U.S Code last checked for updates: Nov 22, 2024
All TitlesTitle 21Chapter 9Subchapter VPart A
§ 355.
New drugs
(a)
Necessity of effective approval of application
(b)
Filing application; contents
(1)
(A)
Any person may file with the Secretary an application with respect to any drug subject to the provisions of subsection (a). Such persons shall submit to the Secretary as part of the application—
(i)
full reports of investigations which have been made to show whether such drug is safe for use and whether such drug is effective in use;
(ii)
a full list of the articles used as components of such drug;
(iii)
a full statement of the composition of such drug;
(iv)
a full description of the methods used in, and the facilities and controls used for, the manufacture, processing, and packing of such drug;
(v)
such samples of such drug and of the articles used as components thereof as the Secretary may require;
(vi)
specimens of the labeling proposed to be used for such drug;
(vii)
any assessments required under section 355c of this title; and
(viii)
the patent number and expiration date of each patent for which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner of the patent engaged in the manufacture, use, or sale of the drug, and that—
(I)
claims the drug for which the applicant submitted the application and is a drug substance (active ingredient) patent or a drug product (formulation or composition) patent; or
(II)
claims a method of using such drug for which approval is sought or has been granted in the application.
(B)
If an application is filed under this subsection for a drug, and a patent of the type described in subparagraph (A)(viii) is issued after the filing date but before approval of the application, the applicant shall amend the application to include the patent number and expiration date.
(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)—
(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) 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) 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—
(i)
(I)
of clinical trials intended to form the primary basis of an effectiveness claim; or
(II)
in the case where human efficacy studies are not ethical or feasible, of animal and any associated clinical trials which, in combination, are intended to form the primary basis of an effectiveness claim; or
(ii)
with respect to an application for approval of a biological product under section 262(k) of title 42, of any necessary clinical study or studies.
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).
(6)
An application submitted under this subsection shall be accompanied by the certification required under section 282(j)(5)(B) of title 42. Such certification shall not be considered an element of such application.
(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), 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) applies, or
(B)
give the applicant notice of an opportunity for a hearing before the Secretary under subsection (d) 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)
Not later than 30 days after the date of approval of an application submitted under subsection (b), the holder of the approved application shall file with the Secretary the patent number and the expiration date of any patent described in subsection (b)(1)(A)(viii), except that a patent that is identified as claiming a method of using such drug shall be filed only if the patent claims a method of use approved in the application. If a patent described in subsection (b)(1)(A)(viii) is issued after the date of approval of an application submitted under subsection (b), the holder of the approved application shall, not later than 30 days after the date of issuance of the patent, file the patent number and the expiration date of the patent, except that a patent that claims a method of using such drug shall be filed only if approval for such use has been granted in the application. If the patent information described in subsection (b) could not be filed with the submission of an application under subsection (b) because the application was filed before the patent information was required under subsection (b) 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 described in subsection (b)(1)(A)(viii). If the holder of an approved application could not file patent information under subsection (b) 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) because no patent of the type for which information is required to be submitted in subsection (b)(1)(A)(viii) 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. Patent information that is not the type of patent information required by subsection (b)(1)(A)(viii) shall not be submitted under this paragraph.
(3)
The approval of an application filed under subsection (b) 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):
(A)
If the applicant only made a certification described in clause (i) or (ii) of subsection (b)(2)(A) 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), 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), 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) 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) 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) 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) 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) 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) 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) 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) 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 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)
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)
Repealed. Pub. L. 117–9, § 1(b)(1)(A), Apr. 23, 2021, 135 Stat. 258.
(ii)
If an application submitted under subsection (b) for a drug, no active moiety (as defined by the Secretary in section 314.3 of title 21, Code of Federal Regulations (or any successor regulations)) of which has been approved in any other application under subsection (b), 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 subsection (b)(1)(A)(i) 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) before the expiration of five years from the date of the approval of the application under subsection (b), except that such an application may be submitted under subsection (b) 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). 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) for a drug, which includes an active moiety (as defined by the Secretary in section 314.3 of title 21, Code of Federal Regulations (or any successor regulations)) that has been approved in another application approved under subsection (b), 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) 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) if the investigations described in subsection (b)(1)(A)(i) 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) is approved after September 24, 1984, and the supplement contains reports of new clinical investigations (other than bioavailabilty 1
1
 So in original. Probably should be “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 subsection (b) 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) if the investigations described in subsection (b)(1)(A)(i) 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) for a drug, which includes an active moiety (as defined by the Secretary in section 314.3 of title 21, Code of Federal Regulations (or any successor regulations)) that has been approved in another application under subsection (b), 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 subsection (b)(1)(A)(i) 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.
(5)
(A)
The Secretary may rely upon qualified data summaries to support the approval of a supplemental application, with respect to a qualified indication for a drug, submitted under subsection (b), if such supplemental application complies with subparagraph (B).
(B)
A supplemental application is eligible for review as described in subparagraph (A) only if—
(i)
there is existing data available and acceptable to the Secretary demonstrating the safety of the drug; and
(ii)
all data used to develop the qualified data summaries are submitted to the Secretary as part of the supplemental application.
(C)
The Secretary shall post on the Internet website of the Food and Drug Administration and update annually—
(i)
the number of applications reviewed solely under subparagraph (A) or section 262(a)(2)(E) of title 42;
(ii)
the average time for completion of review under subparagraph (A) or section 262(a)(2)(E) of title 42;
(iii)
the average time for review of supplemental applications where the Secretary did not use review flexibility under subparagraph (A) or section 262(a)(2)(E) of title 42; and
(iv)
the number of applications reviewed under subparagraph (A) or section 262(a)(2)(E) of title 42 for which the Secretary made use of full data sets in addition to the qualified data summary.
(D)
In this paragraph—
(i)
the term “qualified indication” means an indication for a drug that the Secretary determines to be appropriate for summary level review under this paragraph; and
(ii)
the term “qualified data summary” means a summary of clinical data that demonstrates the safety and effectiveness of a drug with respect to a qualified indication.
(d)
Grounds for refusing application; approval of application; “substantial evidence” defined
(e)
Withdrawal of approval; grounds; immediate suspension upon finding imminent hazard to public health
(f)
Revocation of order refusing, withdrawing or suspending approval of application
(g)
Service of orders
(h)
Appeal from 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 nonclinical tests 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); 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 nonclinical tests 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, it is contrary to the best interests of such human beings, or the proposed clinical testing poses no more than minimal risk to such human beings and includes appropriate safeguards as prescribed to protect the rights, safety, and welfare 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. The Secretary shall update such regulations to require inclusion in the informed consent documents and process a statement that clinical trial information for such clinical investigation has been or will be submitted for inclusion in the registry data bank pursuant to subsection (j) of section 282 of title 42.
(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 (ii) through (vi) of subsection (b)(1)(A);
(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)—
(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) 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) 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 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), the Secretary has published a notice of opportunity for hearing to withdraw approval of the listed drug under subsection (c) for grounds described in the first sentence of subsection (e), 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) 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.
(v)
180-day exclusivity period for competitive generic therapies.—
(I)
Effectiveness of application.—
Subject to subparagraph (D)(iv), if the application is for a drug that is the same as a competitive generic therapy for which any first approved applicant has commenced commercial marketing, the application shall be made effective on the date that is 180 days after the date of the first commercial marketing of the competitive generic therapy (including the commercial marketing of the listed drug) by any first approved applicant.
(II)
Limitation.—
The exclusivity period under subclause (I) shall not apply with respect to a competitive generic therapy that has previously received an exclusivity period under subclause (I).
(III)
Definitions.—
In this clause and subparagraph (D)(iv):
(aa)
The term “competitive generic therapy” means a drug—
(AA)
that is designated as a competitive generic therapy under section 356h of this title; and
(BB)
for which there are no unexpired patents or exclusivities on the list of products described in section 355(j)(7)(A) of this title at the time of submission.
(bb)
The term “first approved applicant” means any applicant that has submitted an application that—
(AA)
is for a competitive generic therapy that is approved on the first day on which any application for such competitive generic therapy is approved;
(BB)
is not eligible for a 180-day exclusivity period under clause (iv) for the drug that is the subject of the application for the competitive generic therapy; and
(CC)
is not for a drug for which all drug versions have forfeited eligibility for a 180-day exclusivity period under clause (iv) pursuant to subparagraph (D).
(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) 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) 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) 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) is withdrawn by the holder of the application approved under subsection (b).
(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.
(iv)
Special forfeiture rule for competitive generic therapy.—
The 180-day exclusivity period described in subparagraph (B)(v) shall be forfeited by a first approved applicant if the applicant fails to market the competitive generic therapy within 75 days after the date on which the approval of the first approved applicant’s application for the competitive generic therapy is made effective.
(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)
Repealed. Pub. L. 117–9, § 1(b)(1)(B), Apr. 23, 2021, 135 Stat. 258.
(ii)
If an application submitted under subsection (b) for a drug, no active moiety (as defined by the Secretary in section 314.3 of title 21, Code of Federal Regulations (or any successor regulations)) of which has been approved in any other application under subsection (b), 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), 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) for a drug, which includes an active moiety (as defined by the Secretary in section 314.3 of title 21, Code of Federal Regulations (or any successor regulations)) that has been approved in another application approved under subsection (b), 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) for such drug.
(iv)
If a supplement to an application approved under subsection (b) 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).
(v)
If an application (or supplement to an application) submitted under subsection (b) for a drug, which includes an active moiety (as defined by the Secretary in section 314.3 of title 21, Code of Federal Regulations (or any successor regulations)) that has been approved in another application under subsection (b), 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
(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) 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) 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) 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) or approved under this subsection during the thirty-day period.
(iii)
When patent information submitted under subsection (c) 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.
(iv)
For each drug included on the list, the Secretary shall specify any exclusivity period that is applicable, for which the Secretary has determined the expiration date, and for which such period has not yet expired, under—
(I)
clause (ii), (iii), or (iv) of subsection (c)(3)(E);
(II)
clause (iv) or (v) of paragraph (5)(B);
(III)
clause (ii), (iii), or (iv) of paragraph (5)(F);
(IV)
section 355a of this title;
(V)
section 355f of this title;
(VI)
section 360cc(a) of this title; or
(VII)
subsection (u).
(v)
(I)
With respect to an application submitted pursuant to subsection (b)(2) for a drug that is subject to section 353(b) of this title for which the sole difference from a listed drug relied upon in the application is a difference in inactive ingredients not permitted under clause (iii) or (iv) of section 314.94(a)(9) of title 21, Code of Federal Regulations (or any successor regulations), the Secretary shall make an evaluation with respect to whether such drug is a therapeutic equivalent (as defined in section 314.3 of title 21, Code of Federal Regulations (or any successor regulations)) to another approved drug product in the prescription drug product section of the list under this paragraph as follows:
(aa)
With respect to such an application submitted after December 29, 2022, the evaluation shall be made with respect to a listed drug relied upon in the application pursuant to subsection (b)(2) that is a pharmaceutical equivalent (as defined in section 314.3 of title 21, Code of Federal Regulations (or any successor regulations)) to the drug in the application pursuant to subsection (b)(2) at the time of approval of such application or not later than 180 days after the date of such approval, provided that the request for such an evaluation is made in the original application (or in a resubmission to a complete response letter), and all necessary data and information are submitted in the original application (or in a resubmission in response to a complete response letter) for the therapeutic equivalence evaluation, including information to demonstrate bioequivalence, in a form and manner prescribed by the Secretary.
(bb)
With respect to such an application approved prior to or on December 29, 2022, the evaluation shall be made not later than 180 days after receipt of a request for a therapeutic equivalence evaluation submitted as part of a supplement to such application; or with respect to an application that was submitted prior to December 29, 2022, but not approved as of December 29, 2022, the evaluation shall be made not later than 180 days after the date of approval of such application if a request for such evaluation is submitted as an amendment to the application, provided that—
(AA)
such request for a therapeutic equivalence evaluation is being sought with respect to a listed drug relied upon in the application, and the relied upon listed drug is in the prescription drug product section of the list under this paragraph and is a pharmaceutical equivalent (as defined in section 314.3 of title 21, Code of Federal Regulations (or any successor regulations)) to the drug for which a therapeutic equivalence evaluation is sought; and
(BB)
the amendment or supplement, as applicable, containing such request, or the relevant application, includes all necessary data and information for the therapeutic equivalence evaluation, including information to demonstrate bioequivalence, in a form and manner prescribed by the Secretary.
(II)
When the Secretary makes an evaluation under subclause (I), the Secretary shall, in revisions made to the list pursuant to clause (ii), include such information for such drug.
(B)
A drug approved for safety and effectiveness under subsection (c) 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) 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) 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.
(D)
In the case of a listed drug for which the list under subparagraph (A)(i) includes a patent for such drug, and any claim of the patent has been cancelled or invalidated pursuant to a final decision issued by the Patent Trial and Appeal Board of the United States Patent and Trademark Office or by a court, from which no appeal has been, or can be, taken, if the holder of the applicable application approved under subsection (c) determines that a patent for such drug, or any patent information for such drug, no longer meets the listing requirements under this section—
(i)
the holder of such approved application shall notify the Secretary, in writing, within 14 days of such decision of such cancellation or invalidation and request that such patent or patent information, as applicable, be amended or withdrawn in accordance with the decision issued by the Patent Trial and Appeal Board or a court;
(ii)
the holder of such approved application shall include in any notification under clause (i) information related to such patent cancellation or invalidation decision and submit such information, including a copy of such decision, to the Secretary; and
(iii)
the Secretary shall, in response to a notification under clause (i), amend or remove patent or patent information in accordance with the relevant decision from the Patent Trial and Appeals Board or court, as applicable, except that the Secretary shall not remove from the list any patent or patent information before the expiration of any 180-day exclusivity period under paragraph (5)(B)(iv) that relies on a certification described in paragraph (2)(A)(vii)(IV).
(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.
(10)
(A)
If the proposed labeling of a drug that is the subject of an application under this subsection differs from the listed drug due to a labeling revision described under clause (i), the drug that is the subject of such application shall, notwithstanding any other provision of this chapter, be eligible for approval and shall not be considered misbranded under section 352 of this title if—
(i)
a revision to the labeling of the listed drug has been approved by the Secretary within 90 days of when the application is otherwise eligible for approval under this subsection;
(ii)
the sponsor of the application agrees to submit revised labeling for the drug that is the subject of the application not later than 60 days after approval under this subsection of the application;
(iii)
the labeling revision described under clause (i) does not include a change to the “Warnings” section of the labeling; and
(iv)
such application otherwise meets the applicable requirements for approval under this subsection.
(B)
If, after a labeling revision described in subparagraph (A)(i), the Secretary determines that the continued presence in interstate commerce of the labeling of the listed drug (as in effect before the revision described in subparagraph (A)(i)) adversely impacts the safe use of the drug, no application under this subsection shall be eligible for approval with such labeling.
(11)
(A)
Subject to subparagraph (B), the Secretary shall prioritize the review of, and act within 8 months of the date of the submission of, an original abbreviated new drug application submitted for review under this subsection that is for a drug—
(i)
for which there are not more than 3 approved drug products listed under paragraph (7) and for which there are no blocking patents and exclusivities; or
(ii)
that has been included on the list under section 356e of this title.
(B)
To qualify for priority review under this paragraph, not later than 60 days prior to the submission of an application described in subparagraph (A) or that the Secretary may prioritize pursuant to subparagraph (D), the applicant shall provide complete, accurate information regarding facilities involved in manufacturing processes and testing of the drug that is the subject of the application, including facilities in corresponding Type II active pharmaceutical ingredients drug master files referenced in an application and sites or organizations involved in bioequivalence and clinical studies used to support the application, to enable the Secretary to make a determination regarding whether an inspection of a facility is necessary. Such information shall include the relevant (as determined by the Secretary) sections of such application, which shall be unchanged relative to the date of the submission of such application, except to the extent that a change is made to such information to exclude a facility that was not used to generate data to meet any application requirements for such submission and that is not the only facility intended to conduct one or more unit operations in commercial production. Information provided by an applicant under this subparagraph shall not be considered the submission of an application under this subsection.
(C)
The Secretary may expedite an inspection or reinspection under section 374 of this title of an establishment that proposes to manufacture a drug described in subparagraph (A).
(D)
Nothing in this paragraph shall prevent the Secretary from prioritizing the review of other applications as the Secretary determines appropriate.
(12)
The Secretary shall publish on the internet website of the Food and Drug Administration, and update at least once every 6 months, a list of all drugs approved under subsection (c) for which all patents and periods of exclusivity under this chapter have expired and for which no application has been approved under this subsection.
(13)
Upon the request of an applicant regarding one or more specified pending applications under this subsection, the Secretary shall, as appropriate, provide review status updates indicating the categorical status of the applications by each relevant review discipline.
(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) 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). Regulations and orders issued under this subsection and under subsection (i) 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.
(3)
Active postmarket risk identification.—
(A)
Definition.—
In this paragraph, the term “data” refers to information with respect to a drug approved under this section or under section 262 of title 42, including claims data, patient survey data, standardized analytic files that allow for the pooling and analysis of data from disparate data environments, and any other data deemed appropriate by the Secretary.
(B)
Development of postmarket risk identification and analysis methods.—
The Secretary shall, not later than 2 years after September 27, 2007, in collaboration with public, academic, and private entities—
(i)
develop methods to obtain access to disparate data sources including the data sources specified in subparagraph (C);
(ii)
develop validated methods for the establishment of a postmarket risk identification and analysis system to link and analyze safety data from multiple sources, with the goals of including, in aggregate—
(I)
at least 25,000,000 patients by July 1, 2010; and
(II)
at least 100,000,000 patients by July 1, 2012; and
(iii)
convene a committee of experts, including individuals who are recognized in the field of protecting data privacy and security, to make recommendations to the Secretary on the development of tools and methods for the ethical and scientific uses for, and communication of, postmarketing data specified under subparagraph (C), including recommendations on the development of effective research methods for the study of drug safety questions.
(C)
Establishment of the postmarket risk identification and analysis system.—
(i)
In general.—
The Secretary shall, not later than 1 year after the development of the risk identification and analysis methods under subparagraph (B), establish and maintain procedures—
(I)
for risk identification and analysis based on electronic health data, in compliance with the regulations promulgated under section 264(c) of the Health Insurance Portability and Accountability Act of 1996, and in a manner that does not disclose individually identifiable health information in violation of paragraph (4)(B);
(II)
for the reporting (in a standardized form) of data on all serious adverse drug experiences (as defined in section 355–1(b) of this title) submitted to the Secretary under paragraph (1), and those adverse events submitted by patients, providers, and drug sponsors, when appropriate;
(III)
to provide for active adverse event surveillance using the following data sources, as available:
(aa)
Federal health-related electronic data (such as data from the Medicare program and the health systems of the Department of Veterans Affairs);
(bb)
private sector health-related electronic data (such as pharmaceutical purchase data and health insurance claims data); and
(cc)
other data as the Secretary deems necessary to create a robust system to identify adverse events and potential drug safety signals;
(IV)
to identify certain trends and patterns with respect to data accessed by the system;
(V)
to provide regular reports to the Secretary concerning adverse event trends, adverse event patterns, incidence and prevalence of adverse events, and other information the Secretary determines appropriate, which may include data on comparative national adverse event trends; and
(VI)
to enable the program to export data in a form appropriate for further aggregation, statistical analysis, and reporting.
(ii)
Timeliness of reporting.—
The procedures established under clause (i) shall ensure that such data are accessed, analyzed, and reported in a timely, routine, and systematic manner, taking into consideration the need for data completeness, coding, cleansing, and standardized analysis and transmission.
(iii)
Private sector resources.—
To ensure the establishment of the active postmarket risk identification and analysis system under this subsection not later than 1 year after the development of the risk identification and analysis methods under subparagraph (B), as required under clause (i), the Secretary may, on a temporary or permanent basis, implement systems or products developed by private entities.
(iv)
Complementary approaches.—
To the extent the active postmarket risk identification and analysis system under this subsection is not sufficient to gather data and information relevant to a priority drug safety question, the Secretary shall develop, support, and participate in complementary approaches to gather and analyze such data and information, including—
(I)
approaches that are complementary with respect to assessing the safety of use of a drug in domestic populations not included, or underrepresented, in the trials used to approve the drug (such as older people, people with comorbidities, pregnant women, or children); and
(II)
existing approaches such as the Vaccine Adverse Event Reporting System and the Vaccine Safety Datalink or successor databases.
(v)
Authority for contracts.—
The Secretary may enter into contracts with public and private entities to fulfill the requirements of this subparagraph.
(4)
Advanced analysis of drug safety data.—
(A)
Purpose.—
The Secretary shall establish collaborations with public, academic, and private entities, which may include the Centers for Education and Research on Therapeutics under section 299b–1 of title 42, to provide for advanced analysis of drug safety data described in paragraph (3)(C) and other information that is publicly available or is provided by the Secretary, in order to—
(i)
improve the quality and efficiency of postmarket drug safety risk-benefit analysis;
(ii)
provide the Secretary with routine access to outside expertise to study advanced drug safety questions; and
(iii)
enhance the ability of the Secretary to make timely assessments based on drug safety data.
(B)
Privacy.—
Such analysis shall not disclose individually identifiable health information when presenting such drug safety signals and trends or when responding to inquiries regarding such drug safety signals and trends.
(C)
Public process for priority questions.—
At least biannually, the Secretary shall seek recommendations from the Drug Safety and Risk Management Advisory Committee (or any successor committee) and from other advisory committees, as appropriate, to the Food and Drug Administration on—
(i)
priority drug safety questions; and
(ii)
mechanisms for answering such questions, including through—
(I)
active risk identification under paragraph (3); and
(II)
when such risk identification is not sufficient, postapproval studies and clinical trials under subsection (o)(3).
(D)
Procedures for the development of drug safety collaborations.—
(i)
In general.—
Not later than 180 days after the date of the establishment of the active postmarket risk identification and analysis system under this subsection, the Secretary shall establish and implement procedures under which the Secretary may routinely contract with one or more qualified entities to—
(I)
classify, analyze, or aggregate data described in paragraph (3)(C) and information that is publicly available or is provided by the Secretary;
(II)
allow for prompt investigation of priority drug safety questions, including—
(aa)
unresolved safety questions for drugs or classes of drugs; and
(bb)
for a newly-approved drugs,2
2
 So in original. Probably should be “drug,”.
safety signals from clinical trials used to approve the drug and other preapproval trials; rare, serious drug side effects; and the safety of use in domestic populations not included, or underrepresented, in the trials used to approve the drug (such as older people, people with comorbidities, pregnant women, or children);
(III)
perform advanced research and analysis on identified drug safety risks;
(IV)
focus postapproval studies and clinical trials under subsection (o)(3) more effectively on cases for which reports under paragraph (1) and other safety signal detection is not sufficient to resolve whether there is an elevated risk of a serious adverse event associated with the use of a drug; and
(V)
carry out other activities as the Secretary deems necessary to carry out the purposes of this paragraph.
(ii)
Request for specific methodology.—
The procedures described in clause (i) shall permit the Secretary to request that a specific methodology be used by the qualified entity. The qualified entity shall work with the Secretary to finalize the methodology to be used.
(E)
Use of analyses.—
The Secretary shall provide the analyses described in this paragraph, including the methods and results of such analyses, about a drug to the sponsor or sponsors of such drug.
(F)
Qualified entities.—
(i)
In general.—
The Secretary shall enter into contracts with a sufficient number of qualified entities to develop and provide information to the Secretary in a timely manner.
(ii)
Qualification.—
The Secretary shall enter into a contract with an entity under clause (i) only if the Secretary determines that the entity has a significant presence in the United States and has one or more of the following qualifications:
(I)
The research, statistical, epidemiologic, or clinical capability and expertise to conduct and complete the activities under this paragraph, including the capability and expertise to provide the Secretary de-identified data consistent with the requirements of this subsection.
(II)
An information technology infrastructure in place to support electronic data and operational standards to provide security for such data.
(III)
Experience with, and expertise on, the development of drug safety and effectiveness research using electronic population data.
(IV)
An understanding of drug development or risk/benefit balancing in a clinical setting.
(V)
Other expertise which the Secretary deems necessary to fulfill the activities under this paragraph.
(G)
Contract requirements.—
Each contract with a qualified entity under subparagraph (F)(i) shall contain the following requirements:
(i)
Ensuring privacy.—
The qualified entity shall ensure that the entity will not use data under this subsection in a manner that—
(I)
violates the regulations promulgated under section 264(c) of the Health Insurance Portability and Accountability Act of 1996;
(II)
violates sections 552 or 552a of title 5 with regard to the privacy of individually-identifiable beneficiary health information; or
(III)
discloses individually identifiable health information when presenting drug safety signals and trends or when responding to inquiries regarding drug safety signals and trends.
Nothing in this clause prohibits lawful disclosure for other purposes.
(ii)
Component of another organization.—
If a qualified entity is a component of another organization—
(I)
the qualified entity shall establish appropriate security measures to maintain the confidentiality and privacy of such data; and
(II)
the entity shall not make an unauthorized disclosure of such data to the other components of the organization in breach of such confidentiality and privacy requirement.
(iii)
Termination or nonrenewal.—
If a contract with a qualified entity under this subparagraph is terminated or not renewed, the following requirements shall apply:
(I)
Confidentiality and privacy protections.—
The entity shall continue to comply with the confidentiality and privacy requirements under this paragraph with respect to all data disclosed to the entity.
(II)
Disposition of data.—
The entity shall return any data disclosed to such entity under this subsection to which it would not otherwise have access or, if returning the data is not practicable, destroy the data.
(H)
Competitive procedures.—
The Secretary shall use competitive procedures (as defined in section 132 of title 41) to enter into contracts under subparagraph (G).
(I)
Review of contract in the event of a merger or acquisition.—
The Secretary shall review the contract with a qualified entity under this paragraph in the event of a merger or acquisition of the entity in order to ensure that the requirements under this paragraph will continue to be met.
(J)
Coordination.—
In carrying out this paragraph, the Secretary shall provide for appropriate communications to the public, scientific, public health, and medical communities, and other key stakeholders, and to the extent practicable shall coordinate with the activities of private entities, professional associations, or other entities that may have sources of drug safety data.
(5)
The Secretary shall—
(A)
conduct regular screenings of the Adverse Event Reporting System database and post a quarterly report on the Adverse Event Reporting System Web site of any new safety information or potential signal of a serious risk identified by Adverse 3
3
 So in original. Probably should be preceded by “the”.
Event Reporting System within the last quarter; and 4
4
 So in original. The word “and” probably should not appear.
(B)
on an annual basis, review the entire backlog of postmarket safety commitments to determine which commitments require revision or should be eliminated, report to the Congress on these determinations, and assign start dates and estimated completion dates for such commitments; and
(C)
make available on the Internet website of the Food and Drug Administration—
(i)
guidelines, developed with input from experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, that detail best practices for drug safety surveillance using the Adverse Event Reporting System; and
(ii)
criteria for public posting of adverse event signals.
(l)
Public disclosure of safety and effectiveness data and action package
(1)
Safety and effectiveness data and information which has been submitted in an application under subsection (b) 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—
(A)
if no work is being or will be undertaken to have the application approved,
(B)
if the Secretary has determined that the application is not approvable and all legal appeals have been exhausted,
(C)
if approval of the application under subsection (c) is withdrawn and all legal appeals have been exhausted,
(D)
if the Secretary has determined that such drug is not a new drug, or
(E)
upon the effective date of the approval of the first application under subsection (j) which refers to such drug or upon the date upon which the approval of an application under subsection (j) which refers to such drug could be made effective if such an application had been submitted.
(2)
Action Package for Approval.—
(A)
Action package.—
The Secretary shall publish the action package for approval of an application under subsection (b) or section 262 of title 42 on the Internet Web site of the Food and Drug Administration—
(i)
not later than 30 days after the date of approval of such applications—
(I)
for a drug, no active moiety (as defined by the Secretary in section 314.3 of title 21, Code of Federal Regulations (or any successor regulations)) of which has been approved in any other application under this section; or
(II)
for a biological product, no active ingredient of which has been approved in any other application under section 262 of title 42; and
(ii)
not later than 30 days after the third request for such action package for approval received under section 552 of title 5 for any other drug or biological product.
(B)
Immediate publication of summary review.—
Notwithstanding subparagraph (A), the Secretary shall publish, on the Internet Web site of the Food and Drug Administration, the materials described in subparagraph (C)(iv) not later than 48 hours after the date of approval of the drug, except where such materials require redaction by the Secretary.
(C)
Contents.—
An action package for approval of an application under subparagraph (A) shall be dated and shall include the following:
(i)
Documents generated by the Food and Drug Administration related to review of the application.
(ii)
Documents pertaining to the format and content of the application generated during drug development.
(iii)
Labeling submitted by the applicant.
(iv)
A summary review that documents conclusions from all reviewing disciplines about the drug, noting any critical issues and disagreements with the applicant and within the review team and how they were resolved, recommendations for action, and an explanation of any nonconcurrence with review conclusions.
(v)
The Division Director and Office Director’s decision document which includes—
(I)
a brief statement of concurrence with the summary review;
(II)
a separate review or addendum to the review if disagreeing with the summary review; and
(III)
a separate review or addendum to the review to add further analysis.
(vi)
Identification by name of each officer or employee of the Food and Drug Administration who—
(I)
participated in the decision to approve the application; and
(II)
consents to have his or her name included in the package.
(D)
Review.—
A scientific review of an application is considered the work of the reviewer and shall not be altered by management or the reviewer once final.
(E)
Confidential information.—
This paragraph does not authorize the disclosure of any trade secret, confidential commercial or financial information, or other matter listed in section 552(b) of title 5.
(m)
“Patent” defined
(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)
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.
(5)
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.
(6)
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.
(7)
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.
(o)
Postmarket studies and clinical trials; labeling
(1)
In general
(2)
Definitions
For purposes of this subsection:
(A)
Responsible person
The term “responsible person” means a person who—
(i)
has submitted to the Secretary a covered application that is pending; or
(ii)
is the holder of an approved covered application.
(B)
Covered application
The term “covered application” means—
(i)
an application under subsection (b) for a drug that is subject to section 353(b) of this title; and
(ii)
an application under section 262 of title 42.
(C)
New safety information; serious risk
(3)
Studies and clinical trials
(A)
In general
(B)
Purposes of study or clinical trial
The purposes referred to in this subparagraph with respect to a postapproval study or postapproval clinical trial are the following:
(i)
To assess a known serious risk related to the use of the drug involved.
(ii)
To assess signals of serious risk related to the use of the drug.
(iii)
To identify an unexpected serious risk when available data indicates the potential for a serious risk.
(C)
Establishment of requirement after approval of covered application
(D)
Determination by Secretary
(i)
Postapproval studies
(ii)
Postapproval clinical trials
(E)
Notification; timetables; periodic reports
(i)
Notification
(ii)
Timetable; periodic reports
(F)
Dispute resolution
(4)
Safety labeling changes requested by Secretary
(A)
New safety or new effectiveness information
(B)
Response to notification
Following notification pursuant to subparagraph (A), the responsible person or the holder of the approved application under subsection (j) shall within 30 days—
(i)
submit a supplement proposing changes to the approved labeling to reflect the new safety information, including changes to boxed warnings, contraindications, warnings, precautions, or adverse reactions, or new effectiveness information; or
(ii)
notify the Secretary that the responsible person or the holder of the approved application under subsection (j) does not believe a labeling change is warranted and submit a statement detailing the reasons why such a change is not warranted.
(C)
Review
(D)
Discussions
(E)
Order
(F)
Dispute resolution
(G)
Violation
(H)
Public health threat
(I)
Rule of construction
(5)
Non-delegation
(p)
Risk evaluation and mitigation strategy
(1)
In general
A person may not introduce or deliver for introduction into interstate commerce a new drug if—
(A)
(i)
the application for such drug is approved under subsection (b) or (j) and is subject to section 353(b) of this title; or
(ii)
the application for such drug is approved under section 262 of title 42; and
(B)
a risk evaluation and mitigation strategy is required under section 355–1 of this title with respect to the drug and the person fails to maintain compliance with the requirements of the approved strategy or with other requirements under section 355–1 of this title, including requirements regarding assessments of approved strategies.
(2)
Certain postmarket studies
(q)
Petitions and civil actions regarding approval of certain applications
(1)
In general
(A)
Determination
The Secretary shall not delay approval of a pending application submitted under subsection (b)(2) or (j) of this section or section 262(k) of title 42 because of any request to take any form of action relating to the application, either before or during consideration of the request, unless—
(i)
the request is in writing and is a petition submitted to the Secretary pursuant to section 10.30 or 10.35 of title 21, Code of Federal Regulations (or any successor regulations); and
(ii)
the Secretary determines, upon reviewing the petition, that a delay is necessary to protect the public health.
Consideration of the petition shall be separate and apart from review and approval of any application.
(B)
Notification
If the Secretary determines under subparagraph (A) that a delay is necessary with respect to an application, the Secretary shall provide to the applicant, not later than 30 days after making such determination, the following information:
(i)
Notification of the fact that a determination under subparagraph (A) has been made.
(ii)
If applicable, any clarification or additional data that the applicant should submit to the docket on the petition to allow the Secretary to review the petition promptly.
(iii)
A brief summary of the specific substantive issues raised in the petition which form the basis of the determination.
(C)
Format
The information described in subparagraph (B) shall be conveyed via either, at the discretion of the Secretary—
(i)
a document; or
(ii)
a meeting with the applicant involved.
(D)
Public disclosure
(E)
Denial based on intent to delay
(F)
Final agency action
The Secretary shall take final agency action on a petition not later than 150 days after the date on which the petition is submitted. The Secretary shall not extend such period for any reason, including—
(i)
any determination made under subparagraph (A);
(ii)
the submission of comments relating to the petition or supplemental information supplied by the petitioner; or
(iii)
the consent of the petitioner.
(G)
Extension of 30-month period
(H)
Certification
(I)
Verification
(2)
Exhaustion of administrative remedies
(A)
Final agency action within 150 days
The Secretary shall be considered to have taken final agency action on a petition if—
(i)
during the 150-day period referred to in paragraph (1)(F), the Secretary makes a final decision within the meaning of section 10.45(d) of title 21, Code of Federal Regulations (or any successor regulation); or
(ii)
such period expires without the Secretary having made such a final decision.
(B)
Dismissal of certain civil actions
(C)
Administrative record
For purposes of judicial review related to the approval of an application for which a petition under paragraph (1) was submitted, the administrative record regarding any issue raised by the petition shall include—
(i)
the petition filed under paragraph (1) and any supplements and comments thereto;
(ii)
the Secretary’s response to such petition, if issued; and
(iii)
other information, as designated by the Secretary, related to the Secretary’s determinations regarding the issues raised in such petition, as long as the information was considered by the agency no later than the date of final agency action as defined under subparagraph (2)(A), and regardless of whether the Secretary responded to the petition at or before the approval of the application at issue in the petition.
(3)
Annual report on delays in approvals per petitions
The Secretary shall annually submit to the Congress a report that specifies—
(A)
the number of applications that were approved during the preceding 12-month period;
(B)
the number of such applications whose effective dates were delayed by petitions referred to in paragraph (1) during such period;
(C)
the number of days by which such applications were so delayed; and
(D)
the number of such petitions that were submitted during such period.
(4)
Exceptions
(A)
This subsection does not apply to—
(i)
a petition that relates solely to the timing of the approval of an application pursuant to subsection (j)(5)(B)(iv); or
(ii)
a petition that is made by the sponsor of an application and that seeks only to have the Secretary take or refrain from taking any form of action with respect to that application.
(B)
Paragraph (2) does not apply to a petition addressing issues concerning an application submitted pursuant to section 262(k) of title 42.
(5)
Definitions
(A)
Application
(B)
Petition
(r)
Postmarket drug safety information for patients and providers
(1)
Establishment
Not later than 1 year after September 27, 2007, the Secretary shall improve the transparency of information about drugs and allow patients and health care providers better access to information about drugs by developing and maintaining an Internet Web site that—
(A)
provides links to drug safety information listed in paragraph (2) for prescription drugs that are approved under this section or licensed under section 262 of title 42; and
(B)
improves communication of drug safety information to patients and providers.
(2)
Internet Web site
The Secretary shall carry out paragraph (1) by—
(A)
developing and maintaining an accessible, consolidated Internet Web site with easily searchable drug safety information, including the information found on United States Government Internet Web sites, such as the United States National Library of Medicine’s Daily Med and Medline Plus Web sites, in addition to other such Web sites maintained by the Secretary;
(B)
ensuring that the information provided on the Internet Web site is comprehensive and includes, when available and appropriate—
(i)
patient labeling and patient packaging inserts;
(ii)
a link to a list of each drug, whether approved under this section or licensed under such section 262, for which a Medication Guide, as provided for under part 208 of title 21, Code of Federal Regulations (or any successor regulations), is required;
(iii)
a link to the registry and results data bank provided for under subsections (i) and (j) of section 282 of title 42;
(iv)
the most recent safety information and alerts issued by the Food and Drug Administration for drugs approved by the Secretary under this section, such as product recalls, warning letters, and import alerts;
(v)
publicly available information about implemented RiskMAPs and risk evaluation and mitigation strategies under subsection (o);
(vi)
guidance documents and regulations related to drug safety; and
(vii)
other material determined appropriate by the Secretary;
(C)
providing access to summaries of the assessed and aggregated data collected from the active surveillance infrastructure under subsection (k)(3) to provide information of known and serious side-effects for drugs approved under this section or licensed under such section 262;
(D)
preparing and making publicly available on the Internet website established under paragraph (1) best practices for drug safety surveillance activities for drugs approved under this section or section 262 of title 42;
(E)
enabling patients, providers, and drug sponsors to submit adverse event reports through the Internet Web site;
(F)
providing educational materials for patients and providers about the appropriate means of disposing of expired, damaged, or unusable medications; and
(G)
supporting initiatives that the Secretary determines to be useful to fulfill the purposes of the Internet Web site.
(3)
Posting of drug labeling
(4)
Private sector resources
(5)
Authority for contracts
(6)
Review
(s)
Referral to advisory committee
The Secretary shall—
(1)
refer a drug or biological product to a Food and Drug Administration advisory committee for review at a meeting of such advisory committee prior to the approval of such drug or biological if it is—
(A)
a drug, no active moiety (as defined by the Secretary in section 314.3 of title 21, Code of Federal Regulations (or any successor regulations)) of which has been approved in any other application under this section; or
(B)
a biological product, no active ingredient of which has been approved in any other application under section 262 of title 42; or
(2)
if the Secretary does not refer a drug or biological product described in paragraph (1) to a Food and Drug Administration advisory committee prior to such approval, provide in the action letter on the application for the drug or biological product a summary of the reasons why the Secretary did not refer the drug or biological product to an advisory committee prior to approval.
(t)
Database for authorized generic drugs
(1)
In general
(A)
Publication
The Commissioner shall—
(i)
not later than 9 months after September 27, 2007, publish a complete list on the Internet Web site of the Food and Drug Administration of all authorized generic drugs (including drug trade name, brand company manufacturer, and the date the authorized generic drug entered the market); and
(ii)
update the list quarterly to include each authorized generic drug included in an annual report submitted to the Secretary by the sponsor of a listed drug during the preceding 3-month period.
(B)
Notification
(2)
Inclusion
(3)
Authorized generic drug
In this section, the term “authorized generic drug” means a listed drug (as that term is used in subsection (j)) that—
(A)
has been approved under subsection (c); and
(B)
is marketed, sold, or distributed directly or indirectly to retail class of trade under a different labeling, packaging (other than repackaging as the listed drug in blister packs, unit doses, or similar packaging for use in institutions), product code, labeler code, trade name, or trade mark than the listed drug.
(u)
Certain drugs containing single enantiomers
(1)
In general
(A)
(i)
the single enantiomer has not been previously approved except in the approved racemic drug; and
(ii)
the application submitted under subsection (b) for such non-racemic drug—
(I)
includes full reports of new clinical investigations (other than bioavailability studies)—
(aa)
necessary for the approval of the application under subsections (c) and (d); and
(bb)
conducted or sponsored by the applicant; and
(II)
does not rely on any clinical investigations (other than bioavailability studies) that are part of an application submitted under subsection (b) for approval of the approved racemic drug; and
(B)
the application submitted under subsection (b) for such non-racemic drug is not submitted for approval of a condition of use—
(i)
in a therapeutic category in which the approved racemic drug has been approved; or
(ii)
for which any other enantiomer of the racemic drug has been approved.
(2)
Limitation
(A)
No approval in certain therapeutic categories
(B)
Labeling
(3)
Definition
(A)
In general
(B)
Publication by Secretary
(4)
Availability
(v)
Antibiotic drugs submitted before November 21, 1997
(1)
Antibiotic drugs approved before November 21, 1997
(A)
In general
(B)
Application; antibiotic drug described
(i)
Application
(ii)
Antibiotic drug
(2)
Antibiotic drugs submitted before November 21, 1997, but not approved
(A)
In general
Notwithstanding any provision of the Food and Drug Administration Modernization Act of 1997 or any other provision of law, a sponsor of a drug that is the subject of an application described in subparagraph (B)(i) may elect to be eligible for, with respect to the drug—
(i)
(I)
the 3-year exclusivity period referred to under clauses (iii) and (iv) of subsection (c)(3)(E) and under clauses (iii) and (iv) of subsection (j)(5)(F), subject to the requirements of such clauses, as applicable; and
(II)
the 5-year exclusivity period referred to under clause (ii) of subsection (c)(3)(E) and under clause (ii) of subsection (j)(5)(F), subject to the requirements of such clauses, as applicable; or
(ii)
a patent term extension under section 156 of title 35, subject to the requirements of such section.
(B)
Application; antibiotic drug described
(i)
Application
(ii)
Antibiotic drug
(3)
Limitations
(A)
Exclusivities and extensions
(B)
Conditions of use
(4)
Application of certain provisions
(w)
Deadline for determination on certain petitions
(x)
Date of approval in the case of recommended controls under the CSA
(1)
In general
(2)
Date of approval
For purposes of this section, with respect to an application described in paragraph (1), the term “date of approval” shall mean the later of—
(A)
the date an application under subsection (b) is approved under subsection (c); or
(B)
the date of issuance of the interim final rule controlling the drug.
(y)
Contrast agents intended for use with applicable medical imaging devices
(1)
In general
(2)
Review of supplement
In reviewing a supplement submitted under this subsection, the agency center charged with the premarket review of drugs may—
(A)
consult with the center charged with the premarket review of devices; and
(B)
review information and data submitted to the Secretary by the sponsor of an applicable medical imaging device pursuant to section 360e, 360(k), or 360c(f)(2) of this title so long as the sponsor of such applicable medical imaging device has provided to the sponsor of the contrast agent a right of reference.
(3)
Definitions
For purposes of this subsection—
(A)
the term “new use” means a use of a contrast agent that is described in the approved labeling of an applicable medical imaging device described in section 360j(p) of this title, but that is not described in the approved labeling of the contrast agent; and
(B)
the terms “applicable medical imaging device” and “contrast agent” have the meanings given such terms in section 360j(p) of this title.
(z)
 6
6
 So in original. Two subsecs. (z) have been enacted.
Nonclinical test defined
For purposes of this section, the term “nonclinical test” means a test conducted in vitro, in silico, or in chemico, or a nonhuman in vivo test, that occurs before or during the clinical trial phase of the investigation of the safety and effectiveness of a drug. Such test may include the following:
(1)
Cell-based assays.
(2)
Organ chips and microphysiological systems.
(3)
Computer modeling.
(4)
Other nonhuman or human biology-based test methods, such as bioprinting.
(5)
Animal tests.
(z)
 6 Diversity action plan for clinical studies 7
7
 See Delayed Applicability of Amendment note below.
(1)
With respect to a clinical investigation of a new drug that is a phase 3 study, as defined in section 312.21(c) of title 21, Code of Federal Regulations (or successor regulations), or, as appropriate, another pivotal study of a new drug (other than bioavailability or bioequivalence studies), the sponsor of such drug shall submit to the Secretary a diversity action plan.
(2)
Such diversity action plan shall include—
(A)
the sponsor’s goals for enrollment in such clinical study;
(B)
the sponsor’s rationale for such goals; and
(C)
an explanation of how the sponsor intends to meet such goals.
(3)
The sponsor shall submit to the Secretary such diversity action plan, in the form and manner specified by the Secretary in guidance, as soon as practicable but not later than the date on which the sponsor submits the protocol to the Secretary for such a phase 3 study or other pivotal study of the drug. The sponsor may submit modifications to the diversity action plan. Any such modifications shall be in the form and manner specified by the Secretary in guidance.
(4)
(A)
On the initiative of the Secretary or at the request of a sponsor, the Secretary may waive any requirement in paragraph (1), (2), or (3) if the Secretary determines that a waiver is necessary based on what is known or what can be determined about the prevalence or incidence of the disease or condition for which the new drug is under investigation (including in terms of the patient population that may use the drug), if conducting a clinical investigation in accordance with a diversity action plan would otherwise be impracticable, or if such waiver is necessary to protect public health during a public health emergency.
(B)
The Secretary shall issue a written response granting or denying a request from a sponsor for a waiver within 60 days of receiving such request.
(5)
No diversity action plan shall be required for a submission described in section 360bbb of this title.
(June 25, 1938, ch. 675, § 505, 52 Stat. 1052; Pub. L. 86–507, § 1(18), June 11, 1960, 74 Stat. 201; Pub. L. 87–781, title I, §§ 102(b)–(d), 103(a), (b), 104(a)–(d)(2), Oct. 10, 1962, 76 Stat. 781–783, 784, 785; Pub. L. 92–387, § 4(d), Aug. 16, 1972, 86 Stat. 562; Pub. L. 98–417, title I, §§ 101, 102(a)–(b)(5), 103, 104, Sept. 24, 1984, 98 Stat. 1585, 1592, 1593, 1597; Pub. L. 102–282, § 5, May 13, 1992, 106 Stat. 161; Pub. L. 103–80, § 3(n), Aug. 13, 1993, 107 Stat. 777; Pub. L. 105–115, title I, §§ 115, 117, 119, 120, 124(a), Nov. 21, 1997, 111 Stat. 2313, 2315, 2316, 2318, 2324; Pub. L. 106–113, div. B, § 1000(a)(9) [title IV, § 4732(b)(11)], Nov. 29, 1999, 113 Stat. 1536, 1501A–584; Pub. L. 107–109, § 15(c)(1), Jan. 4, 2002, 115 Stat. 1420; Pub. L. 108–155, § 2(b)(1), Dec. 3, 2003, 117 Stat. 1941; Pub. L. 108–173, title XI, §§ 1101(a), (b), 1102(a), 1103(a), Dec. 8, 2003, 117 Stat. 2448, 2452, 2457, 2460; Pub. L. 110–85, title VII, § 701(b), title VIII, § 801(b)(3)(A), (B), title IX, §§ 901(a), 903, 905(a), 914(a), 915, 916, 918, 920, 921, title XI, § 1113, Sept. 27, 2007, 121 Stat. 903, 921, 922, 943, 944, 953, 957, 958, 960–962, 976; Pub. L. 110–316, title III, § 301, Aug. 14, 2008, 122 Stat. 3524; Pub. L. 110–379, § 4(a), Oct. 8, 2008, 122 Stat. 4076; Pub. L. 111–31, div. A, title I, § 103(e), June 22, 2009, 123 Stat. 1837; Pub. L. 111–148, title VII, § 7002(d)(1), title X, § 10609, Mar. 23, 2010, 124 Stat. 816, 1014; Pub. L. 112–144, title IX, § 905, title XI, §§ 1101, 1134(a), 1135, July 9, 2012, 126 Stat. 1092, 1108, 1123; Pub. L. 113–5, title III, § 301, Mar. 13, 2013, 127 Stat. 179; Pub. L. 114–89, § 2(a)(1), Nov. 25, 2015, 129 Stat. 698; Pub. L. 114–255, div. A, title III, §§ 3024(b), 3031(a), 3075(a), (b), 3101(a)(2)(B), 3102(1), Dec. 13, 2016, 130 Stat. 1099, 1138, 1152, 1156; Pub. L. 115–52, title VI, § 601, title VII, § 706(b), title VIII, §§ 801, 802, 808, title IX, § 901(a), Aug. 18, 2017, 131 Stat. 1048, 1059, 1068, 1069, 1074, 1076; Pub. L. 115–271, title III, § 3041(b), Oct. 24, 2018, 132 Stat. 3942; Pub. L. 116–290, § 2(a)–(d)(1), (g), Jan. 5, 2021, 134 Stat. 4889–4892; Pub. L. 117–9, § 1(a)(1), (b)(1), Apr. 23, 2021, 135 Stat. 256, 258; Pub. L. 117–180, div. F, title V, § 5004, Sept. 30, 2022,
cite as: 21 USC 355
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