 Although you have not petitioned for an administrative stay of
action under 21 CFR 10.35, we note that
the relief you request also canot be sought under tht regulation because the relief you seek does not fall
within the scope of an "administrative action" that may be the subject of such a petition for stay. FDA's
regulations define "administrative action" to include "an act, including the refusal or failure to act, involved
in the administration of any law by the Commissioner, except that it does not include the referral of
apparent violations to U.S. attorneys for the institution of civil or criminal
preparation ofa referral" (21 CFR 10.3) (emphasis added).
27
proceedings or an act in
refrain from taking any "categorical enforcement action against coughcold drug products
containing tannates" may not properly be the subject of a citizen petition under § 10.30.
Federal courts reflect this same principle: Decisions relating to enforcement rest within
the Agency's discretion and are not subject to review. Courts have long recognized that
they lack jurisdiction to enjoin FDA from initiating enforcement proceedings under the
Act or to review Agency decisions not to exercise its enforcement authority. The
Supreme Court has held that federal distrct courts do not have jurisdiction to review an
FDA determination that there is cause to believe that a product violates the Act because
Congress, in passing the Act, did not intend to permit pre-enforcement
103
judicial review.
Similarly, the Supreme Cour has also found that FDA decisions not to exercise
enforcement authority under the Act are not subject to judicial review under the
Administrative Procedure Act (APA).104 FDA's decisions with respect to initiating
enforcement action are within the discretion ofthe Agency and are not reviewable. Under
FDA regulations, your request that the Agency refrain from enforcement action is beyond
the scope of the Agency's citizen petition procedures and is, therefore, denied.
H. The Agency May Take Enforcement Action Against Unapproved
Cough/Cold Tannate Products Without Engaging in Rulemakig
Finally, although your Petition that the Agency refrain from taking enforcement action is
denied on procedural grounds, we also take this opportnity to address the arguments you
raise in support of your contention that the Agency cannot take enforcement action
against tannate-containing coughcold products without engaging in rulemaking.
"FDA decides to take categorical enforcement action against tannatecontaining coughcold products, such action wil violate every tenet of administrative due
process" (Petition at 7). You base this assertion on the alleged GRAS/E status of
these
drugs, which you claim results from FDA's "historical enforcement approach that. . .
You state that if
(tanate-containing cough/cold products) are GRAS/E, are legally marketed, and may
continue to be legally marketed" (Petition at 6). You believe that this alleged GRAS/E
status would prohibit categorical removal from the market, and that the Agency may
proceed with enforcement action against these drug products only after engaging in the
rulemaking process and any resulting administrative hearing (Petition at 7). You state
that "any FDA action that does not proceed via notice and comment rulemaking as
regulating this
required by the Agency's aTe drug regulations, the Agency's history of
area, and due process. . ." would be "arbitrar, capricious, and uneasonable. . .," and
"undermine over thirty years of regulation by rulemaking" (Petition at 6-7).
First, your claim that the Agency has historically regulated in this area by rulemaking is
erroneous. The Agency has regulated OTC cough/cold products by rulemaking, as par
ofthe OTe Drug Review established by the regulations in 21 eFR part 330. However,
the tanate coughcold products are not marketed as OTC products; they are only
103Ewing v. Mytinger & Casselberr, Inc., 339 U.S. 594,600-601 (1950).
104 Hecklerv. Chaney, 470 U.S. 821 (1985).
28
the aTe Drug Review did
not in any way limit the Agency's authority to take action against unapproved
prescription drugs. Nor does the aTe Drug Review commit the FDA to notice-andcomment rulemaking to address the status of any prescription products; it applies solely
to OTC products. As stated in section LD ofthis response (and reiterated throughout),
the tanate-containing coughcold products are not covered by the coughcold OTC
marketed as prescription products. FDA's establishment of
monograph, and as a result are not subject to the monograph. Thus, even if a tanatecontaining coughcold product were to Qe marketed OTC, it would be an unapproved new
drug that requires an approved NDA to be legally marketed. Nothing in the Act or the
AP A requires FDA to use rulemaking to determine the new drug status of any product or
set of products, prescription or otherwise.
Moreover, FDA does not take "categorical enforcement action" against classes of drugs.
FDA has issued Federal Register notices advising firms marketing various classes of
unapproved drugs that their products are in fact new drugs that require an approved
application in order to be legally marketed, and describing the conditions under which the
Agency intends to take enforcement action against such products. 105 These notices are
not required by the AP A, the Act, any rules issued under the authority of the Act, or any
other legal reason, for the Agency to take enforcement action against an unapproved new
drug product. The Agency issues such notices at its discretion as an efficient mechanism
for securing firms' compliance
with the new drug approval requirements. If
and when
FDA decides to initiate enforcement action (e.g., a seizure or injunction), it does so with
respect to specific products based on a determination that those paricular products are
violative, and not against an entire class of products.
Your other arguments regarding the need for notice-and-comment rulemaking to take
action against the tanate products are also meritless. For example, you state that FDA's
"acquiescence in the marketing of tanate-containing products has created a legally
justified reliance" that the Agency views the products as lawfully marketed GRAS/E
products (Petition at 6). Ths is not correct. FDA is not estopped from enforcing the
requirements of
the Act because it has not previously enforced those requirements against
one or more firms who market unapproved and violative products. 106 As discussed
above, tanate coughcold products are not GRAS/E; manufactuers of such products,
which are unapproved new drugs, are not entitled to distrbute those products simply
because FDA has not previously taken action to stop them from doing so.
los Some examples include carbinoxamine, 71 FR 33462 (June 9,2006); quinne, 71 FR 75557 (December
15,2006); guaifenesin combinations in extended-release form, 72 FR 29517 (May 29,2007);
hydrodcodone, 72 FR 55780 (October 1, 2007); and papain~ 73 FR 54831 (September 23, 2008).
106 Scott Paper Co. v. Marcalus Manufacturing Co., 326 U.S. 249, 257 (1945); Donovan v. Daniel Marr &
Son. Co., 763 F.2d 477,484 (1st Cir. 1985); United States v. Undetermined Quantities of
Clear Plastic
Bags of an Articlefor Veterinary Use, 963 F. Supp. 641, 646-647, affd 1998 U.S. App. LEXIS 9320 at *3-
4 (6th Cir. Ohio May 4, 1998); United States v. 789 Cases of Latex Surgeons' Gloves, 799 F. Supp. 1275,
1297 (D.P.R. 1992).
29
Furthermore, your assertion of a need for notice-and-comment rulemaking
unapproved new drugs.
mischaracterizes FDA's historical approach to the marketing of
Since passage of
the Kefauver-Harrs Amendments and the implementation of
the DES
I
review required by those Amendments, FDA has made numerous determinations
regarding the new drug status of marketed unapproved drugs and has taken appropriate
actions, including enforcement actions. Because the Agency does not have the resources
to immediately and simultaneously take'action against all unapproved
new drugs, it
prioritizes its enforcement efforts and exercises enforcement discretion with regard to
certain unapproved products that remain on the market.
The Agency's enforcement policies and priorities with respect to marketed unapproved
drugs have been set out in Compliance Policy Guides (CPGs) dating back to 1976.107
That initial ePG stated that the Agency's policy was generally to defer action on
unapproved drugs until the Agency made DESI and other determinations regarding their
status as new drugs. In 2003, with the DESI review virtally complete, the Agency
issued a draft version of
the current marketed unapproved drugs ePG, finalizing the CPG
in 2006 in accordance with FDA's good guidance practice regulations (21 CFR 10.1 15),
including the opportnity for notice and comment on the proposed policy. The current
Marketed Unapproved Drugs CPGIOS clearly outlines the Agency's current enforcement
priorities with respect to marketed unapproved drugs. It also states that it is intended to
provide notice that any product that is being marketed ilegally is subject to enforcement
action at any time.
III. CONCLUSION
For the reasons stated above, your Petition is denied.
e Wo
Director
Center for Drug Evaluation and Research
107 For a discussion of
versions of
the CPG under which the Agency operated until 2006, see 49 FR 38190
(September 27, 1984).
los See note 20
30