Regulation of comparable and interchangeable biological products

(a)

In general

Section 351 of the Public Health Service Act (42 U.S.C. 262) is amended— (1)in subsection (a)(1)(A), by inserting under this subsection or subsection (k) after biologics license; and (2)by adding at the end the following subsection:

(k)

Regulation of comparable and interchangeable biological products

(1)

Submission of an abbreviated biological product application

Any person may file with the Secretary an abbreviated biological product application. Any such application shall include the following: (A)Data demonstrating that the biological product is comparable to or interchangeable with the reference product. (B)Data demonstrating that the biological product and reference product contain highly similar principal molecular structural features, notwithstanding minor differences in heterogeneity profile, impurities, or degradation patterns. The Secretary shall find the following types of products to contain highly similar principal molecular structural features: (i)Two protein biological products with differences in structure between them solely due to post-translational events, infidelity of translation or transcription, or minor differences in amino acid sequence. (ii)Two polysaccharide biological products with similar saccharide repeating units, even if the number of units differ and even if there are differences in post-polymerization modifications. (iii)Two glycosylated protein products with differences in structure between them solely due to post-translational events, infidelity of translation or transcription, or minor differences in amino acid sequence, and if they had similar saccharide repeating units, even if the number of units differ and even if there were differences in post-polymerization modifications. (iv)Two polynucleotide biological products with identical sequence of purine and pyrimidine bases (or their derivatives) bound to an identical sugar backbone (ribose, deoxyribose, or modifications of these sugars). (v)Closely related, complex partly definable biological products with similar therapeutic intent, such as two live viral products for the same indication.

Two biological products not enumerated in the foregoing clauses may be demonstrated to contain highly similar principal molecular structural features based upon such data and other information characterizing the two products as the Secretary determines to be necessary.

(C)Data demonstrating that the biological product and reference product utilize the same mechanism or mechanisms of action for the condition or conditions of use prescribed, recommended, or suggested in the proposed labeling, but only to the extent the mechanism or mechanisms of action are known for the reference product. (D)Information to show that the condition or conditions of use prescribed, recommended, or suggested in the labeling proposed for the biological product have been previously approved for the reference product. (E)Information to show that the route of administration, the dosage form, and the strength of the biological product are the same as those of the reference product. (F)Data demonstrating that the facility in which the biological product is manufactured, processed, packed, or held meets standards designed to assure that the biological product continues to be safe, pure, and potent. (G)At the applicant’s option, publicly-available information regarding the Secretary’s previous determination that the reference product is safe, pure, and potent. (H)Any additional data and information in support of the application, including publicly-available information with respect to the reference product or another biological product. (2)

Other applications

Any person, including a person who has not conducted and does not have a right of reference to the studies in the application for a reference product, may submit an application under this paragraph for a biological product that differs from, or incorporates a change to, the reference product with respect to one or more characteristics described in subparagraphs (A) through (E) of paragraph (1), including a difference in safety, purity, or potency, so long as the application contains sufficient information to establish the safety, purity, and potency of the biological product relative to the reference product for its proposed condition or conditions of use. (3)

FDA review of abbreviated biological product applications

(A)

Guidance regarding review of applications

The Secretary shall issue guidance for the individuals who review applications submitted under paragraph (1) or (2), 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)

Meetings with sponsors and applicants

The Secretary shall meet with a sponsor of an investigation or an applicant for approval of a comparable or interchangeable biological product 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 studies needed for approval of the 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)

Agreements

Any agreement regarding the parameters of design and size of the studies of a biological product 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, purity, and potency of the biological product has been identified after the testing has begun. (D)

Procedure regarding certain decisions

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)

Effect of decisions

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)

Delays by reviewing divisions

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, pure, and potent biological product. (4)

Approval of comparable or interchangeable biological products

(A)

Determination of comparability

Upon review of an application submitted under paragraph (1) or (2) for a biological product, the Secretary shall issue a comparable biological product license for all conditions of use of the reference product sharing the same mechanism or mechanisms of action for which the applicant has demonstrated comparability for a single condition of use, or, if the mechanism or mechanisms of action are unknown, for the condition or conditions of use for which the data submitted establishes comparability, unless the Secretary finds and informs the applicant that— (i)information submitted in the application or any other information available to the Secretary is insufficient to show that the biological product is comparable to the reference product for the condition or conditions of use prescribed, recommended, or suggested in the labeling proposed in the application; (ii)information submitted in the application or any other information available to the Secretary is insufficient to show that the biological product and the reference product contain highly similar principal molecular structural features, notwithstanding minor differences in heterogeneity profile, impurities, or degradation patterns; (iii)information submitted in the application or any other information available to the Secretary is insufficient to show that the biological product and reference product utilize the same mechanism or mechanisms of action for the conditions of use prescribed, recommended, or suggested in the labeling proposed for the biological product, unless the mechanism or mechanisms of action are not known for the reference product for such condition or conditions; (iv)information submitted in the application or any other information available to the Secretary is insufficient to show that the route of administration, the dosage form, and the strength of the biological product are the same as those of the reference product; (v)information submitted in the application or any other information available to the Secretary is insufficient to show that the condition or conditions of use prescribed, recommended, or suggested in the labeling proposed for the biological product are limited to one or more of the same use or uses as have been previously approved for the reference product; (vi)information submitted in the application or any other information available to the Secretary shows (I) the inactive ingredients of the biological product are unsafe for use under the conditions prescribed, recommended, or suggested in the labeling proposed for the biological product, or (II) the composition of the biological product 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; (vii)information submitted in the application or any other information available to the Secretary fails to demonstrate that the facility in which the biological product is manufactured, processed, packed, or held meets standards designed to assure that the biological product continues to be safe, pure, and potent; (viii)the Secretary has withdrawn or suspended the license of the reference product, for safety or effectiveness reasons, or has published a notice of opportunity for hearing to withdraw such license for safety or effectiveness reasons, or the Secretary has determined that the reference product has been withdrawn from sale for safety or effectiveness reasons; or (ix)the application contains an untrue statement of material fact; and

provides the applicant with a detailed explanation for the decision.

(B)

Determinations on interchangeability

Subject to subparagraph (C) and paragraph (10), upon issuing a product license for a biological product under subparagraph (A), the Secretary shall make and publish one of the following determinations: (i)Such product is interchangeable with the reference product for one or more specified conditions of use prescribed, recommended, or suggested in the labeling of the biological product. (ii)Interchangeability has not been established. (C)

Determination of interchangeability of subsequent biological product

If the Secretary determines that an application meets the approval requirements of subparagraph (A), and, prior to the issuance of a product license, the Secretary has made a determination of interchangeability of another biological product and the reference product for which the exclusivity period under paragraph (10) has not expired, the Secretary shall— (i)issue the product license for the subsequent biological product; and (ii)defer issuing any determination of interchangeability as to the subsequent biological product and the reference product until the exclusivity period under paragraph (10) has expired. (5)

Postmarketing studies for applications submitted under paragraph (1)

If the Secretary has agreed with the sponsor of the reference product, at the time of approval or any time thereafter, that the sponsor shall conduct one or more postmarketing safety studies, a person submitting an application for a biological product under paragraph (1) may agree with the Secretary to conduct a similar postmarketing safety study or studies upon a reasonable showing that such study or studies would provide relevant information not available from the studies on the reference product. The Secretary shall not, as a condition of approval, propose any additional postmarketing studies for such biological product. (6)

Designation of official name

If, pursuant to section 508 of the Federal Food, Drug, and Cosmetic Act, the Secretary determines that designation of an official name for a comparable biological product is necessary or desirable in the interests of usefulness or simplicity, the Secretary shall designate the same official name for the comparable biological product as the Secretary designated for the reference product. This paragraph shall not apply to products approved under paragraph (7). (7)

Other approval provisions

The Secretary shall approve, under the provisions of paragraph (4)(A), an application for a license submitted under paragraph (2), except that the Secretary shall approve such an application that would otherwise be disapproved by reason of one or more of subparagraphs (A) through (E) of paragraph (4)(A), if the application and any other information available to the Secretary are sufficient to establish the safety, purity, and potency of the comparable biological product relative to the reference product for the proposed condition or conditions of use for such product. (8)

Establishing interchangeability for comparable biological products

(A)

In general

In an original application or a supplement to an application under this subsection, an applicant may submit information to the Secretary to demonstrate the interchangeability of a comparable biological product and the reference product. An applicant may withdraw an interchangeability submission at any time. A request for an interchangeability determination submitted after the filing of an application shall be considered a major amendment to the application. Nothing in this subsection shall be construed to prohibit the Secretary from making a determination of interchangeability at any time after approval. (B)

Guidance

Within one year after enactment of the Access to Life-Saving Medicine Act, the Secretary shall issue guidance regarding standards and requirements for interchangeability. The Secretary may make determinations of interchangeability under paragraph (4)(B) prior to issuing guidance under this subparagraph. (9)

Interchangeability labeling for comparable biological products

Upon a determination of interchangeability, the Secretary, if requested by the applicant, shall provide for the label of the comparable biological product to include a statement that the biological product is interchangeable with the reference product for the conditions of use prescribed, recommended, or suggested in the labeling for which interchangeability has been established. (10)

Exclusivity

(A)

In general

Upon review of an abbreviated biological product application relying on the same reference product for which a prior biological product has received a determination of interchangeability for any condition of use, the Secretary shall not make a determination under paragraph (4)(B) that the second or subsequent biological product is interchangeable for any condition of use, and no holder of a biological product license approved under subsection (a) shall manufacture, market, sell, or distribute a rebranded interchangeable biological product, directly or indirectly, or authorize any other person to manufacture, market, sell, or distribute a rebranded interchangeable biological product, for any condition of use, until the earlier of— (i)180 days after the first commercial marketing of the first interchangeable comparable biological product to be approved as interchangeable for that reference product; (ii)one year after— (I)a final court decision on all patents in suit in an action instituted under paragraph (17)(C) against the applicant that submitted the application for the first approved interchangeable comparable biological product; or (II)the dismissal with or without prejudice of an action instituted under paragraph (17)(C) against the applicant that submitted the application for the first approved interchangeable comparable biological product; or (iii)(I)36 months after approval of the first interchangeable comparable biological product if the applicant has been sued under paragraph (17)(C) and such litigation is still ongoing within such 36-month period; or (II)one year after approval in the event that the first approved interchangeable comparable applicant has not been sued under paragraph (17)(C).

For purposes of this subparagraph, the term final court decision means a final decision of a court from which no appeal (other than a petition to the United States Supreme Court for a writ of certiorari) has been or can be taken.

(B)

Rebranded interchangeable biological product

For purposes of this subsection, the term rebranded interchangeable biological product— (i)means any rebranded interchangeable version of the reference product involved that the holder of the biological product license approved under subsection (a) for that reference product seeks to commence marketing, selling, or distributing, directly or indirectly; and (ii)does not include any product to be marketed, sold, or distributed— (I)by an entity eligible for exclusivity with respect to such product under this paragraph; or (II)after expiration of any exclusivity with respect to such product under this paragraph. (11)

Hearing

If the Secretary decides to disapprove an abbreviated biological product 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. (12)

Final action date

(A)

In general

The Secretary shall take a final action on an abbreviated biological product application by the date that is 8 calendar months following the sponsor’s submission of such application, or 180 days following the Secretary’s notification to the applicant that its application has been accepted for filing, whichever is earlier. (B)

Extension

The final action date provided by subparagraph (A) with respect to an application may be extended for such period of time as is agreed to by the Secretary and the applicant in a jointly executed written agreement that is counter-signed by the Secretary and the applicant no later than 30 days prior to such date. (13)

Request for delay of final action

Notwithstanding paragraph (18) or any other provision of law, the Secretary shall not fail or refuse to take a final action on an abbreviated biological product application by the final action date on the basis that a person, other than the comparable biological product applicant, has requested (in a petition or otherwise) that the Secretary refuse to take or otherwise defer such final action, and no court shall enjoin the Secretary from taking final action or stay the effect of final action previously taken by the Secretary, except by issuance of a permanent injunction based upon an express finding of clear and convincing evidence that the person seeking to have the Secretary refuse to take or otherwise to defer final action by the final action date— (A)has prevailed on the merits of the person’s complaint against the Secretary; (B)will suffer imminent and actual irreparable injury, constituting more than irrecoverable economic loss, and that also will threaten imminent destruction of such person’s business; and (C)has an interest that outweighs the overwhelming interest that the public has in obtaining prompt access to a comparable biological product. (14)

Report on extensions of final action date

The Secretary shall prepare and submit to the President, the Committee on Energy and Commerce of the House of Representatives, and the Committee on Health, Education, Labor, and Pensions of the Senate a report regarding any jointly executed written agreement to extend the final action date under this Act within 15 calendar days after the joint execution of any such written agreement. (15)

Report on failure to take final action

The Secretary shall prepare and submit annually to the President, the Committee on Energy and Commerce of the House of Representatives, and the Committee on Health, Education, Labor, and Pensions of the Senate a report detailing the specific and particularized reasons enumerated by the reviewing division for each instance of the Secretary’s failure to take final action by the final action date in the previous year. (16)

Regulations

The Secretary shall establish, by regulation within 2 years after the date of the enactment of this subsection, requirements for the efficient review, approval, suspension, and revocation of abbreviated biological product applications under this subsection. (17)

Patents

(A)

Request for patent information

(i)

In general

At any time, including at the initial stages of development, an applicant or a prospective applicant under this subsection may send a written request for patent information to the holder of the approved application for the reference product. The holder of the approved application for the reference product shall, not later than 60 days after the date on which the holder receives the request, provide to the applicant or prospective applicant a list of all those patents owned by, or licensed to, the holder of the approved application that the holder believes in good faith relate to the reference product, including patents that claim the approved biological product, any method of using such product, any component of such product, or any method or process of manufacturing such product or component. (ii)

Costs of complying with request

The application holder may demand payment of not more than $1,000 to offset the cost of responding to the request for information. (iii)

Updates

For a period of two years beginning on the date on which the holder of the approved application for the reference product receives the request for information, the holder shall send to the applicant or prospective applicant updates of its response to the request for information by identifying all relevant patents issued or licensed to the holder after the initial response under clause (i). Any such update must be provided, in the case of a new patent, not later than 30 days after the date on which the patent is issued and, in the case of a license, not later than 30 days after the date on which the holder obtains the license. (iv)

Additional requests

The applicant may submit additional requests for patent information, subject to the requirements of this paragraph, at any time. (B)

Patent notifications

At any time after submitting an application under this subsection, the applicant may provide a notice of the application with respect to any one or more patents identified by the holder of the reference product pursuant to subparagraph (A). An applicant may submit additional notices at any time, and each notice shall be subject to the provisions of this subparagraph. Each notice shall— (i)be sent to the holder of the approved application for the reference product and to the owner of any patent identified by the holder pursuant to subparagraph (A); (ii)include a detailed statement of the factual and legal bases for the applicant’s belief that the patents included in the notice are invalid, are unenforceable, or will not be infringed by the commercial sale of the product for which approval is being sought under this subsection; and (iii)identify 1 or more judicial districts in which the applicant consents to such suit being brought. (C)

Action for infringement

Within 45 days after the date on which the holder of the approved application for the reference product, or the owner of a patent, receives a notice under subparagraph (B), the holder or patent owner may bring an action for infringement only with respect to the patent or patents included in the notice, and only in a judicial district identified pursuant to subparagraph (B)(iii). (D)

Limitation on declaratory judgment actions

With respect to any patent relating to a product that is the subject of an application under this subsection, the recipient of a notice under subparagraph (B) with respect to that application may not, prior to the commercial marketing of the product, bring any action under section 2201 of title 28, United States Code, for a declaration of infringement, validity, or enforceability of any such patent that was not identified in the notice. With respect to any such patent identified in the notice, any such action may, notwithstanding chapter 87 of title 28, United States Code, be brought only in a judicial district identified in the notice. (E)

Discretion of applicants

An applicant or prospective applicant for a comparable biological product under this subsection may not be compelled, by court order or otherwise, to initiate the procedures set forth in this paragraph. Nothing in this paragraph requires an applicant or a prospective applicant to invoke the procedures set forth in this paragraph. (18)

Petitions and civil actions regarding approval of certain applications

(A)

In general

With respect to a pending application submitted under paragraph (1) or (2), if a petition is submitted to the Secretary that seeks to have the Secretary take, or refrain from taking, any form of action relating to the approval of the application, including a delay in the effective date of the application, the following applies, subject to subparagraph (E): (i)(I)The Secretary may not, on the basis of the petition, delay approval of the application unless the Secretary determines, within 30 days after receiving the petition, that a delay is necessary to protect the public health. Consideration of a petition shall be separate and apart from the review and approval of the application. (II)With respect to a determination by the Secretary under subclause (I) that a delay is necessary to protect the public health: (aa)The Secretary shall publish on the Internet site of the Food and Drug Administration a statement providing the reasons underlying the determination. (bb)Not later than 10 days after making the determination, the Secretary shall provide notice to the sponsor of the application and an opportunity for a meeting with the Commissioner to discuss the determination. (ii)The Secretary shall take final agency action on the petition not later than 180 days after the date on which the petition is submitted. The Secretary shall not extend such period, even with the consent of the petitioner, for any reason, including based upon the submission of comments relating to the petition or supplemental information supplied by the petitioner. (iii)The Secretary may not consider the petition for review unless it is signed and contains the following verification: I certify that, to my best knowledge and belief: (a) this petition includes all information and views upon which the petition relies; (b) this petition includes representative data and/or information known to the petitioner which are unfavorable to the petition; and (c) I have taken reasonable steps to ensure that any representative data and/or information which are unfavorable to the petition were disclosed to me. I further certify that the information upon which I have based the action requested herein first became known to the party on whose behalf this petition is submitted on or about the following date: _______. I received or expect to receive payments, including cash and other forms of consideration, from the following persons or organizations to file this petition: ________. I verify under penalty of perjury that the foregoing is true and correct.. (B)

Exhaustion of administrative remedies

(i)

Final agency action within 180 days

The Secretary shall be considered to have taken final agency action on a petition referred to in subparagraph (A) if— (I)during the 180-day period referred to in clause (ii) of such subparagraph, the Secretary makes a final decision within the meaning of section 10.45(d) of title 21, Code of Federal Regulations (or any successor regulations); or (II)such period expires without the Secretary having made such a final decision. (ii)

Dismissal of certain civil actions

If a civil action is filed with respect to a petition referred to in subparagraph (A) before final agency action within the meaning of clause (i) has occurred, the court shall dismiss the action for failure to exhaust administrative remedies. (C)

Applicability of certain regulations

The provisions of this section are in addition to the requirements for the submission of a petition to the Secretary that apply under section 10.30 or 10.35 of title 21, Code of Federal Regulations (or any successor regulations). (D)

Annual report on delays in approvals per petitions

The Secretary shall annually submit to the Congress a report that specifies— (i)the number of applications under this subsection that were approved during the preceding 12-month period; (ii)the number of such applications whose effective dates were delayed by petitions referred to in subparagraph (A) during such period; and (iii)the number of days by which the applications were so delayed. (E)

Exception

This paragraph does not apply to a petition that is made by the sponsor of an application under this subsection and that seeks only to have the Secretary take or refrain from taking any form of action with respect to that application. (F)

Definition

For purposes of this paragraph, the term petition includes any request to the Secretary, without regard to whether the request is characterized as a petition.

(b)

Additional amendments

(1)

Patents

Section 271(e) of title 35, United States Code, is amended— (A)in paragraph (2)— (i)by striking or at the end of subparagraph (A); (ii)by adding or at the end of subparagraph (B); (iii)by inserting after subparagraph (B) the following:

(C)a notice described in section 351(k)(17)(B) of the Public Health Service Act, but only with respect to a patent identified in such notice,

; and

(iv)in the matter following subparagraph (C) (as inserted by clause (iii) of this subparagraph), by inserting before the period the following: , or if the notice described in subparagraph (C) is provided in connection with an application to obtain a license to engage in the commercial manufacture, use, or sale of a biological product claimed in a patent or the use of which is claimed in a patent before the expiration of such patent; and (B)by adding at the end the following paragraph:

(6)(A)This paragraph applies, in lieu of paragraph (4), in the case of a patent— (i)which is disclosed in a response to a request for patent information pursuant to subparagraph (A) of section 351(k)(17) of the Public Health Service Act; (ii)with respect to which a notice was provided pursuant to subparagraph (B) of such section; and (iii)for which an action for infringement of the patent— (I)was brought after the expiration of the 45-day period described in subparagraph (C) of such section; or (II)was brought before the expiration of the 45-day period described in subclause (I), but which was dismissed without prejudice or was not prosecuted to judgment in good faith. (B)In an action for infringement of a patent described in subparagraph (A), the sole and exclusive remedy that may be granted by a court, upon a finding that the person who submitted the notice described in subparagraph (A)(ii) infringed the patent, or that any person induced or contributed to infringement of the patent, shall be a reasonable royalty. (C)The owner of a patent that should have been disclosed in response to a request for patent information made by an applicant pursuant to subparagraph (A)(i) of section 351(k)(17) of the Public Health Service Act, but that was not timely disclosed under that subparagraph, may not bring an action under this section for infringement of that patent.

(2)

Conforming amendments

(A)

Title 28

Section 2201(b) of title 28, United States Code, is amended by inserting before the period the following: , or section 351 of the Public Health Service Act. (B)

Public Health Service Act

Subjection (j) of section 351 of the Public Health Service Act (42 U.S.C. 262) is amended by inserting or subsection (k) after subsection (a).