[Federal Register Volume 65, Number 15 (Monday, January 24, 2000)]
[Proposed Rules]
[Pages 3623-3627]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-1536]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 314

[Docket No. 99N-3088]
RIN 0910-AB33


Marketing Exclusivity and Patent Provisions for Certain 
Antibiotic Drugs

AGENCY:  Food and Drug Administration, HHS.

ACTION:  Proposed rule.

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SUMMARY:  The Food and Drug Administration (FDA) is proposing 
regulations to exempt marketing applications for certain antibiotic 
drug products from regulatory provisions governing marketing 
exclusivity and patents. The proposal would apply to marketing 
applications for drug products containing an antibiotic drug that was 
the subject of a marketing application received by FDA before November 
21, 1997, the effective date of the Food and Drug Administration 
Modernization Act of 1997 (Modernization Act). This action is intended 
to bring the agency's regulations into conformance with certain 
transitional provisions of the Modernization Act. FDA is including in 
the proposed regulation a list of the active moieties of antibiotic 
drugs that were the subjects of marketing applications received by FDA 
before November 21, 1997.

DATES:  Written comments by April 24, 2000.

ADDRESSES:  Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT:  Wayne H. Mitchell, Center for Drug 
Evaluation and Research (HFD-7), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-594-2041.

SUPPLEMENTARY INFORMATION:

I. The Modernization Act

    On November 21, 1997, the President signed the Modernization Act 
(Public Law 105-115). Section 125(b) of the Modernization Act repealed 
section 507 of the Federal Food, Drug, and Cosmetic Act (the act) (21 
U.S.C. 357 (1996)). Section 507 was the section of the act under which 
the agency certified antibiotic drugs. Section 125(b) of the 
Modernization Act also made conforming amendments to the act.
    In the Federal Register of May 12, 1998 (63 FR 26066), and January 
5, 1999 (64 FR 396), the agency issued conforming amendments to its 
regulations to remove provisions governing certification of antibiotic 
drugs (21 CFR parts 430 to 460) and to make other changes needed to 
reflect the repeal of section 507 of the act.
    Section 125(d)(1) of the Modernization Act provides that marketing 
applications for antibiotic drugs that were approved under former 
section 507 of the act will be considered to have been submitted and 
approved under the new drug application (NDA) submission and approval 
provisions found at section 505(b) and (c) of the act (21 U.S.C. 355(b) 
and (c)). If the marketing application was an approved abbreviated 
antibiotic drug application, it will be considered to have been 
submitted and approved under the abbreviated new drug application 
(ANDA) provisions found in section 505(j) of the act.
    The Modernization Act also exempts certain antibiotic-related drug 
marketing applications from the marketing exclusivity and patent 
provisions found

[[Page 3624]]

in section 505 of the act.\1\ Under former section 507 of the act, 
antibiotic drug applications were not subject to the patent listing and 
exclusivity provisions in section 505 of the act. Section 125 of the 
Modernization Act preserves this distinction with an expansive line. 
Section 125 exempts those applications that contain an antibiotic drug 
that was the subject of a marketing application received by FDA under 
former section 507 of the act before November 21, 1997 (prerepeal 
antibiotic drugs). Drugs that were approved and marketed under former 
section 507 of the act, as well as those that were the subject of 
applications that may have been withdrawn, not filed, or refused 
approval under section 507 of the act are excluded from the patent 
listing and exclusivity provisions.
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    \1\ The Modernization Act does not affect whatever rights patent 
holders may have regarding patent term extensions under 35 U.S.C. 
156 for patents claiming antibiotic drug products.
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    Specifically, section 125(d)(2) of the Modernization Act provides 
that marketing applications for drug products that contain prerepeal 
antibiotic drugs are not subject to the following provisions of section 
505 of the act:
     The third and fourth sentences of section 505(b)(1) 
(requiring submission of patent information in NDA's).
     Section 505(b)(2)(A) (requiring that 505(b)(2) 
applications contain patent certifications).
     Section 505(b)(2)(B) (requiring that applications 
submitted under section 505(b)(2) of the act (505(b)(2) applications) 
contain a statement about relevant method of use patents).
     Section 505(b)(3) (requiring applicants submitting 
505(b)(2) applications (505(b)(2) applicants) to provide notice to the 
patent owner and NDA holder of the certification of invalidity or 
noninfringement of a patent).
     Section 505(c)(2) (requiring submission of patent 
information if that information becomes available after an NDA is 
submitted).
     Section 505(c)(3) (providing for delayed effective dates 
of approval of 505(b)(2) applications under patent provisions of the 
act).
     Section 505(d)(6) (allowing FDA to refuse to approve an 
application that does not contain required patent information).
     Section 505(e)(4) (requiring FDA to withdraw approval of 
an application if the applicant refuses to submit required patent 
information).
     Section 505(j)(2)(A)(vii) and (j)(2)(A)(viii) (requiring 
ANDA's to contain patent certifications or other patent information).
     Section 505(j)(2)(B) (requiring ANDA applicants to provide 
notice to the patent owner and NDA holder of the certification of 
invalidity or noninfringement of a patent).
     Section 505(j)(5)(B) (providing for delayed effective 
dates of approval of ANDA's under patent provisions of the act).\2\
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    \2\ The Modernization Act added a new section 505(j)(3) to the 
act. This resulted in the renumbering of sections 505(j)(3) through 
(j)(8) as sections 505(j)(4) through (j)(9), respectively.
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     Section 505(j)(5)(D) (describing submission of and 
effective dates of approval of ANDA's under marketing exclusivity 
provisions of the act).
    Section 125(d)(3) of the Modernization Act authorizes FDA to make 
available to the public the established name of each antibiotic drug 
that was the subject of a marketing application received by FDA under 
former section 507 of the act before November 21, 1997.

II. Description of the Rule

 A. List of Regulatory Provisions That Are Not Applicable

    This proposed rule would exempt from the regulatory requirements 
that correspond to the statutory requirements described above, 
applications or abbreviated applications in which the drug product that 
is the subject of the application contains a pre-repeal antibiotic 
drug. Specifically, under the proposed rule, the following provisions 
found in part 314 (21 CFR part 314) would not apply to marketing 
applications for drug products that contain pre-repeal antibiotic 
drugs:
     Sections 314.50(h) and 314.53 (relating to submission of 
patent information in NDA's).
     Section 314.50(i) (relating to patent certifications and 
statements about relevant method of use patents in 505(b)(2) 
applications).
     Section 314.52 (relating to notices to the patent owner 
and NDA holder of certification of invalidity or noninfringement of a 
patent by 505(b)(2) applicants).
     Section 314.94(a)(12) (relating to patent certifications 
and statements about relevant method of use patents in ANDA's).
     Section 314.95 (relating to notices to the patent owner 
and NDA holder of certification of invalidity or noninfringement of a 
patent by ANDA applicants).
     Section 314.107(b) through (f) (relating to delayed 
effective dates of approval of ANDA's and 505(b)(2) applications under 
patent provisions of the act).
     Section 314.108(b) (relating to submission of and 
effective dates of approval of ANDA's and 505(b)(2) applications under 
marketing exclusivity provisions of the act).
     Section 314.125(b)(18) (relating to refusal to approve an 
NDA that does not contain required patent information).
     Section 314.150(a)(2)(v) (relating to withdrawal of 
approval of an NDA if the applicant refuses to submit required patent 
information).
    The brief parenthetical descriptions of the various provisions of 
part 314 in this section and in the codified portion of this proposed 
rule (as well as the similar descriptions of provisions of section 505 
of the act given in section I of this document) are provided merely as 
aids to the reader in understanding the scope of the proposed rule. 
They are not intended to have any regulatory significance and should 
not be understood to be statements of agency policy regarding the 
provisions they describe.

B. List of Pre-Repeal of Antibiotic Drugs

    In applying section 125(d)(2) of the Modernization Act, the agency 
must determine whether a drug that is the subject of an NDA or ANDA 
contains a pre-repeal antibiotic drug. As described in section I, the 
Modernization Act specifies patent listing and exclusivity provisions 
that will not apply when the drug that is the subject of any 
application contains an antibiotic drug, and the antibiotic drug was 
the subject of any application received under section 507 of the act 
prior to November 21, 1997. Section 125(d)(3) of the Modernization Act 
also authorizes FDA to publish the established name of each antibiotic 
drug that was the subject of any application for marketing received by 
FDA under former section 507 of the act.
    The term ``antibiotic drug,'' as used in section 125(d) of the 
Modernization Act, is defined as:

    * * * any drug (except drugs for use in animals other than 
humans) composed wholly or partly of any kind of penicillin, 
streptomycin, chlortetracycline, chloramphenicol, bacitracin, or any 
other drug intended for human use containing any quantity of any 
chemical substance which is produced by a micro-organism and which 
has the capacity to inhibit or destroy micro-organisms in dilute 
solution (including a chemically synthesized equivalent of any such 
substance) or any derivative thereof.

21 U.S.C. 321(jj)
    Thus, the term ``antibiotic drug'' includes not only the ``chemical 
substance which is produced by a

[[Page 3625]]

micro-organism,'' and which ``has the capacity to inhibit or destroy 
micro-organisms,'' but also ``any derivative'' of any such substance, 
such as a salt or ester of the substance.
    For this reason, and the reasons discussed below, the determination 
under section 125(d) of the Modernization Act of whether a drug 
contains a pre-repeal antibiotic depends on whether the drug that is 
the subject of a marketing application contains an active moiety that 
can be found in a pre-repeal antibiotic drug.
    An active moiety is the molecule or ion responsible for 
physiological or pharmacological action, excluding appended portions 
that would cause the drug to be an ester, salt, or other noncovalent 
derivative of the molecule (see Sec. 314.108(a)). FDA has consistently 
looked at active moieties to determine if the exclusivity protection 
granted to a drug product would allow a subsequent ANDA or application 
described in section 505(b)(2) of the act to be submitted or approved.
    The agency's primary regulation governing marketing exclusivity is 
found at Sec. 314.108. This regulation, which was proposed in the 
Federal Register of July 10, 1989 (54 FR 28872), and made final in the 
Federal Register of October 3, 1994 (59 FR 50338), incorporated an 
interpretation of the Drug Price Competition and Patent Term 
Restoration Act of 1984 (Public Law 98-417) (the Hatch-Waxman 
Amendments) that had been adopted by the agency shortly after the 
enactment of the Hatch-Waxman Amendments on September 24, 1984. The 
Hatch-Waxman Amendments established the exclusivity and patent 
provisions that are addressed by the exemptions described in section 
125(d)(2) of the Modernization Act, and are the subject of this 
rulemaking. In interpreting the exclusivity provisions in the Hatch-
Waxman Amendments, the agency concluded that Congress did not intend to 
confer significant periods of exclusivity on minor variations of 
previously approved chemical compounds. (See, e.g., Congressional 
Record H9124 (September 6, 1984) (statement of Representative Waxman); 
H. Rept. 857, Part I, 98th Cong., 2d sess. 38 (1984).) Therefore, the 
agency determined that it is appropriate to assess whether the drug 
seeking exclusivity is a new chemical entity, that is, a drug that does 
not contain any previously approved active moiety.
    This approach is also consistent with FDA's drug classification 
system, which assesses and classifies NDA's based upon the 
characteristics of the active ingredient or ingredients of the product. 
(See 54 FR 28872 at 28897.)
    The language of section 125(d)(2) of the Modernization Act likewise 
supports the conclusion that Congress did not intend to confer 
exclusivity on, or require patent listing for, products that represent 
minor or incremental variations on pre-repeal antibiotic drugs. As 
discussed above, Congress in section 125(d)(2) of the Modernization Act 
chose to exclude all drugs containing pre-repeal ``antibiotic drugs,'' 
a term that by definition includes the active drug substance and ``any 
derivative thereof'' (see section 201(jj) of the act (21 U.S.C. 
321(jj)).
    Accordingly, the agency is proposing to implement section 125(d)(2) 
of the Modernization Act by relying on a comparison of active moieties 
to determine whether the drug that is the subject of an NDA contains a 
pre-repeal antibiotic drug. NDA's for products that contain, for 
example, a salt of a pre-repeal antibiotic drug, or that propose such 
things as a new manufacturing process, new dosage form, or new use of a 
pre-repeal antibiotic drug, will be subject to the exceptions listed in 
section 125(d)(2) of the Modernization Act and proposed 
Sec. 314.109(a).
    To help interested persons determine which drug products would be 
exempt from the marketing exclusivity and patent provisions described 
above, FDA will maintain in the Code of Federal Regulations a list of 
the names of each pre-repeal active moiety. A proposed version of that 
list is included as Sec. 314.109(b).
    The list will provide all of the information required for an 
interested person to determine whether a marketing application is for a 
drug that contains a pre-repeal antibiotic drug. The list is intended 
to be comprehensive, but the inadvertent omission of an active moiety 
found in a pre-repeal antibiotic drug will not affect the regulatory 
status of a marketing application for a drug that contains that active 
moiety; the application will still be exempt from the statutory and 
regulatory requirements regarding marketing exclusivity and patents 
described above. A person who believes that a drug has been improperly 
included or omitted from the list should submit to the Dockets 
Management Branch (address above) written comments suggesting 
amendments to the list, along with any information that supports the 
suggested amendments. Comments should be identified with the docket 
number found in brackets in the heading of this document.

III. Environmental Impact

    The agency has determined under 21 CFR 25.30(h) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

IV. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the 
Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory alternatives and, when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). Executive Order 12866 
classifies a rule as significant if it meets any one of a number of 
specified conditions, including having an annual effect on the economy 
of $100 million or adversely affecting in a material way a sector of 
the economy, competition, or jobs, or if it raises novel legal or 
policy issues. The agency believes that this proposed rule is 
consistent with the regulatory philosophy and principles identified in 
the Executive Order. Because, the proposed rule is a significant 
regulatory action as defined by the Executive Order and it was subject 
to review under the Executive Order.
    The Regulatory Flexibility Act requires that if a rule has a 
significant economic impact on a substantial number of small entities, 
the agency must analyze regulatory options to minimize the economic 
impact on small entities. The agency certifies, for the reasons 
discussed below, that the proposed rule will not have a significant 
economic impact on a substantial number of small entities. Therefore, 
under the Regulatory Flexibility Act, no further analysis is required.
    The Unfunded Mandates Reform Act requires an agency to prepare a 
budgetary impact statement before issuing any rule likely to result in 
a Federal mandate that may result in expenditures by State, local, and 
tribal governments or the private sector of $100 million (adjusted 
annually for inflation) in any one year. Exempting applications for 
certain antibiotic drugs from regulatory provisions dealing with 
marketing exclusivity and patent information will not result in any

[[Page 3626]]

increased expenditures by State, local, and tribal governments or the 
private sector. Because this proposed rule will not result in an 
expenditure of $100 million or more by any governmental entity or the 
private sector, no budgetary impact statement is required.
    This proposed rule is intended to bring FDA's regulations governing 
the new drug approval process into conformance with the transitional 
provisions found in section 125(d)(2) of the Modernization Act. This 
proposed rule is not intended to create any rights or responsibilities 
that are not found in the statute. For these reasons, the agency 
believes that this proposed rule is necessary and that it is consistent 
with the principles of Executive Order 12866; that it is not a 
significant regulatory action under that Executive Order; that it will 
not have a significant economic impact on a substantial number of small 
entities; and that it is not likely to result in an annual expenditure 
in excess of $100 million.

V. Paperwork Reduction Act of 1995

    FDA tentatively concludes that this proposed rule contains no 
collections of information. Therefore, clearance by the Office of 
Management and Budget under the Paperwork Reduction Act of 1995 is not 
required.

VI. Request for Comments

    Interested persons may, on or before April 24, 2000, submit to the 
Dockets Management Branch (address above) written comments regarding 
this proposal. Two copies of any comments are to be submitted, except 
that individuals may submit one copy. Comments are to be identified 
with the docket number found in brackets in the heading of this 
document. Received comments may be seen in the office above between 9 
a.m. and 4 p.m., Monday through Friday.

List of Subjects in 21 CFR Part 314

    Administrative practice and procedure, Confidential business 
information, Drugs, Reporting and recordkeeping requirements.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR part 314 be amended as follows:

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG

    1. The authority citation for 21 CFR part 314 is revised to read as 
follows:

    Authority:  21 U.S.C. 321, 331, 351, 352, 353, 355, 371, 374, 
379e; sec. 125(d), Pub. L. 105-115, 111 Stat. 2296.

    2. Add Sec. 314.109 to subpart D to read as follows:


Sec. 314.109  Marketing exclusivity and patent provisions not 
applicable to certain antibiotic-related drug marketing applications.

    (a) The following regulatory provisions do not apply to any 
application or abbreviated application in which the drug that is the 
subject of the application or abbreviated application contains an 
antibiotic drug that has the same active moiety (as defined in 
Sec. 314.108(a)) as an antibiotic drug that was the subject of a 
marketing application received by FDA under former section 507 of the 
act (21 U.S.C. 357 (1996)) before November 21, 1997:
    (1) Sections 314.50(h) and 314.53 (relating to submission of patent 
information in applications).
    (2) Section 314.50(i) (relating to patent certifications and 
statements about relevant method of use patents in 505(b)(2) 
applications).
    (3) Section 314.52 (relating to notices of certification of 
invalidity or noninfringement of a patent by 505(b)(2) applicants).
    (4) Section 314.94(a)(12) (relating to patent certifications and 
statements about relevant method of use patents in 505(j) 
applications).
    (5) Section 314.95 (relating to notices of certification of 
invalidity or noninfringement of a patent by 505(j) applicants).
    (6) Section 314.107(b) through (f) (relating to delayed effective 
dates of approval of 505(j) applications and 505(b)(2) applications 
under patent provisions of the act).
    (7) Section 314.108(b) (relating to submission of and effective 
dates of approval of 505(j) applications and 505(b)(2) applications 
under marketing exclusivity provisions of the act).
    (8) Section 314.125(b)(18) (relating to refusal to approve an 
application that does not contain required patent information).
    (9) Section 314.150(a)(2)(v) (relating to withdrawal of approval of 
an application if the applicant refuses to submit required patent 
information).
    (b) The following are the active moieties of antibiotic drugs that 
were the subject of marketing applications received by FDA under former 
section 507 of the act before November 21, 1997. The list is intended 
to be comprehensive, but the inadvertent omission of an active moiety 
will not affect the regulatory status of a marketing application for a 
drug product that contains that active moiety.

Almecillin

Amdinocillin

Amikacin

Amoxicillin

Amphomycin

Amphotericin B

Ampicillin

Azacitidine

Azaserine

Azithromycin

Azlocillin

Aztreonam

Bacampicillin

Bacitracin

Benzyl penicilloyl-polylysine

Bleomycin

Candicidin

Capreomycin

Carbenicillin

Cefaclor

Cefadroxil

Cefamandole

Cefazolin

Cefdinir

Cefepime

Cefixime

Cefmenoxime

Cefmetazole

Cefodizime

Cefonicid

Cefoperazone

Ceforanide

Cefotaxime

Cefotetan

Cefotiam

Cefoxitin

Cefpiramide

Cefpodoxime

Cefprozil

Cefsulodin

Ceftazidime

Ceftibuten

Ceftizoxime

Ceftriaxone

Cefuroxime

Cephacetrile

Cephalexin

Cephaloglycin

Cephaloridine

Cephalothin

Cephapirin

Cephradine

Chloramphenicol

Chlortetracycline

Cilastatin

Clarithromycin

Clavulanate/clavulanic acid

Clindamycin

Clioquinol

[[Page 3627]]


Cloxacillin

Colistimethate

Colistin

Cyclacillin

Cycloserine

Cyclosporine

Dactinomycin

Dalfopristin

Daunorubicin

Demeclocycline

Detorubicin

Dicloxacillin

Dihydrostreptomycin

Dirithromycin

Doxorubicin

Doxycycline

Epirubicin

Erythromycin

Floxacillin

Fosfomycin

Fusidate/fusidic acid

Gentamicin

Gramicidin

Griseofulvin

Hetacillin

Idarubicin

Imipenem

Ivermectin

Kanamycin

Lincomycin

Loracarbef

Meclocycline

Meropenem

Methacycline

Methicillin

Mezlocillin

Minocycline

Mitomycin

Moxalactam

Mupirocin

Mycophenolate/mycophenolic acid

Nafcillin

Natamycin

Neomycin

Netilmicin

Niphimycin

Novobiocin

Nystatin

Oleandomycin

Oxacillin

Oxytetracycline

Paromomycin

Penicillamine

Penicillin G

Penicillin V

Phenethicillin

Piperacillin

Plicamycin

Polymyxin B

Quinupristin

Rifabutin

Rifampin

Rifamycin

Rolitetracycline

Sisomicin

Spectinomycin

Streptomycin

Streptozocin

Sulbactam

Sultamicillin

Tacrolimus

Tazobactam

Teicoplanin

Tetracycline

Ticarcillin

Tobramycin

Troleandomycin

Tyrothricin

Vancomycin

Vidarabine

Viomycin

    Dated: October 5, 1999.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 00-1536 Filed 1-21-00; 8:45 am]
BILLING CODE 4160-01-F