42 USC 262 - Regulation of biological products

U.S Code last checked for updates: Apr 28, 2024

§ 262.

Regulation of biological products

(a)

Biologics license

(1)

No person shall introduce or deliver for introduction into interstate commerce any biological product unless—

(A)

a biologics license under this subsection or subsection (k) is in effect for the biological product; and

(B)

each package of the biological product is plainly marked with—

(i)

the proper name of the biological product contained in the package;

(ii)

the name, address, and applicable license number of the manufacturer of the biological product; and

(iii)

the expiration date of the biological product.

(2)

(A)

The Secretary shall establish, by regulation, requirements for the approval, suspension, and revocation of biologics licenses.

(B)

Pediatric studies.—

A person that submits an application for a license under this paragraph shall submit to the Secretary as part of the application any assessments required under section 505B of the Federal Food, Drug, and Cosmetic Act [21 U.S.C. 355c].

(C)

The Secretary shall approve a biologics license application—

(i)

on the basis of a demonstration that—

(I)

the biological product that is the subject of the application is safe, pure, and potent; and

(II)

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; and

(ii)

if the applicant (or other appropriate person) consents to the inspection of the facility that is the subject of the application, in accordance with subsection (c).

(D)

Postmarket studies and clinical trials; labeling; risk evaluation and mitigation strategy.—

A person that submits an application for a license under this paragraph is subject to sections 505(o), 505(p), and 505–1 of the Federal Food, Drug, and Cosmetic Act [21 U.S.C. 355(o), (p), 355–1].

(E)

(i)

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 this subsection, if such supplemental application complies with the requirements of subparagraph (B) of section 505(c)(5) of the Federal Food, Drug, and Cosmetic Act [21 U.S.C. 355(c)(5)].

(ii)

In this subparagraph, the terms “qualified indication” and “qualified data summary” have the meanings given such terms in section 505(c)(5) of the Federal Food, Drug, and Cosmetic Act.

(3)

The Secretary shall prescribe requirements under which a biological product undergoing investigation shall be exempt from the requirements of paragraph (1).

(b)

Falsely labeling or marking package or container; altering label or mark

(c)

Inspection of establishment for propagation and preparation

(d)

Recall of product presenting imminent hazard; violations

(1)

Upon a determination that a batch, lot, or other quantity of a product licensed under this section presents an imminent or substantial hazard to the public health, the Secretary shall issue an order immediately ordering the recall of such batch, lot, or other quantity of such product. An order under this paragraph shall be issued in accordance with section 554 of title 5.

(2)

Any violation of paragraph (1) shall subject the violator to a civil penalty of up to $100,000 per day of violation. The amount of a civil penalty under this paragraph shall, effective December 1 of each year beginning 1 year after the effective date of this paragraph, be increased by the percent change in the Consumer Price Index for the base quarter of such year over the Consumer Price Index for the base quarter of the preceding year, adjusted to the nearest ⅒ of 1 percent. For purposes of this paragraph, the term “base quarter”, as used with respect to a year, means the calendar quarter ending on September 30 of such year and the price index for a base quarter is the arithmetical mean of such index for the 3 months comprising such quarter.

(e)

Interference with officers

(f)

Penalties for offenses

(g)

Construction with other laws

(h)

Exportation of partially processed biological products

A partially processed biological product which—

(1)

is not in a form applicable to the prevention, treatment, or cure of diseases or injuries of man;

(2)

is not intended for sale in the United States; and

(3)

is intended for further manufacture into final dosage form outside the United States,

shall be subject to no restriction on the export of the product under this chapter or the Federal Food, Drug, and Cosmetic Act [21 U.S.C. 301 et seq.] if the product is manufactured, processed, packaged, and held in conformity with current good manufacturing practice requirements or meets international manufacturing standards as certified by an international standards organization recognized by the Secretary and meets the requirements of section 801(e)(1) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 381(e)).

(i)

“Biological product” defined

In this section:

(1)

The term “biological product” means a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein, or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings.

(2)

The term “biosimilar” or “biosimilarity”, in reference to a biological product that is the subject of an application under subsection (k), means—

(A)

that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; and

(B)

there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.

(3)

The term “interchangeable” or “interchangeability”, in reference to a biological product that is shown to meet the standards described in subsection (k)(4), means that the biological product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.

(4)

The term “reference product” means the single biological product licensed under subsection (a) against which a biological product is evaluated in an application submitted under subsection (k).

(j)

Application of Federal Food, Drug, and Cosmetic Act

(k)

Licensure of biological products as biosimilar or interchangeable

(1)

In general

(2)

Content

(A)

In general

(i)

Required information

An application submitted under this subsection shall include information demonstrating that—

(I)

the biological product is biosimilar to a reference product based upon data derived from—

(aa)

analytical studies that demonstrate that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components;

(bb)

an assessment of toxicity (which may rely on, or consist of, a study or studies described in item (aa) or (cc)); and

(cc)

a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in 1 or more appropriate conditions of use for which the reference product is licensed and intended to be used and for which licensure is sought for the biological product;

(II)

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;

(III)

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;

(IV)

the route of administration, the dosage form, and the strength of the biological product are the same as those of the reference product; and

(V)

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.

(ii)

Determination by Secretary

(iii)

Additional information

An application submitted under this subsection—

(I)

shall include publicly-available information regarding the Secretary’s previous determination that the reference product is safe, pure, and potent;

(II)

may include any additional information in support of the application, including publicly-available information with respect to the reference product or another biological product; and

(III)

may include information to show that the conditions of use prescribed, recommended, or suggested in the labeling proposed for the biological product have been previously approved for the reference product.

(B)

Interchangeability

(3)

Evaluation by Secretary

Upon review of an application (or a supplement to an application) submitted under this subsection, the Secretary shall license the biological product under this subsection if—

(A)

the Secretary determines that the information submitted in the application (or the supplement) is sufficient to show that the biological product—

(i)

is biosimilar to the reference product; or

(ii)

meets the standards described in paragraph (4), and therefore is interchangeable with the reference product; and

(B)

the applicant (or other appropriate person) consents to the inspection of the facility that is the subject of the application, in accordance with subsection (c).

(4)

Safety standards for determining interchangeability

Upon review of an application submitted under this subsection or any supplement to such application, the Secretary shall determine the biological product to be interchangeable with the reference product if the Secretary determines that the information submitted in the application (or a supplement to such application) is sufficient to show that—

(A)

the biological product—

(i)

is biosimilar to the reference product; and

(ii)

can be expected to produce the same clinical result as the reference product in any given patient; and

(B)

for a biological product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.

(5)

General rules

(A)

One reference product per application

(B)

Review

(C)

Risk evaluation and mitigation strategies

(6)

Exclusivity for first interchangeable biological product

The Secretary shall not make approval as an interchangeable biological product effective with respect to an application submitted under this subsection that relies on the same reference product for which a prior biological product has received a determination of interchangeability for any condition of use, until the earlier of—

(A)

1 year after the first commercial marketing of the first interchangeable biosimilar biological product to be approved as interchangeable for that reference product;

(B)

18 months after—

(i)

a final court decision on all patents in suit in an action instituted under subsection (l)(6) against the applicant that submitted the application for the first approved interchangeable biosimilar biological product; or

(ii)

the dismissal with or without prejudice of an action instituted under subsection (l)(6) against the applicant that submitted the application for the first approved interchangeable biosimilar biological product; or

(C)

(i)

42 months after approval of the first interchangeable biosimilar biological product if the applicant that submitted such application has been sued under subsection (l)(6) and such litigation is still ongoing within such 42-month period; or

(ii)

18 months after approval of the first interchangeable biosimilar biological product if the applicant that submitted such application has not been sued under subsection (l)(6).

For purposes of this paragraph, 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, and the term “first interchangeable biosimilar biological product” means any interchangeable biosimilar biological product that is approved on the first day on which such a product is approved as interchangeable with the reference product.

(7)

Exclusivity for reference product

(A)

Effective date of biosimilar application approval

(B)

Filing period

(C)

First licensure

Subparagraphs (A) and (B) shall not apply to a license for or approval of—

(i)

a supplement for the biological product that is the reference product; or

(ii)

a subsequent application filed by the same sponsor or manufacturer of the biological product that is the reference product (or a licensor, predecessor in interest, or other related entity) for—

(I)

a change (not including a modification to the structure of the biological product) that results in a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device, or strength; or

(II)

a modification to the structure of the biological product that does not result in a change in safety, purity, or potency.

(D)

Deemed licenses

(i)

No additional exclusivity through deeming

(ii)

Application of limitations on exclusivity

(iii)

Applicability

(8)

Guidance documents

(A)

In general

(B)

Public comment

(i)

In general

(ii)

Input regarding most valuable guidance

(C)

No requirement for application consideration

(D)

Requirement for product class-specific guidance

If the Secretary issues product class-specific guidance under subparagraph (A), such guidance shall include a description of—

(i)

the criteria that the Secretary will use to determine whether a biological product is highly similar to a reference product in such product class; and

(ii)

the criteria, if available, that the Secretary will use to determine whether a biological product meets the standards described in paragraph (4).

(E)

Certain product classes

(i)

Guidance

(ii)

Modification or reversal

(iii)

No effect on ability to deny license

(9)

Public listing

(A)

In general

(i)

Initial publication

Not later than 180 days after December 27, 2020, the Secretary shall publish and make available to the public in a searchable, electronic format—

(I)

a list of each biological product, by nonproprietary name (proper name), for which, as of December 27, 2020, a biologics license under subsection (a) or this subsection is in effect, or that, as of such date of enactment, is deemed to be licensed under this section pursuant to section 7002(e)(4) of the Biologics Price Competition and Innovation Act of 2009;

(II)

the date of licensure of the marketing application and the application number; and

(III)

with respect to each biological product described in subclause (I), the licensure status, and, as available, the marketing status.

(ii)

Revisions

(iii)

Patent information

(iv)

Listing of exclusivities

(B)

Revocation or suspension of license

If the license of a biological product is determined by the Secretary to have been revoked or suspended for safety, purity, or potency reasons, it may not be published in the list under subparagraph (A). If such revocation or suspension occurred after inclusion of such biological product in the list published under subparagraph (A), the reference product sponsor shall notify the Secretary that—

(i)

the biological product shall be immediately removed from such list for the same period as the revocation or suspension; and

(ii)

a notice of the removal shall be published in the Federal Register.

(l)

Patents

(1)

Confidential access to subsection (k) application

(A)

Application of paragraph

(B)

In general

(i)

Provision of confidential information

(ii)

Recipients of information

The persons described in this clause are the following:

(I)

Outside counsel

(II)

In-house counsel

(iii)

Patent owner access

(C)

Limitation on disclosure

(D)

Use of confidential information

(E)

Ownership of confidential information

(F)

Effect of infringement action

(G)

Rule of construction

Nothing in this paragraph shall be construed—

(i)

as an admission by the subsection (k) applicant regarding the validity, enforceability, or infringement of any patent; or

(ii)

as an agreement or admission by the subsection (k) applicant with respect to the competency, relevance, or materiality of any confidential information.

(H)

Effect of violation

(2)

Subsection (k) application information

Not later than 20 days after the Secretary notifies the subsection (k) applicant that the application has been accepted for review, the subsection (k) applicant—

(A)

shall provide to the reference product sponsor a copy of the application submitted to the Secretary under subsection (k), and such other information that describes the process or processes used to manufacture the biological product that is the subject of such application; and

(B)

may provide to the reference product sponsor additional information requested by or on behalf of the reference product sponsor.

(3)

List and description of patents

(A)

List by reference product sponsor

Not later than 60 days after the receipt of the application and information under paragraph (2), the reference product sponsor shall provide to the subsection (k) applicant—

(i)

a list of patents for which the reference product sponsor believes a claim of patent infringement could reasonably be asserted by the reference product sponsor, or by a patent owner that has granted an exclusive license to the reference product sponsor with respect to the reference product, if a person not licensed by the reference product sponsor engaged in the making, using, offering to sell, selling, or importing into the United States of the biological product that is the subject of the subsection (k) application; and

(ii)

an identification of the patents on such list that the reference product sponsor would be prepared to license to the subsection (k) applicant.

(B)

List and description by subsection (k) applicant

Not later than 60 days after receipt of the list under subparagraph (A), the subsection (k) applicant—

(i)

may provide to the reference product sponsor a list of patents to which the subsection (k) applicant believes a claim of patent infringement could reasonably be asserted by the reference product sponsor if a person not licensed by the reference product sponsor engaged in the making, using, offering to sell, selling, or importing into the United States of the biological product that is the subject of the subsection (k) application;

(ii)

shall provide to the reference product sponsor, with respect to each patent listed by the reference product sponsor under subparagraph (A) or listed by the subsection (k) applicant under clause (i)—

(I)

a detailed statement that describes, on a claim by claim basis, the factual and legal basis of the opinion of the subsection (k) applicant that such patent is invalid, unenforceable, or will not be infringed by the commercial marketing of the biological product that is the subject of the subsection (k) application; or

(II)

a statement that the subsection (k) applicant does not intend to begin commercial marketing of the biological product before the date that such patent expires; and

(iii)

shall provide to the reference product sponsor a response regarding each patent identified by the reference product sponsor under subparagraph (A)(ii).

(C)

Description by reference product sponsor

(4)

Patent resolution negotiations

(A)

In general

(B)

Failure to reach agreement

(5)

Patent resolution if no agreement

(A)

Number of patents

(B)

Exchange of patent lists

(i)

In general

On a date agreed to by the subsection (k) applicant and the reference product sponsor, but in no case later than 5 days after the subsection (k) applicant notifies the reference product sponsor under subparagraph (A), the subsection (k) applicant and the reference product sponsor shall simultaneously exchange—

(I)

the list of patents that the subsection (k) applicant believes should be the subject of an action for patent infringement under paragraph (6); and

(II)

the list of patents, in accordance with clause (ii), that the reference product sponsor believes should be the subject of an action for patent infringement under paragraph (6).

(ii)

Number of patents listed by reference product sponsor

(I)

In general

(II)

Exception

(6)

Immediate patent infringement action

(A)

Action if agreement on patent list

(B)

Action if no agreement on patent list

(C)

Notification and publication of complaint

(i)

Notification to Secretary

(ii)

Publication by Secretary

(7)

Newly issued or licensed patents

In the case of a patent that—

(A)

is issued to, or exclusively licensed by, the reference product sponsor after the date that the reference product sponsor provided the list to the subsection (k) applicant under paragraph (3)(A); and

(B)

the reference product sponsor reasonably believes that, due to the issuance of such patent, a claim of patent infringement could reasonably be asserted by the reference product sponsor if a person not licensed by the reference product sponsor engaged in the making, using, offering to sell, selling, or importing into the United States of the biological product that is the subject of the subsection (k) application,

not later than 30 days after such issuance or licensing, the reference product sponsor shall provide to the subsection (k) applicant a supplement to the list provided by the reference product sponsor under paragraph (3)(A) that includes such patent, not later than 30 days after such supplement is provided, the subsection (k) applicant shall provide a statement to the reference product sponsor in accordance with paragraph (3)(B), and such patent shall be subject to paragraph (8).

(8)

Notice of commercial marketing and preliminary injunction

(A)

Notice of commercial marketing

(B)

Preliminary injunction

After receiving the notice under subparagraph (A) and before such date of the first commercial marketing of such biological product, the reference product sponsor may seek a preliminary injunction prohibiting the subsection (k) applicant from engaging in the commercial manufacture or sale of such biological product until the court decides the issue of patent validity, enforcement, and infringement with respect to any patent that is—

(i)

included in the list provided by the reference product sponsor under paragraph (3)(A) or in the list provided by the subsection (k) applicant under paragraph (3)(B); and

(ii)

not included, as applicable, on—

(I)

the list of patents described in paragraph (4); or

(II)

the lists of patents described in paragraph (5)(B).

(C)

Reasonable cooperation

(9)

Limitation on declaratory judgment action

(A)

Subsection (k) application provided

(B)

Subsequent failure to act by subsection (k) applicant

(C)

Subsection (k) application not provided

(m)

Pediatric studies

(1)

Application of certain provisions

(2)

Market exclusivity for new biological products

If, prior to approval of an application that is submitted under subsection (a), the Secretary determines that information relating to the use of a new biological product in the pediatric population may produce health benefits in that population, the Secretary makes a written request for pediatric studies (which shall include a timeframe for completing such studies), the applicant agrees to the request, such studies are completed using appropriate formulations for each age group for which the study is requested within any such timeframe, and the reports thereof are submitted and accepted in accordance with section 505A(d)(4) of the Federal Food, Drug, and Cosmetic Act [21 U.S.C. 355a(d)(4)]—

(A)

the periods for such biological product referred to in subsection (k)(7) are deemed to be 4 years and 6 months rather than 4 years and 12 years and 6 months rather than 12 years; and

(B)

if the biological product is designated under section 526 1

 See References in Text note below.

[21 U.S.C. 360bb] for a rare disease or condition, the period for such biological product referred to in section 527(a) 1 [21 U.S.C. 360cc(a)] is deemed to be 7 years and 6 months rather than 7 years.

(3)

Market exclusivity for already-marketed biological products

If the Secretary determines that information relating to the use of a licensed biological product in the pediatric population may produce health benefits in that population and makes a written request to the holder of an approved application under subsection (a) for pediatric studies (which shall include a timeframe for completing such studies), the holder agrees to the request, such studies are completed using appropriate formulations for each age group for which the study is requested within any such timeframe, and the reports thereof are submitted and accepted in accordance with section 505A(d)(4) of the Federal Food, Drug, and Cosmetic Act [21 U.S.C. 355a(d)(4)]—

(A)

the periods for such biological product referred to in subsection (k)(7) are deemed to be 4 years and 6 months rather than 4 years and 12 years and 6 months rather than 12 years; and

(B)

if the biological product is designated under section 526 ¹ [21 U.S.C. 360bb] for a rare disease or condition, the period for such biological product referred to in section 527(a) ¹ [21 U.S.C. 360cc(a)] is deemed to be 7 years and 6 months rather than 7 years.

(4)

Exception

(n)

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), references to the date of approval of such application, or licensure of the product subject to such application, shall mean the later of—

(A)

the date an application is approved under subsection (a); or

(B)

the date of issuance of the interim final rule controlling the biological product.

(July 1, 1944, ch. 373, title III, § 351, 58 Stat. 702; 1953 Reorg. Plan No. 1, §§ 5, 8, eff. Apr. 11, 1953, 18 F.R. 2053, 67 Stat. 631; Pub. L. 85–881, § 2, Sept. 2, 1958, 72 Stat. 1704; Pub. L. 91–515, title II, § 291, Oct. 30, 1970, 84 Stat. 1308; Pub. L. 96–88, title V, § 509(b), Oct. 17, 1979, 93 Stat. 695; Pub. L. 99–660, title I, § 105(a), title III, § 315, Nov. 14, 1986, 100 Stat. 3751, 3783; Pub. L. 102–300, § 6(b)(1), June 16, 1992, 106 Stat. 240; Pub. L. 104–134, title II, §§ 2102(d)(2), 2104, Apr. 26, 1996, 110 Stat. 1321–319, 1321–320; Pub. L. 105–115, title I, § 123(a)–(d), (g), Nov. 21, 1997, 111 Stat. 2323, 2324; Pub. L. 108–155, § 2(b)(3), Dec. 3, 2003, 117 Stat. 1941; Pub. L. 110–85, title IX, § 901(c), Sept. 27, 2007, 121 Stat. 939; Pub. L. 111–148, title VII, § 7002(a), (b), (g)(1), Mar. 23, 2010, 124 Stat. 804, 814, 819; Pub. L. 112–144, title V, § 502(a)(2), July 9, 2012, 126 Stat. 1040; Pub. L. 114–89, § 2(a)(2), Nov. 25, 2015, 129 Stat. 698; Pub. L. 114–255, div. A, title III, § 3031(b), Dec. 13, 2016, 130 Stat. 1100; Pub. L. 115–52, title V, § 505(b)(2)(B), Aug. 18, 2017, 131 Stat. 1046; Pub. L. 116–94, div. N, title I, §§ 605, 606, Dec. 20, 2019, 133 Stat. 3127; Pub. L. 116–260, div. BB, title III, §§ 322, 325(a), Dec. 27, 2020, 134 Stat. 2933, 2936; Pub. L. 117–328, div. FF, title III, §§ 3206, 3209(b), Dec. 29, 2022, 136 Stat. 5820, 5822.)

cite as: 42 USC 262

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