[Federal Register Volume 68, Number 148 (Friday, August 1, 2003)]
[Notices]
[Pages 45252-45256]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-19590]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 2003D-0325]


Guidance for Industry on 180-Day Exclusivity When Multiple 
Abbreviated New Drug Applications Are Submitted on the Same Day; 
Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing the 
availability of a guidance for industry entitled ``180-Day Exclusivity 
When Multiple ANDAs Are Submitted on the Same Day.'' This guidance 
explains how FDA intends to determine eligibility for 180-day 
exclusivity when multiple substantially complete abbreviated new drug 
applications (ANDAs) that contain a paragraph IV certification to the 
same

[[Page 45253]]

patent(s) are submitted on the same day or when paragraph IV 
certifications are submitted in an amendment or supplement on the same 
day.

DATES: Submit written or electronic comments on agency guidances at any 
time.

ADDRESSES: Submit written requests for single copies of this guidance 
to the Division of Drug Information (HFD-240), Center for Drug 
Evaluation and Research (CDER), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857. Send one self-addressed adhesive 
label to assist that office in processing your requests. Submit written 
comments on the guidance to the Division of Dockets Management (HFA-
305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/dockets/ecomments. See the SUPPLEMENTARY INFORMATION section for 
electronic access to the guidance document.

FOR FURTHER INFORMATION CONTACT: Cecelia Parise, Center for Drug 
Evaluation and Research (CDER) (HFD-600), Food and Drug Administration, 
7500 Standish Pl., Rockville, MD 20855, 301-827-5845.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a guidance for industry 
entitled ``180-Day Exclusivity When Multiple ANDAs Are Submitted on the 
Same Day.'' This guidance document provides information to sponsors 
and/or applicants regarding how the agency intends to determine 
eligibility for 180-day exclusivity under section 505(j)(5)(B)(iv) of 
the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C 
355(j)(5)(B)(iv)) when multiple ANDA applicants submit a paragraph IV 
certification to a listed patent on the same day and no paragraph IV 
certification to the patent has been submitted on any previous day.

A. Statute and Regulations

    A new drug application (NDA) applicant must include in its NDA 
information about any patents that claim the drug product that is the 
subject of the NDA or the use of such drug product (section 505(b)(1) 
and (c)(2) of the act). FDA publishes this patent information upon 
approval of the NDA or a supplemental NDA in ``Approved Drug Products 
with Therapeutic Equivalence Evaluations,'' which is generally known as 
the ``Orange Book.''
    An ANDA applicant must include in its ANDA a patent certification 
as described in section 505(j)(2)(A)(vii) of the act. The certification 
must make one of the following statements: (1) Such patent information 
has not been filed; (2) such patent has expired; (3) the date on which 
such patent expires; or (4) such patent is invalid or will not be 
infringed by the manufacture, use, or sale of the drug product for 
which the ANDA is submitted. This last certification is known as a 
paragraph IV certification. The ANDA applicant must provide appropriate 
notice of a paragraph IV certification to each owner of the patent that 
is the subject of the certification and to the holder of the approved 
NDA to which the ANDA refers (section 505(j)(2)(B)(i) of the act (part 
314 (21 CFR part 314))).
    The act provides an incentive for generic drug manufacturers to 
file paragraph IV certifications and challenge listed patents as 
invalid or not infringed, thereby permitting generic drugs to reach the 
market more quickly. Section 505(j)(5)(B)(iv) of the act provides for a 
180-day period of marketing protection for certain ANDA products as 
follows:
    If the [ANDA] contains a [paragraph IV certification] and is for 
a drug for which a previous application has been submitted under 
this subsection continuing [sic] such a certification, the 
application shall be made effective not earlier than one hundred and 
eighty days after-
    (I) the date the Secretary receives notice from the applicant 
under the previous [ANDA] of the first commercial marketing of the 
drug under the previous [ANDA], or
    (II) the date of a decision of a court in [a patent infringement 
action] holding the patent which is the subject of the certification 
to be invalid or not infringed, whichever is earlier (emphasis 
added).
    The statute does not further define the phrase ``for which a 
previous application has been submitted.'' In its regulation at Sec.  
314.107(c), FDA uses both the terms ``previously submitted'' and 
``first'' in implementing this provision of the statute. It adopts the 
phrase ``for which one or more substantially complete abbreviated new 
drug applications were previously submitted'' to restate the conditions 
under which exclusivity will apply. The regulation at Sec.  
314.107(c)(1)(i) states that exclusivity may begin to run from ``[t]he 
date the applicant submitting the first application first commences 
commercial marketing of its drug product.'' The phrase ``applicant 
submitting the first application'' is defined in the regulation as 
``the applicant that submits an application that is both substantially 
complete and contains a certification that the patent was invalid, 
unenforceable, or not infringed prior to the submission of any other 
application for the same listed drug that is both substantially 
complete and contains the same certification.'' (Sec.  314.107(c)(2)) 
Thus, the agency has adopted the terms ``previous,'' ``first,'' and 
``prior'' to identify the ANDA eligible for exclusivity. However, the 
agency has not elaborated on how these terms should be applied when 
more than one applicant submits a paragraph IV certification to the 
same patent on the same day.

B. 180-Day Exclusivity and Different Day Patent Certifications

    The statute and the regulations at Sec.  314.107(c) are 
straightforward to apply when ANDAs, amendments, or supplements are 
submitted to FDA on different days. An ANDA submitted on the day before 
another application is submitted, when no application has been 
submitted on an earlier day, is clearly the ``previous,'' the ``prior'' 
and the ``first'' application. To date, FDA's exclusivity decisions 
have involved applications or amendments submitted on different days, 
and thus have not required additional interpretation of the statute or 
regulations on this point.
    Recently, FDA has had to consider how to apply the 180-day 
exclusivity provision when multiple challenges to the same patent are 
submitted on the same ``first'' day. After the decisions in Mova 
Pharmaceuticals, Inc. v. Shalala, 140 F.3d 1060 (D.C.Cir. 1998) 
andGranutec, Inc. v. Shalala, 46 U.S.P.Q.2d 1398 (4th Cir. 1998), the 
first applicant who submits a substantially complete ANDA containing a 
paragraph IV certification to a listed patent is eligible for 180-day 
generic drug exclusivity.\1\ As noted in a 1999 citizen petition 
response,\2\  many of the current regulations were adopted prior to the 
Mova decision, when the agency interpreted the statute to require that 
an ANDA applicant had to be sued and win its patent litigation to 
qualify for 180-day exclusivity. FDA's pre-Mova interpretation limited 
the number of times 180-day exclusivity was awarded because an ANDA 
applicant had to be first to challenge a patent and then win the patent 
litigation to be eligible for 180-day exclusivity. The chance of

[[Page 45254]]

having multiple ANDA applicants qualify for 180-day exclusivity was 
extremely low, as evidenced by the number of times that 180-day 
exclusivity was granted.\3\ By contrast, after the Mova decision, it is 
now relatively easy to qualify for 180-day exclusivity. As a result, 
FDA has had to address a number of new issues, including eligibility 
for exclusivity when multiple paragraph IV certifications are submitted 
on the same day.
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    \1\ The regulatory history of this issue has been previously 
described in the June 1998 CDER guidance for industry entitled 
``180-Day Generic Drug Exclusivity Under the Hatch-Waxman Amendment 
to the Federal Food, Drug, and Cosmetic Act.''
    \2\ See response to 99P-1271/PSA1 and PSA2 issued August 2, 
1999.
    \3\ In the years from 1984 to 1998, only three ANDA applicants 
qualified for 180-day exclusivity. Since the Mova decision in 1999, 
more than 60 ANDAs have received 180 days of exclusivity.
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    Congress did not address the possibility that multiple applicants 
would submit patent challenges to FDA on the same day in the 180-day 
exclusivity provisions of the act. Similarly, FDA regulations now in 
effect do not address this specific situation. However, in an August 
1999 proposed rule addressing 180-day exclusivity issues, FDA proposed 
an approach whereby all applicants submitting a paragraph IV 
certification to a patent on the first day such a certification is 
submitted are ``first applicants'' for 180-day exclusivity purposes (64 
FR 42873, August 6, 1999). FDA received comments both for and against 
this approach (see Docket No. 85N-0214). The August 1999 proposed rule 
was withdrawn in November 2002 for reasons unrelated to the merits of 
the multiple first applicant approach (67 FR 66593, November 1, 2002). 
When the proposed rule was withdrawn, the agency noted it would 
continue to regulate directly from the statute and any applicable 
regulations, and make decisions on an issue-by-issue basis. The agency 
continues to believe that the approach to multiple first day patent 
challenges described in the proposed rule is a reasonable and 
appropriate interpretation of the statute. Two citizen petitions have 
specifically asked the agency to follow the approach described in the 
proposed rule when addressing 180-day exclusivity in cases where there 
are multiple ANDAs containing challenges to the same patent(s) 
submitted on the same day (see Docket Nos. 00P-1445 and 03P-0217).
    Same day patent challenges generally occur when the expiration of 4 
years of a 5-year exclusivity period under section 505(j)(5)(D)(ii) of 
the act permits submission of ANDAs containing a paragraph IV 
certification as of a specific date, and multiple applicants vie to be 
first to make such a submission. Multiple submissions on the same day 
may also occur when a new patent is issued by the Patent and Trademark 
Office and submitted to FDA by the NDA sponsor after ANDAs have been 
submitted. Because new patents must be submitted to FDA within 30 days 
of issuance, ANDA applicants position themselves to be the first to 
submit a paragraph IV certification as soon as the patent is submitted 
to FDA, often exactly 30 days after patent issuance.
    Implementation of a rule that determined eligibility for 180-day 
exclusivity by the minute or second of submission would be problematic 
for several reasons. First, applications arrive at CDER by different 
means and at different locations. They are delivered by U.S. mail, 
delivery service, courier, and in person by the applicant or its 
agent.\4\ They may be delivered to mailrooms at FDA's Parklawn Bldg. or 
at its Metro Park North Bldg., which have different zip codes and are 
miles apart (Sec.  314.440). Second, when multiple ANDAs are delivered 
to the mailrooms on the same day, there is no effective way to 
determine in what order the documents were submitted. Also, when more 
than one application is present in a given delivery, the order in which 
the applications are date-stamped by the document room is random and 
reflects only the application's arbitrary place in the pile of mail. 
Moreover, a submission delivered to the agency early in the day may, in 
fact, be date-stamped after a submission delivered later in the day 
because the former submission was underneath the latter in the mail 
pile. Third, some ANDA applicants have assumed that hand delivery would 
be the best way to secure the ``first'' application slot. Applicants 
have arrived outside of an FDA-occupied building on or before the date 
on which ANDAs may be submitted. Recently, there have been a number of 
cases in which multiple ANDA applicants or their representatives have 
camped out adjacent to an FDA-occupied building for periods ranging 
from 1 day to more than 3 weeks to await the first date on which 
applications could be submitted to the agency. FDA does not have a 
system for determining which of those multiple applicants who are 
present either before the date of submission, or at 12:01 a.m. on the 
date of submission, or when FDA opens its doors to receive submissions, 
should be considered ``first.'' The order of applicants in a line that 
has formed before applications may be submitted is as random as the 
location of an application in a pile of mail in the mailroom.
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    \4\ FDA does not consider submission by facsimile or e-mail 
official for purposes of determining the date of submission.
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    Where multiple applicants are simultaneously present to submit 
patent certifications on the first day that such submissions are made, 
rewarding only the first applicant in line does not further any of the 
goals of the Hatch-Waxman amendments. Even if it were reasonable to 
argue that someone who is willing to stand in line for days or months 
should benefit by being considered the first to submit a patent 
challenge, security and other concerns have foreclosed that option.
    The agency can no longer permit applicants to line up outside FDA-
occupied buildings in advance of the date ANDA submissions are 
permitted. For example, when an applicant arrived outside of the FDA-
occupied building in mid-May 2003 to establish first place for a number 
of ANDA submissions, one of which could not be submitted until mid-
December 2003, the owner of the government-leased building informed FDA 
in a June 4, 2003, letter that the 24-hour presence of the 
pharmaceutical company representatives violated the policy described in 
the rules and regulations governing the use of the property. In 
addition, the owner noted its serious liability concerns regarding 
safety and security. Because of the owner's concerns, FDA directed the 
waiting ANDA applicant representative to leave the premises.
    Furthermore, measuring submissions by the minute or second would be 
inconsistent with CDER's general administrative practices. CDER 
conducts its business by calendar day, not by the hour, minute, or 
second. For example, NDA review times under the Prescription Drug User 
Fee Act are based upon the date an application was submitted, and 
approvals are effective as of the date of the issuance of the approval 
letter (Sec.  314.105). In addition, 180-day exclusivity runs for 180 
calendar days from the date of a commercial marketing or court decision 
triggering event, without regard to the precise time of day the 
exclusivity was triggered (Sec.  314.107(c)(1)). CDER considers most 
documents, including NDAs, ANDAs, and application amendments and 
supplements, to have been submitted to FDA as of the date-stamped on 
the document by the appropriate CDER document room.
    In considering how to apply the 180-day exclusivity provisions to 
multiple patent challenges, FDA reviewed a number of possible 
approaches. First, the agency examined whether there was a safe and 
practical way to determine whose patent challenge is actually submitted 
to the agency first. The only

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way to ensure the order of submission would be to require all 
submissions to be made in person, with the establishment of some kind 
of monitored line. The owner of the FDA-occupied building has given the 
agency the option of permitting applicants to line up outside the 
building at 12:01 a.m. on the morning submissions may be accepted. 
However, such lines would raise issues of security and fairness for 
applicants and could lead to evidentiary disputes over which applicant, 
if any, was in line first. FDA is already aware of at least one 
instance in which an applicant videotaped its arrival on government 
property in an attempt to document that it was first to submit a patent 
challenge. Thus, this approach could lead to administrative proceedings 
and litigation over tie-breaking virtually simultaneous submissions. In 
addition, such an approach would disadvantage applicants who do not 
make submissions in person, because mail deliveries are likely to be 
made to FDA after the door opens for in person submissions.
    The agency also considered requiring submission by mail and then 
date- and time-stamping submissions based on the order they were 
processed by the mailroom and document room. This approach would 
require FDA to determine, from among the various submissions made in 
the same delivery, which submission was first, itself an arbitrary 
process. Is the first submission the first ANDA to be removed from the 
mail bag, or the document on top of the pile after the mail is removed 
from the delivery container?
    The agency even considered adopting a lottery approach, in which 
one ANDA would be chosen at random from among all the eligible ANDAs 
submitted on the same first day. This approach, although appealing in 
its simplicity and no less random than mail delivery or an applicant's 
place in line, has no support in the statute.
    Finally, FDA considered permitting submission by facsimile. 
However, this approach raises many practical concerns involving after-
hours submissions, jammed fax machines, and disputes over submission 
order. In sum, all of these approaches were rejected because they raise 
safety concerns, are administratively unworkable, or would arbitrarily 
and unfairly distinguish between similarly situated applicants. In 
addition, none of them addresses the fundamentally arbitrary nature of 
declaring any one patent challenge made on a certain day to be previous 
to all other challenges made on that day.

C. 180-Day Exclusivity and Multiple Same Day Patent Challenges

    FDA intends to interpret the phrase ``for which a previous 
application has been submitted'' in section 505(j)(4)(B)(iv) of the act 
to mean an ANDA that has been submitted on a previous day. Thus, when 
multiple ANDAs containing paragraph IV challenges to patents are 
submitted to FDA on the same day--and no paragraph IV certification to 
that patent has been submitted on a previous day--FDA intends to 
consider none of the patent challenges to be previous to other 
challenges to the same patent submitted on the same day and all of 
those challenges as previous to paragraph IV certifications to the same 
patent submitted on a subsequent day. This is the general 
interpretation described in the 1999 proposed rule.
    Under this approach, all of the applicants submitting substantially 
complete ANDAs, amendments, or supplements containing a paragraph IV 
certification for a listed patent on the same first day would be 
eligible for 180-day exclusivity. That exclusivity would begin to run 
for all of the applicants eligible for 180-day exclusivity from the 
earlier of the initial commercial marketing of the drug by any of the 
first applicants or by a court decision finding the specific patent as 
to which the applicants were first to file paragraph IV certifications 
invalid, unenforceable, or not infringed. During the exclusivity 
period, FDA may approve any other first applicant's ANDA, but no other 
ANDAs. Any first applicant's ANDA approved after the exclusivity has 
been triggered will share in the remaining period of exclusivity. Once 
the 180-day exclusivity period has run, FDA may approve all subsequent 
ANDAs.
    The agency believes that this exclusivity approach is consistent 
with the statutory language in that, under at least one reasonable 
reading of section 505(j)(5)(B)(iv) of the act, none of the 
applications submitted on the same day is ``previous'' to any other 
application submitted on the same day, and all applications submitted 
on the same day are previous to any application submitted on any day 
thereafter.
    This interpretation is also consistent with the intent of both the 
180-day exclusivity provision, in particular, and the Hatch-Waxman 
Amendments, in general. Instead of giving exclusivity to a single 
applicant who may be first only by dint of jockeying for a better place 
in line, or by the happenstance of location within a pile of mail, this 
approach recognizes that all of the applicants who challenged a patent 
on the first day such a challenge is submitted challenged the patent at 
essentially the same time, and rewards them accordingly.
    The approach maintains the incentive to be first to submit a patent 
challenge but, in the case where there are multiple applicants 
submitting patent challenges on the same first day, it will provide an 
equal chance at the benefits of exclusivity to all of those applicants. 
The approach will also provide the opportunity to be the sole 
beneficiary of exclusivity if an applicant obtains approval of its ANDA 
and begins to market at least 180 days before any of the other first 
applicants begins to market.
    Finally, this approach will permit applicants to submit ANDAs by 
U.S. mail, courier, delivery service, or in person on a more reasonable 
timetable; preserve the safety and security of the applicants and FDA 
property and staff; and prevent time-consuming disputes over ``who's 
first,'' which rely on video and other evidence.
    This guidance is being issued as a level 1 guidance for immediate 
implementation, consistent with FDA's good guidance practices 
regulation (21 CFR 10.115). The agency believes that given the need for 
public guidance on this pressing issue and existing liability, safety, 
and security concerns, public comment is neither feasible nor 
appropriate before implementing this guidance. Comments on the guidance 
are welcome at any time.
    FDA intends to implement this approach immediately for all 
applicable 180-day exclusivity determinations made by FDA on or after 
the date of the notice announcing the availability of this guidance 
(including for patent certifications that were submitted prior to the 
date of the notice where the exclusivity determination has not yet been 
made). The approach described in this guidance will remain in effect 
until superseded. As noted in this section I, to date, FDA's 
exclusivity decisions have only involved applications or amendments 
submitted on different days.
    This guidance represents the agency's current thinking on 180-day 
exclusivity when multiple ANDAs are submitted on the same day. It does 
not create or confer any rights for or on any person and does not 
operate to bind FDA or the public. An alternative approach may be used 
if such approach satisfies the requirements of the applicable statutes 
and regulations.

II. Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic

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comments on the guidance at any time. Two paper copies of mailed 
comments are to be submitted, except that individuals may submit one 
paper copy. Comments are to be identified with the docket number found 
in brackets in the heading of this document. The guidance and received 
comments are available for public examination in the Division of 
Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.

III. Electronic Access

    Persons with access to the Internet may obtain the document at 
either http://www.fda.gov/cder/guidance/index.htm or http://www.fda.gov/ohrms/dockets/default.htm.

    Dated: July 25, 2003.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 03-19590 Filed 7-31-03; 8:45 am]
BILLING CODE 4160-01-S