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U.S. Code as of:
01/19/04
Section 355. New drugs
(a) Necessity of effective approval of application
No person shall introduce or deliver for introduction into
interstate commerce any new drug, unless an approval of an
application filed pursuant to subsection (b) or (j) of this section
is effective with respect to such drug.
(b) Filing application; contents
(1) Any person may file with the Secretary an application with
respect to any drug subject to the provisions of subsection (a) of
this section. Such person shall submit to the Secretary as a part
of the application (A) full reports of investigations which have
been made to show whether or not such drug is safe for use and
whether such drug is effective in use; (B) a full list of the
articles used as components of such drug; (C) a full statement of
the composition of such drug; (D) a full description of the methods
used in, and the facilities and controls used for, the manufacture,
processing, and packing of such drug; (E) such samples of such drug
and of the articles used as components thereof as the Secretary may
require; (F) specimens of the labeling proposed to be used for such
drug, and (G) any assessments required under section 355c of this
title. The applicant shall file with the application the patent
number and the expiration date of any patent which claims the drug
for which the applicant submitted the application or which claims a
method of using such drug and with respect to which a claim of
patent infringement could reasonably be asserted if a person not
licensed by the owner engaged in the manufacture, use, or sale of
the drug. If an application is filed under this subsection for a
drug and a patent which claims such drug or a method of using such
drug is issued after the filing date but before approval of the
application, the applicant shall amend the application to include
the information required by the preceding sentence. Upon approval
of the application, the Secretary shall publish information
submitted under the two preceding sentences. The Secretary shall,
in consultation with the Director of the National Institutes of
Health and with representatives of the drug manufacturing industry,
review and develop guidance, as appropriate, on the inclusion of
women and minorities in clinical trials required by clause (A).
(2) An application submitted under paragraph (1) for a drug for
which the investigations described in clause (A) of such paragraph
and relied upon by the applicant for approval of the application
were not conducted by or for the applicant and for which the
applicant has not obtained a right of reference or use from the
person by or for whom the investigations were conducted shall also
include -
(A) a certification, in the opinion of the applicant and to the
best of his knowledge, with respect to each patent which claims
the drug for which such investigations were conducted or which
claims a use for such drug for which the applicant is seeking
approval under this subsection and for which information is
required to be filed under paragraph (1) or subsection (c) of
this section -
(i) that such patent information has not been filed,
(ii) that such patent has expired,
(iii) of the date on which such patent will expire, or
(iv) that such patent is invalid or will not be infringed by
the manufacture, use, or sale of the new drug for which the
application is submitted; and
(B) if with respect to the drug for which investigations
described in paragraph (1)(A) were conducted information was
filed under paragraph (1) or subsection (c) of this section for a
method of use patent which does not claim a use for which the
applicant is seeking approval under this subsection, a statement
that the method of use patent does not claim such a use.
(3) Notice of opinion that patent is invalid or will not be
infringed. -
(A) Agreement to give notice. - An applicant that makes a
certification described in paragraph (2)(A)(iv) shall include in
the application a statement that the applicant will give notice
as required by this paragraph.
(B) Timing of notice. - An applicant that makes a certification
described in paragraph (2)(A)(iv) shall give notice as required
under this paragraph -
(i) if the certification is in the application, not later
than 20 days after the date of the postmark on the notice with
which the Secretary informs the applicant that the application
has been filed; or
(ii) if the certification is in an amendment or supplement to
the application, at the time at which the applicant submits the
amendment or supplement, regardless of whether the applicant
has already given notice with respect to another such
certification contained in the application or in an amendment
or supplement to the application.
(C) Recipients of notice. - An applicant required under this
paragraph to give notice shall give notice to -
(i) each owner of the patent that is the subject of the
certification (or a representative of the owner designated to
receive such a notice); and
(ii) the holder of the approved application under this
subsection for the drug that is claimed by the patent or a use
of which is claimed by the patent (or a representative of the
holder designated to receive such a notice).
(D) Contents of notice. - A notice required under this
paragraph shall -
(i) state that an application that contains data from
bioavailability or bioequivalence studies has been submitted
under this subsection for the drug with respect to which the
certification is made to obtain approval to engage in the
commercial manufacture, use, or sale of the drug before the
expiration of the patent referred to in the certification; and
(ii) include a detailed statement of the factual and legal
basis of the opinion of the applicant that the patent is
invalid or will not be infringed.
(4)(A) An applicant may not amend or supplement an application
referred to in paragraph (2) to seek approval of a drug that is a
different drug than the drug identified in the application as
submitted to the Secretary.
(B) With respect to the drug for which such an application is
submitted, nothing in this subsection or subsection (c)(3) of this
section prohibits an applicant from amending or supplementing the
application to seek approval of a different strength.
(5)(A) The Secretary shall issue guidance for the individuals who
review applications submitted under paragraph (1) or under section
262 of title 42, which shall relate to promptness in conducting the
review, technical excellence, lack of bias and conflict of
interest, and knowledge of regulatory and scientific standards, and
which shall apply equally to all individuals who review such
applications.
(B) The Secretary shall meet with a sponsor of an investigation
or an applicant for approval for a drug under this subsection or
section 262 of title 42 if the sponsor or applicant makes a
reasonable written request for a meeting for the purpose of
reaching agreement on the design and size of clinical trials
intended to form the primary basis of an effectiveness claim. The
sponsor or applicant shall provide information necessary for
discussion and agreement on the design and size of the clinical
trials. Minutes of any such meeting shall be prepared by the
Secretary and made available to the sponsor or applicant upon
request.
(C) Any agreement regarding the parameters of the design and size
of clinical trials of a new drug under this paragraph that is
reached between the Secretary and a sponsor or applicant shall be
reduced to writing and made part of the administrative record by
the Secretary. Such agreement shall not be changed after the
testing begins, except -
(i) with the written agreement of the sponsor or applicant; or
(ii) pursuant to a decision, made in accordance with
subparagraph (D) by the director of the reviewing division, that
a substantial scientific issue essential to determining the
safety or effectiveness of the drug has been identified after the
testing has begun.
(D) A decision under subparagraph (C)(ii) by the director shall
be in writing and the Secretary shall provide to the sponsor or
applicant an opportunity for a meeting at which the director and
the sponsor or applicant will be present and at which the director
will document the scientific issue involved.
(E) The written decisions of the reviewing division shall be
binding upon, and may not directly or indirectly be changed by, the
field or compliance division personnel unless such field or
compliance division personnel demonstrate to the reviewing division
why such decision should be modified.
(F) No action by the reviewing division may be delayed because of
the unavailability of information from or action by field personnel
unless the reviewing division determines that a delay is necessary
to assure the marketing of a safe and effective drug.
(G) For purposes of this paragraph, the reviewing division is the
division responsible for the review of an application for approval
of a drug under this subsection or section 262 of title 42
(including all scientific and medical matters, chemistry,
manufacturing, and controls).
(c) Period for approval of application; period for, notice, and
expedition of hearing; period for issuance of order
(1) Within one hundred and eighty days after the filing of an
application under subsection (b) of this section, or such
additional period as may be agreed upon by the Secretary and the
applicant, the Secretary shall either -
(A) approve the application if he then finds that none of the
grounds for denying approval specified in subsection (d) of this
section applies, or
(B) give the applicant notice of an opportunity for a hearing
before the Secretary under subsection (d) of this section on the
question whether such application is approvable. If the applicant
elects to accept the opportunity for hearing by written request
within thirty days after such notice, such hearing shall commence
not more than ninety days after the expiration of such thirty
days unless the Secretary and the applicant otherwise agree. Any
such hearing shall thereafter be conducted on an expedited basis
and the Secretary's order thereon shall be issued within ninety
days after the date fixed by the Secretary for filing final
briefs.
(2) If the patent information described in subsection (b) of this
section could not be filed with the submission of an application
under subsection (b) of this section because the application was
filed before the patent information was required under subsection
(b) of this section or a patent was issued after the application
was approved under such subsection, the holder of an approved
application shall file with the Secretary the patent number and the
expiration date of any patent which claims the drug for which the
application was submitted or which claims a method of using such
drug and with respect to which a claim of patent infringement could
reasonably be asserted if a person not licensed by the owner
engaged in the manufacture, use, or sale of the drug. If the holder
of an approved application could not file patent information under
subsection (b) of this section because it was not required at the
time the application was approved, the holder shall file such
information under this subsection not later than thirty days after
September 24, 1984, and if the holder of an approved application
could not file patent information under subsection (b) of this
section because no patent had been issued when an application was
filed or approved, the holder shall file such information under
this subsection not later than thirty days after the date the
patent involved is issued. Upon the submission of patent
information under this subsection, the Secretary shall publish it.
(3) The approval of an application filed under subsection (b) of
this section which contains a certification required by paragraph
(2) of such subsection shall be made effective on the last
applicable date determined by applying the following to each
certification made under subsection (b)(2)(A) of this section:
(A) If the applicant only made a certification described in
clause (i) or (ii) of subsection (b)(2)(A) of this section or in
both such clauses, the approval may be made effective
immediately.
(B) If the applicant made a certification described in clause
(iii) of subsection (b)(2)(A) of this section, the approval may
be made effective on the date certified under clause (iii).
(C) If the applicant made a certification described in clause
(iv) of subsection (b)(2)(A) of this section, the approval shall
be made effective immediately unless, before the expiration of 45
days after the date on which the notice described in subsection
(b)(3) of this section is received, an action is brought for
infringement of the patent that is the subject of the
certification and for which information was submitted to the
Secretary under paragraph (2) or subsection (b)(1) of this
section before the date on which the application (excluding an
amendment or supplement to the application) was submitted. If
such an action is brought before the expiration of such days, the
approval may be made effective upon the expiration of the
thirty-month period beginning on the date of the receipt of the
notice provided under subsection (b)(3) of this section or such
shorter or longer period as the court may order because either
party to the action failed to reasonably cooperate in expediting
the action, except that -
(i) if before the expiration of such period the district
court decides that the patent is invalid or not infringed
(including any substantive determination that there is no cause
of action for patent infringement or invalidity), the approval
shall be made effective on -
(I) the date on which the court enters judgment reflecting
the decision; or
(II) the date of a settlement order or consent decree
signed and entered by the court stating that the patent that
is the subject of the certification is invalid or not
infringed;
(ii) if before the expiration of such period the district
court decides that the patent has been infringed -
(I) if the judgment of the district court is appealed, the
approval shall be made effective on -
(aa) the date on which the court of appeals decides that
the patent is invalid or not infringed (including any
substantive determination that there is no cause of action
for patent infringement or invalidity); or
(bb) the date of a settlement order or consent decree
signed and entered by the court of appeals stating that the
patent that is the subject of the certification is invalid
or not infringed; or
(II) if the judgment of the district court is not appealed
or is affirmed, the approval shall be made effective on the
date specified by the district court in a court order under
section 271(e)(4)(A) of title 35;
(iii) if before the expiration of such period the court
grants a preliminary injunction prohibiting the applicant from
engaging in the commercial manufacture or sale of the drug
until the court decides the issues of patent validity and
infringement and if the court decides that such patent is
invalid or not infringed, the approval shall be made effective
as provided in clause (i); or
(iv) if before the expiration of such period the court grants
a preliminary injunction prohibiting the applicant from
engaging in the commercial manufacture or sale of the drug
until the court decides the issues of patent validity and
infringement and if the court decides that such patent has been
infringed, the approval shall be made effective as provided in
clause (ii).
In such an action, each of the parties shall reasonably cooperate
in expediting the action.
(D) Civil action to obtain patent certainty. -
(i) Declaratory judgment absent infringement action. -
(I) In general. - No action may be brought under section
2201 of title 28 by an applicant referred to in subsection
(b)(2) of this section for a declaratory judgment with
respect to a patent which is the subject of the certification
referred to in subparagraph (C) unless -
(aa) the 45-day period referred to in such subparagraph
has expired;
(bb) neither the owner of such patent nor the holder of
the approved application under subsection (b) of this
section for the drug that is claimed by the patent or a use
of which is claimed by the patent brought a civil action
against the applicant for infringement of the patent before
the expiration of such period; and
(cc) in any case in which the notice provided under
paragraph (2)(B) relates to noninfringement, the notice was
accompanied by a document described in subclause (III).
(II) Filing of civil action. - If the conditions described
in items (aa), (bb), and as applicable, (cc) of subclause (I)
have been met, the applicant referred to in such subclause
may, in accordance with section 2201 of title 28, bring a
civil action under such section against the owner or holder
referred to in such subclause (but not against any owner or
holder that has brought such a civil action against the
applicant, unless that civil action was dismissed without
prejudice) for a declaratory judgment that the patent is
invalid or will not be infringed by the drug for which the
applicant seeks approval, except that such civil action may
be brought for a declaratory judgment that the patent will
not be infringed only in a case in which the condition
described in subclause (I)(cc) is applicable. A civil action
referred to in this subclause shall be brought in the
judicial district where the defendant has its principal place
of business or a regular and established place of business.
(III) Offer of confidential access to application. - For
purposes of subclause (I)(cc), the document described in this
subclause is a document providing an offer of confidential
access to the application that is in the custody of the
applicant referred to in subsection (b)(2) of this section
for the purpose of determining whether an action referred to
in subparagraph (C) should be brought. The document providing
the offer of confidential access shall contain such
restrictions as to persons entitled to access, and on the use
and disposition of any information accessed, as would apply
had a protective order been entered for the purpose of
protecting trade secrets and other confidential business
information. A request for access to an application under an
offer of confidential access shall be considered acceptance
of the offer of confidential access with the restrictions as
to persons entitled to access, and on the use and disposition
of any information accessed, contained in the offer of
confidential access, and those restrictions and other terms
of the offer of confidential access shall be considered terms
of an enforceable contract. Any person provided an offer of
confidential access shall review the application for the sole
and limited purpose of evaluating possible infringement of
the patent that is the subject of the certification under
subsection (b)(2)(A)(iv) of this section and for no other
purpose, and may not disclose information of no relevance to
any issue of patent infringement to any person other than a
person provided an offer of confidential access. Further, the
application may be redacted by the applicant to remove any
information of no relevance to any issue of patent
infringement.
(ii) Counterclaim to infringement action. -
(I) In general. - If an owner of the patent or the holder
of the approved application under subsection (b) of this
section for the drug that is claimed by the patent or a use
of which is claimed by the patent brings a patent
infringement action against the applicant, the applicant may
assert a counterclaim seeking an order requiring the holder
to correct or delete the patent information submitted by the
holder under subsection (b) of this section or this
subsection on the ground that the patent does not claim
either -
(aa) the drug for which the application was approved; or
(bb) an approved method of using the drug.
(II) No independent cause of action. - Subclause (I) does
not authorize the assertion of a claim described in subclause
(I) in any civil action or proceeding other than a
counterclaim described in subclause (I).
(iii) No damages. - An applicant shall not be entitled to
damages in a civil action under clause (i) or a counterclaim
under clause (ii).
(E)(i) If an application (other than an abbreviated new drug
application) submitted under subsection (b) of this section for a
drug, no active ingredient (including any ester or salt of the
active ingredient) of which has been approved in any other
application under subsection (b) of this section, was approved
during the period beginning January 1, 1982, and ending on
September 24, 1984, the Secretary may not make the approval of
another application for a drug for which the investigations
described in clause (A) of subsection (b)(1) of this section and
relied upon by the applicant for approval of the application were
not conducted by or for the applicant and for which the applicant
has not obtained a right of reference or use from the person by
or for whom the investigations were conducted effective before
the expiration of ten years from the date of the approval of the
application previously approved under subsection (b) of this
section.
(ii) If an application submitted under subsection (b) of this
section for a drug, no active ingredient (including any ester or
salt of the active ingredient) of which has been approved in any
other application under subsection (b) of this section, is
approved after September 24, 1984, no application which refers to
the drug for which the subsection (b) application was submitted
and for which the investigations described in clause (A) of
subsection (b)(1) of this section and relied upon by the
applicant for approval of the application were not conducted by
or for the applicant and for which the applicant has not obtained
a right of reference or use from the person by or for whom the
investigations were conducted may be submitted under subsection
(b) of this section before the expiration of five years from the
date of the approval of the application under subsection (b) of
this section, except that such an application may be submitted
under subsection (b) of this section after the expiration of four
years from the date of the approval of the subsection (b)
application if it contains a certification of patent invalidity
or noninfringement described in clause (iv) of subsection
(b)(2)(A) of this section. The approval of such an application
shall be made effective in accordance with this paragraph except
that, if an action for patent infringement is commenced during
the one-year period beginning forty-eight months after the date
of the approval of the subsection (b) application, the
thirty-month period referred to in subparagraph (C) shall be
extended by such amount of time (if any) which is required for
seven and one-half years to have elapsed from the date of
approval of the subsection (b) application.
(iii) If an application submitted under subsection (b) of this
section for a drug, which includes an active ingredient
(including any ester or salt of the active ingredient) that has
been approved in another application approved under subsection
(b) of this section, is approved after September 24, 1984, and if
such application contains reports of new clinical investigations
(other than bioavailability studies) essential to the approval of
the application and conducted or sponsored by the applicant, the
Secretary may not make the approval of an application submitted
under subsection (b) of this section for the conditions of
approval of such drug in the approved subsection (b) application
effective before the expiration of three years from the date of
the approval of the application under subsection (b) of this
section if the investigations described in clause (A) of
subsection (b)(1) of this section and relied upon by the
applicant for approval of the application were not conducted by
or for the applicant and if the applicant has not obtained a
right of reference or use from the person by or for whom the
investigations were conducted.
(iv) If a supplement to an application approved under
subsection (b) of this section is approved after September 24,
1984, and the supplement contains reports of new clinical
investigations (other than bioavailabilty (!1) studies) essential
to the approval of the supplement and conducted or sponsored by
the person submitting the supplement, the Secretary may not make
the approval of an application submitted under subsection (b) of
this section for a change approved in the supplement effective
before the expiration of three years from the date of the
approval of the supplement under subsection (b) of this section
if the investigations described in clause (A) of subsection
(b)(1) of this section and relied upon by the applicant for
approval of the application were not conducted by or for the
applicant and if the applicant has not obtained a right of
reference or use from the person by or for whom the
investigations were conducted.
(v) If an application (or supplement to an application)
submitted under subsection (b) of this section for a drug, which
includes an active ingredient (including any ester or salt of the
active ingredient) that has been approved in another application
under subsection (b) of this section, was approved during the
period beginning January 1, 1982, and ending on September 24,
1984, the Secretary may not make the approval of an application
submitted under this subsection and for which the investigations
described in clause (A) of subsection (b)(1) of this section and
relied upon by the applicant for approval of the application were
not conducted by or for the applicant and for which the applicant
has not obtained a right of reference or use from the person by
or for whom the investigations were conducted and which refers to
the drug for which the subsection (b) application was submitted
effective before the expiration of two years from September 24,
1984.
(4) A drug manufactured in a pilot or other small facility may be
used to demonstrate the safety and effectiveness of the drug and to
obtain approval for the drug prior to manufacture of the drug in a
larger facility, unless the Secretary makes a determination that a
full scale production facility is necessary to ensure the safety or
effectiveness of the drug.
(d) Grounds for refusing application; approval of application;
"substantial evidence" defined
If the Secretary finds, after due notice to the applicant in
accordance with subsection (c) of this section and giving him an
opportunity for a hearing, in accordance with said subsection, that
(1) the investigations, reports of which are required to be
submitted to the Secretary pursuant to subsection (b) of this
section, do not include adequate tests by all methods reasonably
applicable to show whether or not such drug is safe for use under
the conditions prescribed, recommended, or suggested in the
proposed labeling thereof; (2) the results of such tests show that
such drug is unsafe for use under such conditions or do not show
that such drug is safe for use under such conditions; (3) the
methods used in, and the facilities and controls used for, the
manufacture, processing, and packing of such drug are inadequate to
preserve its identity, strength, quality, and purity; (4) upon the
basis of the information submitted to him as part of the
application, or upon the basis of any other information before him
with respect to such drug, he has insufficient information to
determine whether such drug is safe for use under such conditions;
or (5) evaluated on the basis of the information submitted to him
as part of the application and any other information before him
with respect to such drug, there is a lack of substantial evidence
that the drug will have the effect it purports or is represented to
have under the conditions of use prescribed, recommended, or
suggested in the proposed labeling thereof; or (6) the application
failed to contain the patent information prescribed by subsection
(b) of this section; or (7) based on a fair evaluation of all
material facts, such labeling is false or misleading in any
particular; he shall issue an order refusing to approve the
application. If, after such notice and opportunity for hearing, the
Secretary finds that clauses (1) through (6) do not apply, he shall
issue an order approving the application. As used in this
subsection and subsection (e) of this section, the term
"substantial evidence" means evidence consisting of adequate and
well-controlled investigations, including clinical investigations,
by experts qualified by scientific training and experience to
evaluate the effectiveness of the drug involved, on the basis of
which it could fairly and responsibly be concluded by such experts
that the drug will have the effect it purports or is represented to
have under the conditions of use prescribed, recommended, or
suggested in the labeling or proposed labeling thereof. If the
Secretary determines, based on relevant science, that data from one
adequate and well-controlled clinical investigation and
confirmatory evidence (obtained prior to or after such
investigation) are sufficient to establish effectiveness, the
Secretary may consider such data and evidence to constitute
substantial evidence for purposes of the preceding sentence.
(e) Withdrawal of approval; grounds; immediate suspension upon
finding imminent hazard to public health
The Secretary shall, after due notice and opportunity for hearing
to the applicant, withdraw approval of an application with respect
to any drug under this section if the Secretary finds (1) that
clinical or other experience, tests, or other scientific data show
that such drug is unsafe for use under the conditions of use upon
the basis of which the application was approved; (2) that new
evidence of clinical experience, not contained in such application
or not available to the Secretary until after such application was
approved, or tests by new methods, or tests by methods not deemed
reasonably applicable when such application was approved, evaluated
together with the evidence available to the Secretary when the
application was approved, shows that such drug is not shown to be
safe for use under the conditions of use upon the basis of which
the application was approved; or (3) on the basis of new
information before him with respect to such drug, evaluated
together with the evidence available to him when the application
was approved, that there is a lack of substantial evidence that the
drug will have the effect it purports or is represented to have
under the conditions of use prescribed, recommended, or suggested
in the labeling thereof; or (4) the patent information prescribed
by subsection (c) of this section was not filed within thirty days
after the receipt of written notice from the Secretary specifying
the failure to file such information; or (5) that the application
contains any untrue statement of a material fact: Provided, That if
the Secretary (or in his absence the officer acting as Secretary)
finds that there is an imminent hazard to the public health, he may
suspend the approval of such application immediately, and give the
applicant prompt notice of his action and afford the applicant the
opportunity for an expedited hearing under this subsection; but the
authority conferred by this proviso to suspend the approval of an
application shall not be delegated. The Secretary may also, after
due notice and opportunity for hearing to the applicant, withdraw
the approval of an application submitted under subsection (b) or
(j) of this section with respect to any drug under this section if
the Secretary finds (1) that the applicant has failed to establish
a system for maintaining required records, or has repeatedly or
deliberately failed to maintain such records or to make required
reports, in accordance with a regulation or order under subsection
(k) of this section or to comply with the notice requirements of
section 360(k)(2) of this title, or the applicant has refused to
permit access to, or copying or verification of, such records as
required by paragraph (2) of such subsection; or (2) that on the
basis of new information before him, evaluated together with the
evidence before him when the application was approved, the methods
used in, or the facilities and controls used for, the manufacture,
processing, and packing of such drug are inadequate to assure and
preserve its identity, strength, quality, and purity and were not
made adequate within a reasonable time after receipt of written
notice from the Secretary specifying the matter complained of; or
(3) that on the basis of new information before him, evaluated
together with the evidence before him when the application was
approved, the labeling of such drug, based on a fair evaluation of
all material facts, is false or misleading in any particular and
was not corrected within a reasonable time after receipt of written
notice from the Secretary specifying the matter complained of. Any
order under this subsection shall state the findings upon which it
is based.
(f) Revocation of order refusing, withdrawing or suspending
approval of application
Whenever the Secretary finds that the facts so require, he shall
revoke any previous order under subsection (d) or (e) of this
section refusing, withdrawing, or suspending approval of an
application and shall approve such application or reinstate such
approval, as may be appropriate.
(g) Service of orders
Orders of the Secretary issued under this section shall be served
(1) in person by any officer or employee of the department
designated by the Secretary or (2) by mailing the order by
registered mail or by certified mail addressed to the applicant or
respondent at his last-known address in the records of the
Secretary.
(h) Appeal from order
An appeal may be taken by the applicant from an order of the
Secretary refusing or withdrawing approval of an application under
this section. Such appeal shall be taken by filing in the United
States court of appeals for the circuit wherein such applicant
resides or has his principal place of business, or in the United
States Court of Appeals for the District of Columbia Circuit,
within sixty days after the entry of such order, a written petition
praying that the order of the Secretary be set aside. A copy of
such petition shall be forthwith transmitted by the clerk of the
court to the Secretary, or any officer designated by him for that
purpose, and thereupon the Secretary shall certify and file in the
court the record upon which the order complained of was entered, as
provided in section 2112 of title 28. Upon the filing of such
petition such court shall have exclusive jurisdiction to affirm or
set aside such order, except that until the filing of the record
the Secretary may modify or set aside his order. No objection to
the order of the Secretary shall be considered by the court unless
such objection shall have been urged before the Secretary or unless
there were reasonable grounds for failure so to do. The finding of
the Secretary as to the facts, if supported by substantial
evidence, shall be conclusive. If any person shall apply to the
court for leave to adduce additional evidence, and shall show to
the satisfaction of the court that such additional evidence is
material and that there were reasonable grounds for failure to
adduce such evidence in the proceeding before the Secretary, the
court may order such additional evidence to be taken before the
Secretary and to be adduced upon the hearing in such manner and
upon such terms and conditions as to the court may seem proper. The
Secretary may modify his findings as to the facts by reason of the
additional evidence so taken, and he shall file with the court such
modified findings which, if supported by substantial evidence,
shall be conclusive, and his recommendation, if any, for the
setting aside of the original order. The judgment of the court
affirming or setting aside any such order of the Secretary shall be
final, subject to review by the Supreme Court of the United States
upon certiorari or certification as provided in section 1254 of
title 28. The commencement of proceedings under this subsection
shall not, unless specifically ordered by the court to the
contrary, operate as a stay of the Secretary's order.
(i) Exemptions of drugs for research; discretionary and mandatory
conditions; direct reports to Secretary
(1) The Secretary shall promulgate regulations for exempting from
the operation of the foregoing subsections of this section drugs
intended solely for investigational use by experts qualified by
scientific training and experience to investigate the safety and
effectiveness of drugs. Such regulations may, within the discretion
of the Secretary, among other conditions relating to the protection
of the public health, provide for conditioning such exemption upon
-
(A) the submission to the Secretary, before any clinical
testing of a new drug is undertaken, of reports, by the
manufacturer or the sponsor of the investigation of such drug, of
preclinical tests (including tests on animals) of such drug
adequate to justify the proposed clinical testing;
(B) the manufacturer or the sponsor of the investigation of a
new drug proposed to be distributed to investigators for clinical
testing obtaining a signed agreement from each of such
investigators that patients to whom the drug is administered will
be under his personal supervision, or under the supervision of
investigators responsible to him, and that he will not supply
such drug to any other investigator, or to clinics, for
administration to human beings;
(C) the establishment and maintenance of such records, and the
making of such reports to the Secretary, by the manufacturer or
the sponsor of the investigation of such drug, of data (including
but not limited to analytical reports by investigators) obtained
as the result of such investigational use of such drug, as the
Secretary finds will enable him to evaluate the safety and
effectiveness of such drug in the event of the filing of an
application pursuant to subsection (b) of this section; and
(D) the submission to the Secretary by the manufacturer or the
sponsor of the investigation of a new drug of a statement of
intent regarding whether the manufacturer or sponsor has plans
for assessing pediatric safety and efficacy.
(2) Subject to paragraph (3), a clinical investigation of a new
drug may begin 30 days after the Secretary has received from the
manufacturer or sponsor of the investigation a submission
containing such information about the drug and the clinical
investigation, including -
(A) information on design of the investigation and adequate
reports of basic information, certified by the applicant to be
accurate reports, necessary to assess the safety of the drug for
use in clinical investigation; and
(B) adequate information on the chemistry and manufacturing of
the drug, controls available for the drug, and primary data
tabulations from animal or human studies.
(3)(A) At any time, the Secretary may prohibit the sponsor of an
investigation from conducting the investigation (referred to in
this paragraph as a "clinical hold") if the Secretary makes a
determination described in subparagraph (B). The Secretary shall
specify the basis for the clinical hold, including the specific
information available to the Secretary which served as the basis
for such clinical hold, and confirm such determination in writing.
(B) For purposes of subparagraph (A), a determination described
in this subparagraph with respect to a clinical hold is that -
(i) the drug involved represents an unreasonable risk to the
safety of the persons who are the subjects of the clinical
investigation, taking into account the qualifications of the
clinical investigators, information about the drug, the design of
the clinical investigation, the condition for which the drug is
to be investigated, and the health status of the subjects
involved; or
(ii) the clinical hold should be issued for such other reasons
as the Secretary may by regulation establish (including reasons
established by regulation before November 21, 1997).
(C) Any written request to the Secretary from the sponsor of an
investigation that a clinical hold be removed shall receive a
decision, in writing and specifying the reasons therefor, within 30
days after receipt of such request. Any such request shall include
sufficient information to support the removal of such clinical
hold.
(4) Regulations under paragraph (1) shall provide that such
exemption shall be conditioned upon the manufacturer, or the
sponsor of the investigation, requiring that experts using such
drugs for investigational purposes certify to such manufacturer or
sponsor that they will inform any human beings to whom such drugs,
or any controls used in connection therewith, are being
administered, or their representatives, that such drugs are being
used for investigational purposes and will obtain the consent of
such human beings or their representatives, except where it is not
feasible or it is contrary to the best interests of such human
beings. Nothing in this subsection shall be construed to require
any clinical investigator to submit directly to the Secretary
reports on the investigational use of drugs.
(j) Abbreviated new drug applications
(1) Any person may file with the Secretary an abbreviated
application for the approval of a new drug.
(2)(A) An abbreviated application for a new drug shall contain -
(i) information to show that the conditions of use prescribed,
recommended, or suggested in the labeling proposed for the new
drug have been previously approved for a drug listed under
paragraph (7) (hereinafter in this subsection referred to as a
"listed drug");
(ii)(I) if the listed drug referred to in clause (i) has only
one active ingredient, information to show that the active
ingredient of the new drug is the same as that of the listed
drug;
(II) if the listed drug referred to in clause (i) has more than
one active ingredient, information to show that the active
ingredients of the new drug are the same as those of the listed
drug, or
(III) if the listed drug referred to in clause (i) has more
than one active ingredient and if one of the active ingredients
of the new drug is different and the application is filed
pursuant to the approval of a petition filed under subparagraph
(C), information to show that the other active ingredients of the
new drug are the same as the active ingredients of the listed
drug, information to show that the different active ingredient is
an active ingredient of a listed drug or of a drug which does not
meet the requirements of section 321(p) of this title, and such
other information respecting the different active ingredient with
respect to which the petition was filed as the Secretary may
require;
(iii) information to show that the route of administration, the
dosage form, and the strength of the new drug are the same as
those of the listed drug referred to in clause (i) or, if the
route of administration, the dosage form, or the strength of the
new drug is different and the application is filed pursuant to
the approval of a petition filed under subparagraph (C), such
information respecting the route of administration, dosage form,
or strength with respect to which the petition was filed as the
Secretary may require;
(iv) information to show that the new drug is bioequivalent to
the listed drug referred to in clause (i), except that if the
application is filed pursuant to the approval of a petition filed
under subparagraph (C), information to show that the active
ingredients of the new drug are of the same pharmacological or
therapeutic class as those of the listed drug referred to in
clause (i) and the new drug can be expected to have the same
therapeutic effect as the listed drug when administered to
patients for a condition of use referred to in clause (i);
(v) information to show that the labeling proposed for the new
drug is the same as the labeling approved for the listed drug
referred to in clause (i) except for changes required because of
differences approved under a petition filed under subparagraph
(C) or because the new drug and the listed drug are produced or
distributed by different manufacturers;
(vi) the items specified in clauses (B) through (F) of
subsection (b)(1) of this section;
(vii) a certification, in the opinion of the applicant and to
the best of his knowledge, with respect to each patent which
claims the listed drug referred to in clause (i) or which claims
a use for such listed drug for which the applicant is seeking
approval under this subsection and for which information is
required to be filed under subsection (b) or (c) of this section
-
(I) that such patent information has not been filed,
(II) that such patent has expired,
(III) of the date on which such patent will expire, or
(IV) that such patent is invalid or will not be infringed by
the manufacture, use, or sale of the new drug for which the
application is submitted; and
(viii) if with respect to the listed drug referred to in clause
(i) information was filed under subsection (b) or (c) of this
section for a method of use patent which does not claim a use for
which the applicant is seeking approval under this subsection, a
statement that the method of use patent does not claim such a
use.
The Secretary may not require that an abbreviated application
contain information in addition to that required by clauses (i)
through (viii).
(B) Notice of opinion that patent is invalid or will not be
infringed. -
(i) Agreement to give notice. - An applicant that makes a
certification described in subparagraph (A)(vii)(IV) shall
include in the application a statement that the applicant will
give notice as required by this subparagraph.
(ii) Timing of notice. - An applicant that makes a
certification described in subparagraph (A)(vii)(IV) shall give
notice as required under this subparagraph -
(I) if the certification is in the application, not later
than 20 days after the date of the postmark on the notice with
which the Secretary informs the applicant that the application
has been filed; or
(II) if the certification is in an amendment or supplement to
the application, at the time at which the applicant submits the
amendment or supplement, regardless of whether the applicant
has already given notice with respect to another such
certification contained in the application or in an amendment
or supplement to the application.
(iii) Recipients of notice. - An applicant required under this
subparagraph to give notice shall give notice to -
(I) each owner of the patent that is the subject of the
certification (or a representative of the owner designated to
receive such a notice); and
(II) the holder of the approved application under subsection
(b) of this section for the drug that is claimed by the patent
or a use of which is claimed by the patent (or a representative
of the holder designated to receive such a notice).
(iv) Contents of notice. - A notice required under this
subparagraph shall -
(I) state that an application that contains data from
bioavailability or bioequivalence studies has been submitted
under this subsection for the drug with respect to which the
certification is made to obtain approval to engage in the
commercial manufacture, use, or sale of the drug before the
expiration of the patent referred to in the certification; and
(II) include a detailed statement of the factual and legal
basis of the opinion of the applicant that the patent is
invalid or will not be infringed.
(C) If a person wants to submit an abbreviated application for a
new drug which has a different active ingredient or whose route of
administration, dosage form, or strength differ from that of a
listed drug, such person shall submit a petition to the Secretary
seeking permission to file such an application. The Secretary shall
approve or disapprove a petition submitted under this subparagraph
within ninety days of the date the petition is submitted. The
Secretary shall approve such a petition unless the Secretary finds
-
(i) that investigations must be conducted to show the safety
and effectiveness of the drug or of any of its active
ingredients, the route of administration, the dosage form, or
strength which differ from the listed drug; or
(ii) that any drug with a different active ingredient may not
be adequately evaluated for approval as safe and effective on the
basis of the information required to be submitted in an
abbreviated application.
(D)(i) An applicant may not amend or supplement an application to
seek approval of a drug referring to a different listed drug from
the listed drug identified in the application as submitted to the
Secretary.
(ii) With respect to the drug for which an application is
submitted, nothing in this subsection prohibits an applicant from
amending or supplementing the application to seek approval of a
different strength.
(iii) Within 60 days after December 8, 2003, the Secretary shall
issue guidance defining the term "listed drug" for purposes of this
subparagraph.
(3)(A) The Secretary shall issue guidance for the individuals who
review applications submitted under paragraph (1), which shall
relate to promptness in conducting the review, technical
excellence, lack of bias and conflict of interest, and knowledge of
regulatory and scientific standards, and which shall apply equally
to all individuals who review such applications.
(B) The Secretary shall meet with a sponsor of an investigation
or an applicant for approval for a drug under this subsection if
the sponsor or applicant makes a reasonable written request for a
meeting for the purpose of reaching agreement on the design and
size of bioavailability and bioequivalence studies needed for
approval of such application. The sponsor or applicant shall
provide information necessary for discussion and agreement on the
design and size of such studies. Minutes of any such meeting shall
be prepared by the Secretary and made available to the sponsor or
applicant.
(C) Any agreement regarding the parameters of design and size of
bioavailability and bioequivalence studies of a drug under this
paragraph that is reached between the Secretary and a sponsor or
applicant shall be reduced to writing and made part of the
administrative record by the Secretary. Such agreement shall not be
changed after the testing begins, except -
(i) with the written agreement of the sponsor or applicant; or
(ii) pursuant to a decision, made in accordance with
subparagraph (D) by the director of the reviewing division, that
a substantial scientific issue essential to determining the
safety or effectiveness of the drug has been identified after the
testing has begun.
(D) A decision under subparagraph (C)(ii) by the director shall
be in writing and the Secretary shall provide to the sponsor or
applicant an opportunity for a meeting at which the director and
the sponsor or applicant will be present and at which the director
will document the scientific issue involved.
(E) The written decisions of the reviewing division shall be
binding upon, and may not directly or indirectly be changed by, the
field or compliance office personnel unless such field or
compliance office personnel demonstrate to the reviewing division
why such decision should be modified.
(F) No action by the reviewing division may be delayed because of
the unavailability of information from or action by field personnel
unless the reviewing division determines that a delay is necessary
to assure the marketing of a safe and effective drug.
(G) For purposes of this paragraph, the reviewing division is the
division responsible for the review of an application for approval
of a drug under this subsection (including scientific matters,
chemistry, manufacturing, and controls).
(4) Subject to paragraph (5), the Secretary shall approve an
application for a drug unless the Secretary finds -
(A) the methods used in, or the facilities and controls used
for, the manufacture, processing, and packing of the drug are
inadequate to assure and preserve its identity, strength,
quality, and purity;
(B) information submitted with the application is insufficient
to show that each of the proposed conditions of use have been
previously approved for the listed drug referred to in the
application;
(C)(i) if the listed drug has only one active ingredient,
information submitted with the application is insufficient to
show that the active ingredient is the same as that of the listed
drug;
(ii) if the listed drug has more than one active ingredient,
information submitted with the application is insufficient to
show that the active ingredients are the same as the active
ingredients of the listed drug, or
(iii) if the listed drug has more than one active ingredient
and if the application is for a drug which has an active
ingredient different from the listed drug, information submitted
with the application is insufficient to show -
(I) that the other active ingredients are the same as the
active ingredients of the listed drug, or
(II) that the different active ingredient is an active
ingredient of a listed drug or a drug which does not meet the
requirements of section 321(p) of this title,
or no petition to file an application for the drug with the
different ingredient was approved under paragraph (2)(C);
(D)(i) if the application is for a drug whose route of
administration, dosage form, or strength of the drug is the same
as the route of administration, dosage form, or strength of the
listed drug referred to in the application, information submitted
in the application is insufficient to show that the route of
administration, dosage form, or strength is the same as that of
the listed drug, or
(ii) if the application is for a drug whose route of
administration, dosage form, or strength of the drug is different
from that of the listed drug referred to in the application, no
petition to file an application for the drug with the different
route of administration, dosage form, or strength was approved
under paragraph (2)(C);
(E) if the application was filed pursuant to the approval of a
petition under paragraph (2)(C), the application did not contain
the information required by the Secretary respecting the active
ingredient, route of administration, dosage form, or strength
which is not the same;
(F) information submitted in the application is insufficient to
show that the drug is bioequivalent to the listed drug referred
to in the application or, if the application was filed pursuant
to a petition approved under paragraph (2)(C), information
submitted in the application is insufficient to show that the
active ingredients of the new drug are of the same
pharmacological or therapeutic class as those of the listed drug
referred to in paragraph (2)(A)(i) and that the new drug can be
expected to have the same therapeutic effect as the listed drug
when administered to patients for a condition of use referred to
in such paragraph;
(G) information submitted in the application is insufficient to
show that the labeling proposed for the drug is the same as the
labeling approved for the listed drug referred to in the
application except for changes required because of differences
approved under a petition filed under paragraph (2)(C) or because
the drug and the listed drug are produced or distributed by
different manufacturers;
(H) information submitted in the application or any other
information available to the Secretary shows that (i) the
inactive ingredients of the drug are unsafe for use under the
conditions prescribed, recommended, or suggested in the labeling
proposed for the drug, or (ii) the composition of the drug is
unsafe under such conditions because of the type or quantity of
inactive ingredients included or the manner in which the inactive
ingredients are included;
(I) the approval under subsection (c) of this section of the
listed drug referred to in the application under this subsection
has been withdrawn or suspended for grounds described in the
first sentence of subsection (e) of this section, the Secretary
has published a notice of opportunity for hearing to withdraw
approval of the listed drug under subsection (c) of this section
for grounds described in the first sentence of subsection (e) of
this section, the approval under this subsection of the listed
drug referred to in the application under this subsection has
been withdrawn or suspended under paragraph (6), or the Secretary
has determined that the listed drug has been withdrawn from sale
for safety or effectiveness reasons;
(J) the application does not meet any other requirement of
paragraph (2)(A); or
(K) the application contains an untrue statement of material
fact.
(5)(A) Within one hundred and eighty days of the initial receipt
of an application under paragraph (2) or within such additional
period as may be agreed upon by the Secretary and the applicant,
the Secretary shall approve or disapprove the application.
(B) The approval of an application submitted under paragraph (2)
shall be made effective on the last applicable date determined by
applying the following to each certification made under paragraph
(2)(A)(vii):
(i) If the applicant only made a certification described in
subclause (I) or (II) of paragraph (2)(A)(vii) or in both such
subclauses, the approval may be made effective immediately.
(ii) If the applicant made a certification described in
subclause (III) of paragraph (2)(A)(vii), the approval may be
made effective on the date certified under subclause (III).
(iii) If the applicant made a certification described in
subclause (IV) of paragraph (2)(A)(vii), the approval shall be
made effective immediately unless, before the expiration of 45
days after the date on which the notice described in paragraph
(2)(B) is received, an action is brought for infringement of the
patent that is the subject of the certification and for which
information was submitted to the Secretary under subsection
(b)(1) or (c)(2) of this section before the date on which the
application (excluding an amendment or supplement to the
application), which the Secretary later determines to be
substantially complete, was submitted. If such an action is
brought before the expiration of such days, the approval shall be
made effective upon the expiration of the thirty-month period
beginning on the date of the receipt of the notice provided under
paragraph (2)(B)(i) or such shorter or longer period as the court
may order because either party to the action failed to reasonably
cooperate in expediting the action, except that -
(I) if before the expiration of such period the district
court decides that the patent is invalid or not infringed
(including any substantive determination that there is no cause
of action for patent infringement or invalidity), the approval
shall be made effective on -
(aa) the date on which the court enters judgment reflecting
the decision; or
(bb) the date of a settlement order or consent decree
signed and entered by the court stating that the patent that
is the subject of the certification is invalid or not
infringed;
(II) if before the expiration of such period the district
court decides that the patent has been infringed -
(aa) if the judgment of the district court is appealed, the
approval shall be made effective on -
(AA) the date on which the court of appeals decides that
the patent is invalid or not infringed (including any
substantive determination that there is no cause of action
for patent infringement or invalidity); or
(BB) the date of a settlement order or consent decree
signed and entered by the court of appeals stating that the
patent that is the subject of the certification is invalid
or not infringed; or
(bb) if the judgment of the district court is not appealed
or is affirmed, the approval shall be made effective on the
date specified by the district court in a court order under
section 271(e)(4)(A) of title 35;
(III) if before the expiration of such period the court
grants a preliminary injunction prohibiting the applicant from
engaging in the commercial manufacture or sale of the drug
until the court decides the issues of patent validity and
infringement and if the court decides that such patent is
invalid or not infringed, the approval shall be made effective
as provided in subclause (I); or
(IV) if before the expiration of such period the court grants
a preliminary injunction prohibiting the applicant from
engaging in the commercial manufacture or sale of the drug
until the court decides the issues of patent validity and
infringement and if the court decides that such patent has been
infringed, the approval shall be made effective as provided in
subclause (II).
In such an action, each of the parties shall reasonably cooperate
in expediting the action.
(iv) 180-day exclusivity period. -
(I) Effectiveness of application. - Subject to subparagraph
(D), if the application contains a certification described in
paragraph (2)(A)(vii)(IV) and is for a drug for which a first
applicant has submitted an application containing such a
certification, the application shall be made effective on the
date that is 180 days after the date of the first commercial
marketing of the drug (including the commercial marketing of
the listed drug) by any first applicant.
(II) Definitions. - In this paragraph:
(aa) 180-day exclusivity period. - The term "180-day
exclusivity period" means the 180-day period ending on the
day before the date on which an application submitted by an
applicant other than a first applicant could become effective
under this clause.
(bb) First applicant. - As used in this subsection, the
term "first applicant" means an applicant that, on the first
day on which a substantially complete application containing
a certification described in paragraph (2)(A)(vii)(IV) is
submitted for approval of a drug, submits a substantially
complete application that contains and lawfully maintains a
certification described in paragraph (2)(A)(vii)(IV) for the
drug.
(cc) Substantially complete application. - As used in this
subsection, the term "substantially complete application"
means an application under this subsection that on its face
is sufficiently complete to permit a substantive review and
contains all the information required by paragraph (2)(A).
(dd) Tentative approval. -
(AA) In general. - The term "tentative approval" means
notification to an applicant by the Secretary that an
application under this subsection meets the requirements of
paragraph (2)(A), but cannot receive effective approval
because the application does not meet the requirements of
this subparagraph, there is a period of exclusivity for the
listed drug under subparagraph (F) or section 355a of this
title, or there is a 7-year period of exclusivity for the
listed drug under section 360cc of this title.
(BB) Limitation. - A drug that is granted tentative
approval by the Secretary is not an approved drug and shall
not have an effective approval until the Secretary issues
an approval after any necessary additional review of the
application.
(C) Civil action to obtain patent certainty. -
(i) Declaratory judgment absent infringement action. -
(I) In general. - No action may be brought under section 2201
of title 28 by an applicant under paragraph (2) for a
declaratory judgment with respect to a patent which is the
subject of the certification referred to in subparagraph
(B)(iii) unless -
(aa) the 45-day period referred to in such subparagraph has
expired;
(bb) neither the owner of such patent nor the holder of the
approved application under subsection (b) of this section for
the drug that is claimed by the patent or a use of which is
claimed by the patent brought a civil action against the
applicant for infringement of the patent before the
expiration of such period; and
(cc) in any case in which the notice provided under
paragraph (2)(B) relates to noninfringement, the notice was
accompanied by a document described in subclause (III).
(II) Filing of civil action. - If the conditions described in
items (aa), (bb), and as applicable, (cc) of subclause (I) have
been met, the applicant referred to in such subclause may, in
accordance with section 2201 of title 28, bring a civil action
under such section against the owner or holder referred to in
such subclause (but not against any owner or holder that has
brought such a civil action against the applicant, unless that
civil action was dismissed without prejudice) for a declaratory
judgment that the patent is invalid or will not be infringed by
the drug for which the applicant seeks approval, except that
such civil action may be brought for a declaratory judgment
that the patent will not be infringed only in a case in which
the condition described in subclause (I)(cc) is applicable. A
civil action referred to in this subclause shall be brought in
the judicial district where the defendant has its principal
place of business or a regular and established place of
business.
(III) Offer of confidential access to application. - For
purposes of subclause (I)(cc), the document described in this
subclause is a document providing an offer of confidential
access to the application that is in the custody of the
applicant under paragraph (2) for the purpose of determining
whether an action referred to in subparagraph (B)(iii) should
be brought. The document providing the offer of confidential
access shall contain such restrictions as to persons entitled
to access, and on the use and disposition of any information
accessed, as would apply had a protective order been entered
for the purpose of protecting trade secrets and other
confidential business information. A request for access to an
application under an offer of confidential access shall be
considered acceptance of the offer of confidential access with
the restrictions as to persons entitled to access, and on the
use and disposition of any information accessed, contained in
the offer of confidential access, and those restrictions and
other terms of the offer of confidential access shall be
considered terms of an enforceable contract. Any person
provided an offer of confidential access shall review the
application for the sole and limited purpose of evaluating
possible infringement of the patent that is the subject of the
certification under paragraph (2)(A)(vii)(IV) and for no other
purpose, and may not disclose information of no relevance to
any issue of patent infringement to any person other than a
person provided an offer of confidential access. Further, the
application may be redacted by the applicant to remove any
information of no relevance to any issue of patent
infringement.
(ii) Counterclaim to infringement action. -
(I) In general. - If an owner of the patent or the holder of
the approved application under subsection (b) of this section
for the drug that is claimed by the patent or a use of which is
claimed by the patent brings a patent infringement action
against the applicant, the applicant may assert a counterclaim
seeking an order requiring the holder to correct or delete the
patent information submitted by the holder under subsection (b)
or (c) of this section on the ground that the patent does not
claim either -
(aa) the drug for which the application was approved; or
(bb) an approved method of using the drug.
(II) No independent cause of action. - Subclause (I) does not
authorize the assertion of a claim described in subclause (I)
in any civil action or proceeding other than a counterclaim
described in subclause (I).
(iii) No damages. - An applicant shall not be entitled to
damages in a civil action under clause (i) or a counterclaim
under clause (ii).
(D) Forfeiture of 180-day exclusivity period. -
(i) Definition of forfeiture event. - In this subparagraph, the
term "forfeiture event", with respect to an application under
this subsection, means the occurrence of any of the following:
(I) Failure to market. - The first applicant fails to market
the drug by the later of -
(aa) the earlier of the date that is -
(AA) 75 days after the date on which the approval of the
application of the first applicant is made effective under
subparagraph (B)(iii); or
(BB) 30 months after the date of submission of the
application of the first applicant; or
(bb) with respect to the first applicant or any other
applicant (which other applicant has received tentative
approval), the date that is 75 days after the date as of
which, as to each of the patents with respect to which the
first applicant submitted and lawfully maintained a
certification qualifying the first applicant for the 180-day
exclusivity period under subparagraph (B)(iv), at least 1 of
the following has occurred:
(AA) In an infringement action brought against that
applicant with respect to the patent or in a declaratory
judgment action brought by that applicant with respect to
the patent, a court enters a final decision from which no
appeal (other than a petition to the Supreme Court for a
writ of certiorari) has been or can be taken that the
patent is invalid or not infringed.
(BB) In an infringement action or a declaratory judgment
action described in subitem (AA), a court signs a
settlement order or consent decree that enters a final
judgment that includes a finding that the patent is invalid
or not infringed.
(CC) The patent information submitted under subsection
(b) or (c) of this section is withdrawn by the holder of
the application approved under subsection (b) of this
section.
(II) Withdrawal of application. - The first applicant
withdraws the application or the Secretary considers the
application to have been withdrawn as a result of a
determination by the Secretary that the application does not
meet the requirements for approval under paragraph (4).
(III) Amendment of certification. - The first applicant
amends or withdraws the certification for all of the patents
with respect to which that applicant submitted a certification
qualifying the applicant for the 180-day exclusivity period.
(IV) Failure to obtain tentative approval. - The first
applicant fails to obtain tentative approval of the application
within 30 months after the date on which the application is
filed, unless the failure is caused by a change in or a review
of the requirements for approval of the application imposed
after the date on which the application is filed.
(V) Agreement with another applicant, the listed drug
application holder, or a patent owner. - The first applicant
enters into an agreement with another applicant under this
subsection for the drug, the holder of the application for the
listed drug, or an owner of the patent that is the subject of
the certification under paragraph (2)(A)(vii)(IV), the Federal
Trade Commission or the Attorney General files a complaint, and
there is a final decision of the Federal Trade Commission or
the court with regard to the complaint from which no appeal
(other than a petition to the Supreme Court for a writ of
certiorari) has been or can be taken that the agreement has
violated the antitrust laws (as defined in section 12 of title
15, except that the term includes section 45 of title 15 to the
extent that that section applies to unfair methods of
competition).
(VI) Expiration of all patents. - All of the patents as to
which the applicant submitted a certification qualifying it for
the 180-day exclusivity period have expired.
(ii) Forfeiture. - The 180-day exclusivity period described in
subparagraph (B)(iv) shall be forfeited by a first applicant if a
forfeiture event occurs with respect to that first applicant.
(iii) Subsequent applicant. - If all first applicants forfeit
the 180-day exclusivity period under clause (ii) -
(I) approval of any application containing a certification
described in paragraph (2)(A)(vii)(IV) shall be made effective
in accordance with subparagraph (B)(iii); and
(II) no applicant shall be eligible for a 180-day exclusivity
period.
(E) If the Secretary decides to disapprove an application, the
Secretary shall give the applicant notice of an opportunity for a
hearing before the Secretary on the question of whether such
application is approvable. If the applicant elects to accept the
opportunity for hearing by written request within thirty days after
such notice, such hearing shall commence not more than ninety days
after the expiration of such thirty days unless the Secretary and
the applicant otherwise agree. Any such hearing shall thereafter be
conducted on an expedited basis and the Secretary's order thereon
shall be issued within ninety days after the date fixed by the
Secretary for filing final briefs.
(F)(i) If an application (other than an abbreviated new drug
application) submitted under subsection (b) of this section for a
drug, no active ingredient (including any ester or salt of the
active ingredient) of which has been approved in any other
application under subsection (b) of this section, was approved
during the period beginning January 1, 1982, and ending on
September 24, 1984, the Secretary may not make the approval of an
application submitted under this subsection which refers to the
drug for which the subsection (b) application was submitted
effective before the expiration of ten years from the date of the
approval of the application under subsection (b) of this section.
(ii) If an application submitted under subsection (b) of this
section for a drug, no active ingredient (including any ester or
salt of the active ingredient) of 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 drug for which the subsection
(b) application was submitted before the expiration of five years
from the date of the approval of the application under subsection
(b) of this section, except that such an application may be
submitted under this subsection after the expiration of four years
from the date of the approval of the subsection (b) application if
it contains a certification of patent invalidity or noninfringement
described in subclause (IV) of paragraph (2)(A)(vii). The approval
of such an application shall be made effective in accordance with
subparagraph (B) except that, if an action for patent infringement
is commenced during the one-year period beginning forty-eight
months after the date of the approval of the subsection (b)
application, the thirty-month period referred to in subparagraph
(B)(iii) shall be extended by such amount of time (if any) which is
required for seven and one-half years to have elapsed from the date
of approval of the subsection (b) application.
(iii) If an application submitted under subsection (b) of this
section for a drug, which includes an active ingredient (including
any ester or salt of the active ingredient) that has been approved
in another application approved under subsection (b) of this
section, is approved after September 24, 1984, and if such
application contains reports of new clinical investigations (other
than bioavailability studies) essential to the approval of the
application and conducted or sponsored by the applicant, the
Secretary may not make the approval of an application submitted
under this subsection for the conditions of approval of such drug
in the subsection (b) application effective before the expiration
of three years from the date of the approval of the application
under subsection (b) of this section for such drug.
(iv) If a supplement to an application approved under subsection
(b) of this section is approved after September 24, 1984, and the
supplement contains reports of new clinical investigations (other
than bioavailability studies) essential to the approval of the
supplement and conducted or sponsored by the person submitting the
supplement, the Secretary may not make the approval of an
application submitted under this subsection for a change approved
in the supplement effective before the expiration of three years
from the date of the approval of the supplement under subsection
(b) of this section.
(v) If an application (or supplement to an application) submitted
under subsection (b) of this section for a drug, which includes an
active ingredient (including any ester or salt of the active
ingredient) that has been approved in another application under
subsection (b) of this section, was approved during the period
beginning January 1, 1982, and ending on September 24, 1984, the
Secretary may not make the approval of an application submitted
under this subsection which refers to the drug for which the
subsection (b) application was submitted or which refers to a
change approved in a supplement to the subsection (b) application
effective before the expiration of two years from September 24,
1984.
(6) If a drug approved under this subsection refers in its
approved application to a drug the approval of which was withdrawn
or suspended for grounds described in the first sentence of
subsection (e) of this section or was withdrawn or suspended under
this paragraph or which, as determined by the Secretary, has been
withdrawn from sale for safety or effectiveness reasons, the
approval of the drug under this subsection shall be withdrawn or
suspended -
(A) for the same period as the withdrawal or suspension under
subsection (e) of this section or this paragraph, or
(B) if the listed drug has been withdrawn from sale, for the
period of withdrawal from sale or, if earlier, the period ending
on the date the Secretary determines that the withdrawal from
sale is not for safety or effectiveness reasons.
(7)(A)(i) Within sixty days of September 24, 1984, the Secretary
shall publish and make available to the public -
(I) a list in alphabetical order of the official and
proprietary name of each drug which has been approved for safety
and effectiveness under subsection (c) of this section before
September 24, 1984;
(II) the date of approval if the drug is approved after 1981
and the number of the application which was approved; and
(III) whether in vitro or in vivo bioequivalence studies, or
both such studies, are required for applications filed under this
subsection which will refer to the drug published.
(ii) Every thirty days after the publication of the first list
under clause (i) the Secretary shall revise the list to include
each drug which has been approved for safety and effectiveness
under subsection (c) of this section or approved under this
subsection during the thirty-day period.
(iii) When patent information submitted under subsection (b) or
(c) of this section respecting a drug included on the list is to be
published by the Secretary, the Secretary shall, in revisions made
under clause (ii), include such information for such drug.
(B) A drug approved for safety and effectiveness under subsection
(c) of this section or approved under this subsection shall, for
purposes of this subsection, be considered to have been published
under subparagraph (A) on the date of its approval or September 24,
1984, whichever is later.
(C) If the approval of a drug was withdrawn or suspended for
grounds described in the first sentence of subsection (e) of this
section or was withdrawn or suspended under paragraph (6) or if the
Secretary determines that a drug has been withdrawn from sale for
safety or effectiveness reasons, it may not be published in the
list under subparagraph (A) or, if the withdrawal or suspension
occurred after its publication in such list, it shall be
immediately removed from such list -
(i) for the same period as the withdrawal or suspension under
subsection (e) of this section or paragraph (6), or
(ii) if the listed drug has been withdrawn from sale, for the
period of withdrawal from sale or, if earlier, the period ending
on the date the Secretary determines that the withdrawal from
sale is not for safety or effectiveness reasons.
A notice of the removal shall be published in the Federal Register.
(8) For purposes of this subsection:
(A)(i) The term "bioavailability" means the rate and extent to
which the active ingredient or therapeutic ingredient is absorbed
from a drug and becomes available at the site of drug action.
(ii) For a drug that is not intended to be absorbed into the
bloodstream, the Secretary may assess bioavailability by
scientifically valid measurements intended to reflect the rate
and extent to which the active ingredient or therapeutic
ingredient becomes available at the site of drug action.
(B) A drug shall be considered to be bioequivalent to a listed
drug if -
(i) the rate and extent of absorption of the drug do not show
a significant difference from the rate and extent of absorption
of the listed drug when administered at the same molar dose of
the therapeutic ingredient under similar experimental
conditions in either a single dose or multiple doses; or
(ii) the extent of absorption of the drug does not show a
significant difference from the extent of absorption of the
listed drug when administered at the same molar dose of the
therapeutic ingredient under similar experimental conditions in
either a single dose or multiple doses and the difference from
the listed drug in the rate of absorption of the drug is
intentional, is reflected in its proposed labeling, is not
essential to the attainment of effective body drug
concentrations on chronic use, and is considered medically
insignificant for the drug.
(C) For a drug that is not intended to be absorbed into the
bloodstream, the Secretary may establish alternative,
scientifically valid methods to show bioequivalence if the
alternative methods are expected to detect a significant
difference between the drug and the listed drug in safety and
therapeutic effect.
(9) The Secretary shall, with respect to each application
submitted under this subsection, maintain a record of -
(A) the name of the applicant,
(B) the name of the drug covered by the application,
(C) the name of each person to whom the review of the chemistry
of the application was assigned and the date of such assignment,
and
(D) the name of each person to whom the bioequivalence review
for such application was assigned and the date of such
assignment.
The information the Secretary is required to maintain under this
paragraph with respect to an application submitted under this
subsection shall be made available to the public after the approval
of such application.
(k) Records and reports; required information; regulations and
orders; access to records
(1) In the case of any drug for which an approval of an
application filed under subsection (b) or (j) of this section is in
effect, the applicant shall establish and maintain such records,
and make such reports to the Secretary, of data relating to
clinical experience and other data or information, received or
otherwise obtained by such applicant with respect to such drug, as
the Secretary may by general regulation, or by order with respect
to such application, prescribe on the basis of a finding that such
records and reports are necessary in order to enable the Secretary
to determine, or facilitate a determination, whether there is or
may be ground for invoking subsection (e) of this section.
Regulations and orders issued under this subsection and under
subsection (i) of this section shall have due regard for the
professional ethics of the medical profession and the interests of
patients and shall provide, where the Secretary deems it to be
appropriate, for the examination, upon request, by the persons to
whom such regulations or orders are applicable, of similar
information received or otherwise obtained by the Secretary.
(2) Every person required under this section to maintain records,
and every person in charge or custody thereof, shall, upon request
of an officer or employee designated by the Secretary, permit such
officer or employee at all reasonable times to have access to and
copy and verify such records.
(l) Public disclosure of safety and effectiveness data
Safety and effectiveness data and information which has been
submitted in an application under subsection (b) of this section
for a drug and which has not previously been disclosed to the
public shall be made available to the public, upon request, unless
extraordinary circumstances are shown -
(1) if no work is being or will be undertaken to have the
application approved,
(2) if the Secretary has determined that the application is not
approvable and all legal appeals have been exhausted,
(3) if approval of the application under subsection (c) of this
section is withdrawn and all legal appeals have been exhausted,
(4) if the Secretary has determined that such drug is not a new
drug, or
(5) upon the effective date of the approval of the first
application under subsection (j) of this section which refers to
such drug or upon the date upon which the approval of an
application under subsection (j) of this section which refers to
such drug could be made effective if such an application had been
submitted.
(m) "Patent" defined
For purposes of this section, the term "patent" means a patent
issued by the United States Patent and Trademark Office.
(n) Scientific advisory panels
(1) For the purpose of providing expert scientific advice and
recommendations to the Secretary regarding a clinical investigation
of a drug or the approval for marketing of a drug under this
section or section 262 of title 42, the Secretary shall establish
panels of experts or use panels of experts established before
November 21, 1997, or both.
(2) The Secretary may delegate the appointment and oversight
authority granted under section 394 of this title to a director of
a center or successor entity within the Food and Drug
Administration.
(3) The Secretary shall make appointments to each panel
established under paragraph (1) so that each panel shall consist of
-
(A) members who are qualified by training and experience to
evaluate the safety and effectiveness of the drugs to be referred
to the panel and who, to the extent feasible, possess skill and
experience in the development, manufacture, or utilization of
such drugs;
(B) members with diverse expertise in such fields as clinical
and administrative medicine, pharmacy, pharmacology,
pharmacoeconomics, biological and physical sciences, and other
related professions;
(C) a representative of consumer interests, and a
representative of interests of the drug manufacturing industry
not directly affected by the matter to be brought before the
panel; and
(D) two or more members who are specialists or have other
expertise in the particular disease or condition for which the
drug under review is proposed to be indicated.
Scientific, trade, and consumer organizations shall be afforded an
opportunity to nominate individuals for appointment to the panels.
No individual who is in the regular full-time employ of the United
States and engaged in the administration of this chapter may be a
voting member of any panel. The Secretary shall designate one of
the members of each panel to serve as chairman thereof.
(4) Each member of a panel shall publicly disclose all conflicts
of interest that member may have with the work to be undertaken by
the panel. No member of a panel may vote on any matter where the
member or the immediate family of such member could gain
financially from the advice given to the Secretary. The Secretary
may grant a waiver of any conflict of interest requirement upon
public disclosure of such conflict of interest if such waiver is
necessary to afford the panel essential expertise, except that the
Secretary may not grant a waiver for a member of a panel when the
member's own scientific work is involved.
(5) The Secretary shall, as appropriate, provide education and
training to each new panel member before such member participates
in a panel's activities, including education regarding requirements
under this chapter and related regulations of the Secretary, and
the administrative processes and procedures related to panel
meetings.
(6) Panel members (other than officers or employees of the United
States), while attending meetings or conferences of a panel or
otherwise engaged in its business, shall be entitled to receive
compensation for each day so engaged, including traveltime, at
rates to be fixed by the Secretary, but not to exceed the daily
equivalent of the rate in effect for positions classified above
grade GS-15 of the General Schedule. While serving away from their
homes or regular places of business, panel members may be allowed
travel expenses (including per diem in lieu of subsistence) as
authorized by section 5703 of title 5, for persons in the
Government service employed intermittently.
(7) The Secretary shall ensure that scientific advisory panels
meet regularly and at appropriate intervals so that any matter to
be reviewed by such a panel can be presented to the panel not more
than 60 days after the matter is ready for such review. Meetings of
the panel may be held using electronic communication to convene the
meetings.
(8) Within 90 days after a scientific advisory panel makes
recommendations on any matter under its review, the Food and Drug
Administration official responsible for the matter shall review the
conclusions and recommendations of the panel, and notify the
affected persons of the final decision on the matter, or of the
reasons that no such decision has been reached. Each such final
decision shall be documented including the rationale for the
decision.
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