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[Congressional Bills 114th Congress]
[From the U.S. Government Publishing Office]
[S. 1767 Reported in Senate (RS)]

<DOC>

                                                       Calendar No. 414
114th CONGRESS
  2d Session
                                S. 1767

   To amend the Federal Food, Drug, and Cosmetic Act with respect to 
             combination products, and for other purposes.

_______________________________________________________________________

                   IN THE SENATE OF THE UNITED STATES

                             July 15, 2015

Mr. Isakson (for himself, Mr. Casey, Mr. Roberts, Mr. Toomey, Mr. Kirk, 
Mr. Donnelly, and Mr. Cassidy) introduced the following bill; which was 
 read twice and referred to the Committee on Health, Education, Labor, 
                              and Pensions

                             April 5, 2016

              Reported by Mr. Alexander, with an amendment
 [Strike out all after the enacting clause and insert the part printed 
                               in italic]

_______________________________________________________________________

                                 A BILL

 
   To amend the Federal Food, Drug, and Cosmetic Act with respect to 
             combination products, and for other purposes.

    Be it enacted by the Senate and House of Representatives of the 
United States of America in Congress assembled,

<DELETED>SECTION 1. SHORT TITLE.</DELETED>

<DELETED>    This Act may be cited as the ``Combination Product 
Regulatory Fairness Act of 2015''.</DELETED>

<DELETED>SEC. 2. DEVICE DEFINITION.</DELETED>

<DELETED>    Section 201(h) of the Federal Food, Drug, and Cosmetic Act 
(21 U.S.C. 321(h)) is amended--</DELETED>
        <DELETED>    (1) by redesignating subparagraphs (1), (2), and 
        (3) as clauses (A), (B), and (C), respectively;</DELETED>
        <DELETED>    (2) by striking ``(h)'' and inserting ``(h)(1)''; 
        and</DELETED>
        <DELETED>    (3) by adding at the end the following:</DELETED>
<DELETED>    ``(2)(A) Before determining that an article does not meet 
the definition of a device under this paragraph, the Secretary shall 
provide to the sponsor of the article competent and reliable scientific 
rationale that--</DELETED>
        <DELETED>    ``(i) cites any scientific evidence relied upon to 
        support the rationale; and</DELETED>
        <DELETED>    ``(ii) supports such determination. </DELETED>
<DELETED>    ``(B) If the Secretary makes a determination described in 
clause (A)--</DELETED>
        <DELETED>    ``(i) the sponsor of the article may propose a 
        nonclinical or clinical study, limited to not more data than 
        necessary to establish the significance, if any, of the 
        chemical action in achieving the primary intended purpose of 
        the article; and</DELETED>
        <DELETED>    ``(ii) the Secretary and the sponsor of the 
        article shall collaborate in good faith to reach agreement, 
        within a reasonable time not to exceed 90 days, on the design 
        of such study.</DELETED>
<DELETED>    ``(C) The data resulting from a study conducted under 
clause (B) shall inform the classification of the article.''.</DELETED>

<DELETED>SEC. 3. COMBINATION PRODUCTS.</DELETED>

<DELETED>    Section 503(g) of the Federal Food, Drug, and Cosmetic Act 
(21 U.S.C. 353(g)) is amended--</DELETED>
        <DELETED>    (1) by redesignating paragraphs (2) through (5) as 
        paragraphs (6) through (9), respectively;</DELETED>
        <DELETED>    (2) by striking ``(g)(1)'' and all that follows 
        through the end of paragraph (1) and inserting the 
        following:</DELETED>
<DELETED>    ``(g)(1)(A) The Secretary shall, in accordance with this 
subsection, assign an agency center to regulate products that 
constitute a combination of a drug, device, or biological product 
(referred to in this subsection as the `lead center').</DELETED>
<DELETED>    ``(B) The Secretary shall conduct the premarket review of 
any combination product, whenever possible, under a single application 
using existing premarket review authorities.</DELETED>
<DELETED>    ``(C) The Secretary shall determine the primary mode of 
action of the combination product. If the Secretary determines that the 
primary mode of action is that of--</DELETED>
        <DELETED>    ``(i) a drug (other than a biological product), 
        the agency center charged with premarket review of drugs shall 
        have primary jurisdiction;</DELETED>
        <DELETED>    ``(ii) a device, the agency center charged with 
        premarket review of devices shall have primary jurisdiction; 
        or</DELETED>
        <DELETED>    ``(iii) a biological product, the agency center 
        charged with premarket review of biological products shall have 
        primary jurisdiction.</DELETED>
<DELETED>    ``(D) In determining the primary mode of action of a 
combination product, the Secretary shall not determine that the primary 
mode of action is that of a drug or biological product solely because 
the combination product has any chemical action within or on the human 
body.</DELETED>
<DELETED>    ``(E) If the Secretary disagrees with the conclusions of 
the sponsor on the primary mode of action of the combination product, 
the Secretary shall provide a competent and reliable scientific 
rationale to the product sponsor that cites any scientific evidence 
relied upon to support the decision.</DELETED>
<DELETED>    ``(F) For purposes of this paragraph--</DELETED>
        <DELETED>    ``(i) the term `primary mode of action' means the 
        single mode of action of a combination product that provides 
        the most important therapeutic action of the combination 
        product; and</DELETED>
        <DELETED>    ``(ii) the term `most important therapeutic 
        action' means the mode of action expected to make the greatest 
        contribution to the overall intended therapeutic effects of the 
        combination product.</DELETED>
<DELETED>    ``(2)(A) The sponsor of a combination product may submit a 
combination product review plan (referred to in this subsection as a 
`CPRP') for the combination product, and may request a meeting prior to 
submission of the CPRP, to establish clarity and certainty for the 
sponsor regarding the standards and requirements applicable to--
</DELETED>
        <DELETED>    ``(i) the review of safety and effectiveness, or 
        substantial equivalence, of the combination product;</DELETED>
        <DELETED>    ``(ii) a postmarket modification of the 
        combination product; or</DELETED>
        <DELETED>    ``(iii) good manufacturing practices for the 
        combination product.</DELETED>
<DELETED>    ``(B) Not later than 60 days after the sponsor of a 
combination product submits a proposed CPRP, including a revision to a 
previously proposed or approved CPRP, the Secretary shall review the 
CPRP and--</DELETED>
        <DELETED>    ``(i) if the Secretary determines that the CPRP is 
        appropriate to ensure adequate review of the safety and 
        effectiveness, or substantial equivalence, of the combination 
        product--</DELETED>
                <DELETED>    ``(I) approve the CPRP; and</DELETED>
                <DELETED>    ``(II) issue to the sponsor a response 
                indicating such approval; or</DELETED>
        <DELETED>    ``(ii) if the Secretary finds that the CPRP does 
        not meet the standard specified in clause (i)--</DELETED>
                <DELETED>    ``(I) decline to approve the CPRP; 
                and</DELETED>
                <DELETED>    ``(II) issue to the sponsor a response 
                indicating that the Secretary has declined such 
                approval and specifying any deficiencies in the 
                proposed CPRP.</DELETED>
<DELETED>    ``(C)(i) In the case of a CPRP that the Secretary declines 
to approve under subparagraph (B)(ii), unless the sponsor submitting 
such CPRP determines a meeting is not necessary, the Secretary shall, 
not later than 30 days after submitting a response under such 
subparagraph, meet with such sponsor to discuss the CPRP.</DELETED>
<DELETED>    ``(ii) A meeting under clause (i) shall--</DELETED>
        <DELETED>    ``(I) include any necessary experts from the 
        relevant agency centers; and</DELETED>
        <DELETED>    ``(II) coordinate the advice of such 
        experts.</DELETED>
<DELETED>    ``(D) The sponsor or applicant shall provide information 
necessary for discussion and agreement on the level of evidence 
necessary to ensure adequate review of the safety and effectiveness, or 
substantial equivalence, of the combination product.</DELETED>
<DELETED>    ``(E) Not later than 30 days after the date on which a 
meeting is held under subparagraph (A)(i), the minutes of such meeting 
shall be prepared by the sponsor and made available to the 
Secretary.</DELETED>
<DELETED>    ``(F) Any agreement that is reached between the Secretary 
and a sponsor or applicant through a meeting held under subparagraph 
(A)(i) shall be reduced to writing by the sponsor or applicant, and, 
once approved by the Secretary, made part of the administrative record 
by the Secretary within 60 days of such meeting.</DELETED>
<DELETED>    ``(G) An agreement described in subparagraph (F) shall not 
be changed after approval of the agreement, except--</DELETED>
        <DELETED>    ``(i) with the written agreement of the sponsor or 
        applicant; or</DELETED>
        <DELETED>    ``(ii) pursuant to a decision, made in accordance 
        with subparagraph (H) by the director of the reviewing division 
        of the lead center, in consultation with consulting centers and 
        the Office, that a substantial scientific issue essential to 
        determining the safety or effectiveness, or substantial 
        equivalence, of the combination product has been 
        identified.</DELETED>
<DELETED>    ``(H) With respect to a decision under subparagraph 
(G)(ii), the Secretary shall provide notice, within 2 business days of 
such decision, to the sponsor of the combination product and an 
opportunity for a meeting to take place not later than 14 calendar days 
after issuing such notice, at which--</DELETED>
        <DELETED>    ``(i) the director of the reviewing division of 
        the lead center, staff from the consulting agency centers, 
        representatives of the Office, and the sponsor will be present; 
        and</DELETED>
        <DELETED>    ``(ii) the director of the reviewing division of 
        the lead center will document the scientific issue 
        involved.</DELETED>
<DELETED>    ``(3) For purposes of conducting the premarket review of a 
combination product that contains an approved constituent product 
described in paragraph (4), the Secretary may require only that the 
sponsor of such combination product submit to the Secretary data or 
information that--</DELETED>
        <DELETED>    ``(A) the Secretary determines is necessary to 
        assess the specific safety and effectiveness questions and 
        incremental risks posed by the combination product, using a 
        risk-based approach and taking into account any prior finding 
        of safety and efficacy or substantial equivalence for the 
        approved constituent product; and</DELETED>
        <DELETED>    ``(B) is not duplicative of data or information 
        included in an application or other material submitted to the 
        Secretary in connection with the approved constituent 
        product.</DELETED>
<DELETED>    ``(4) For purposes of paragraph (3), an approved 
constituent product is--</DELETED>
        <DELETED>    ``(A) a drug constituent part of a combination 
        product being reviewed in a single application under section 
        515 or 510(k), provided such drug constituent part was 
        previously approved under section 505 and such application 
        complies with subparagraph (A) of paragraph (5) and is subject 
        to subparagraphs (D) and (E) of such paragraph;</DELETED>
        <DELETED>    ``(B) a device constituent part approved under 
        section 515 that is referenced by the sponsor and which is 
        available for use by the Secretary under section 520(h)(4); 
        or</DELETED>
        <DELETED>    ``(C) any constituent part that was previously 
        approved, cleared, or licensed under section 505, 510(k), or 
        515 of this Act or section 351 of the Public Health Service 
        Act, for which the sponsor has a right of reference or which is 
        otherwise available for consideration by the Secretary under 
        this Act or the Public Health Service Act.</DELETED>
<DELETED>    ``(5)(A) If an application is submitted under section 515 
or 510(k) for a combination product containing as a constituent part an 
approved drug--</DELETED>
        <DELETED>    ``(i) the application shall include the 
        certification or statement required pursuant section 505(b)(2); 
        and</DELETED>
        <DELETED>    ``(ii) the applicant shall provide notice as 
        required pursuant to section 505(b)(3).</DELETED>
<DELETED>    ``(B) For purposes of this paragraph, the term `approved 
drug' means a drug--</DELETED>
        <DELETED>    ``(i) that was previously approved under section 
        505;</DELETED>
        <DELETED>    ``(ii) for which full reports of investigations 
        that have been made to show whether such drug is safe for use 
        and whether such drug is effective in use--</DELETED>
                <DELETED>    ``(I) are relied upon by the applicant 
                submitting the application described in subparagraph 
                (A); and</DELETED>
                <DELETED>    ``(II) were not conducted by or for such 
                applicant; and</DELETED>
        <DELETED>    ``(iii) with respect to which, the applicant 
        submitting the application described in subparagraph (A) has 
        not obtained a right of reference or use from the person by or 
        for whom the investigations were conducted.</DELETED>
<DELETED>    ``(C) The following provisions shall apply with respect an 
application described in subparagraph (A):</DELETED>
        <DELETED>    ``(i) Subparagraphs (A), (B), (C), and (D) of 
        section 505(c)(3).</DELETED>
        <DELETED>    ``(ii) Clauses (ii), (iii), and (iv) of section 
        505(c)(3)(E).</DELETED>
        <DELETED>    ``(iii) Paragraphs (b) and (c) of section 
        505A.</DELETED>
        <DELETED>    ``(iv) Section 505E(a).</DELETED>
        <DELETED>    ``(v) Section 527(a).</DELETED>
<DELETED>    ``(D) Notwithstanding section 520(h)(4)(A)(i), information 
contained in an application for premarket approval filed with the 
Secretary pursuant to section 515(c) may not be used to approve any 
application submitted under section 515 or 510(k) for a combination 
product containing as a constituent part a drug previously approved 
under section 505 unless--</DELETED>
        <DELETED>    ``(i) the application includes the certification 
        or statement referenced in subparagraph (A);</DELETED>
        <DELETED>    ``(ii) the applicant provides notice as described 
        in subparagraph (A); and</DELETED>
        <DELETED>    ``(iii) the Secretary's approval of such 
        application is subject to the provisions specified in 
        subparagraph (C).</DELETED>
<DELETED>    ``(E) An application for a combination product described 
in subparagraph (A) or (D) shall be considered an application submitted 
under Section 505(b)(2) solely for purposes of section 271(e)(2)(A) of 
the Patent Act.'';</DELETED>
        <DELETED>    (3) in paragraph (8) (as redesignated by paragraph 
        (1))--</DELETED>
                <DELETED>    (A) in subparagraph (C)--</DELETED>
                        <DELETED>    (i) by amending clause (i) to read 
                        as follows:</DELETED>
<DELETED>    ``(i) In carrying out this subsection, the Office shall 
ensure timely and effective premarket reviews involving more than one 
agency center by--</DELETED>
        <DELETED>    ``(I) overseeing the timeliness and alignment of 
        reviews; and</DELETED>
        <DELETED>    ``(II) coordinating reviews.'';</DELETED>
                        <DELETED>    (ii) in clause (ii), by inserting 
                        ``and alignment'' after ``the timeliness'' each 
                        place it appears; and</DELETED>
                        <DELETED>    (iii) by adding at the end the 
                        following new clauses:</DELETED>
<DELETED>    ``(iii) The Office shall ensure that the lead center be 
the primary point of contact for the sponsor of the product. The Office 
shall also coordinate communications to and from any consulting agency 
center involved in such premarket review. Agency communications and 
commitments, to the extent consistent with other provisions of law and 
the requirements of all affected agency centers, from the lead center 
shall be binding on all other centers involved in the review.</DELETED>
<DELETED>    ``(iv) The Office shall, with respect to the premarket 
review of a combination product--</DELETED>
        <DELETED>    ``(I) ensure that any meeting between the Food and 
        Drug Administration and the sponsor of the product is attended 
        by each agency center involved in the review, as 
        appropriate;</DELETED>
        <DELETED>    ``(II) require that each consulting agency center 
        has completed its premarket review and provided the results of 
        such review to the lead center within timeframes that allow the 
        lead center to meet the review goals established pursuant to 
        the most recent authorization or reauthorization of parts 2, 3, 
        7, and 8, as applicable, of subchapter C of title VII; 
        and</DELETED>
        <DELETED>    ``(III) ensure that each consulting agency center 
        complies with the guidance described in clause (vi) and other 
        relevant regulations, guidances, and policies.</DELETED>
<DELETED>    ``(v) Not later than 10 days after the receipt by an 
agency center of an application under section 505, 510(k), or 520 of 
this Act, or under section 351 of the Public Health Service Act, for a 
combination product or an application for investigational use of a 
combination product under section 505(i) or 520(g), the agency center 
shall inform the Office of such receipt.</DELETED>
<DELETED>    ``(vi) Not later than 2 years after the date of enactment 
of the Combination Product Regulatory Fairness Act of 2015, the 
Secretary shall issue final guidance that describes the 
responsibilities of each agency center regarding its review of 
combination products, including each center's role in evaluating 
evidence development and review under a risk-based approach, dispute 
resolution, labeling, product usability assessments, and human factors 
testing. The Office shall, after soliciting public comment, review and 
update the guidance at least biannually and specify in such updated 
guidance the reasons for updates.'';</DELETED>
                <DELETED>    (B) in subparagraph (E)--</DELETED>
                        <DELETED>    (i) by striking clause (i) and 
                        inserting the following new clause:</DELETED>
<DELETED>    ``(i) During the review process, any dispute regarding the 
substance, timeliness, review process, requirements, or alignment of 
the premarket review may be presented to the Office for resolution and 
the Office shall convene the relevant parties and resolve conflicts not 
later than 90 days after the date on which the Office receives written 
notice of such conflicts.''; and</DELETED>
                        <DELETED>    (ii) in clause (ii), by striking 
                        ``During the review process, any dispute 
                        regarding the substance of the premarket 
                        review'' and inserting ``Any remaining 
                        dispute'';</DELETED>
                <DELETED>    (C) in subparagraph (F), in the first 
                sentence--</DELETED>
                        <DELETED>    (i) by inserting ``or which 
                        involves determining the safety or efficacy of 
                        a component of a combination product'' after 
                        ``assignment of combination products to agency 
                        centers''; and</DELETED>
                        <DELETED>    (ii) by inserting ``and with the 
                        guidance described in subparagraph (C)(vi).'' 
                        before the period at the end; and</DELETED>
                <DELETED>    (D) in subparagraph (G)--</DELETED>
                        <DELETED>    (i) in clause (ii), by striking 
                        ``and'' at the end;</DELETED>
                        <DELETED>    (ii) in clause (iii), by striking 
                        the period at the end and inserting a 
                        semicolon; and</DELETED>
                        <DELETED>    (iii) by adding at the end the 
                        following new clauses:</DELETED>
        <DELETED>    ``(iv) identifying the percentage of combination 
        products for which a dispute resolution, with respect to 
        premarket review, was requested by the combination product's 
        sponsor; and</DELETED>
        <DELETED>    ``(v) identifying the percentage of meetings 
        between the Food and Drug Administration and the sponsor of a 
        combination product at which all of the centers participating 
        in the review of the combination product were in attendance, in 
        accordance with subparagraph (C)(iv)(I).'';</DELETED>
        <DELETED>    (4) in paragraph (9) (as redesignated by paragraph 
        (1)), by adding at the end the following:</DELETED>
        <DELETED>    ``(D) The terms `premarket review' and `reviews' 
        include all activities of the Food and Drug Administration 
        conducted prior to approval or clearance of an application or 
        notification submitted under section 505, 510(k), 515, or 520 
        of this Act or under section 351 of the Public Health Service 
        Act, including with respect to investigational use of the 
        product.''; and</DELETED>
        <DELETED>    (5) by adding at the end the following:</DELETED>
<DELETED>    ``(10) Rule of Construction.--Nothing in this subsection 
shall be construed as prohibiting a sponsor, at the sponsor's 
discretion, from submitting separate applications for the constituent 
parts of a combination product, unless the Secretary determines that a 
single application is necessary to ensure the safety and effectiveness, 
or substantial equivalence, as applicable, of the combination 
product.''.</DELETED>

SECTION 1. SHORT TITLE.

    This Act may be cited as the ``Combination Product Regulatory 
Fairness Act of 2016''.

SEC. 2. COMBINATION PRODUCTS.

    (a) In General.--Section 503(g) of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 353(g)) is amended--
            (1) by striking paragraph (3);
            (2) by redesignating paragraph (2) as paragraph (7);
            (3) by redesignating paragraphs (4) and (5) as paragraphs 
        (8) and (9), respectively; and
            (4) by striking ``(g)(1)'' and all that follows through the 
        end of paragraph (1) and inserting the following:
    ``(g)(1)(A) The Secretary shall, in accordance with this 
subsection, assign a primary agency center to regulate products that 
constitute a combination of a drug, device, or biological product.
    ``(B) The Secretary shall conduct the premarket review of any 
combination product under a single application, whenever appropriate.
    ``(C) For purposes of this subsection, the term `primary mode of 
action' means the single mode of action of a combination product 
expected to make the greatest contribution to the overall intended 
therapeutic effects of the combination product.
    ``(D) The Secretary shall determine the primary mode of action of 
the combination product. If the Secretary determines that the primary 
mode of action is that of--
            ``(i) a drug (other than a biological product), the agency 
        center charged with premarket review of drugs shall have 
        primary jurisdiction;
            ``(ii) a device, the agency center charged with premarket 
        review of devices shall have primary jurisdiction; or
            ``(iii) a biological product, the agency center charged 
        with premarket review of biological products shall have primary 
        jurisdiction.
    ``(E) In determining the primary mode of action of a combination 
product, the Secretary shall not determine that the primary mode of 
action is that of a drug or biological product solely because the 
combination product has any chemical action within or on the human 
body.
    ``(F) If a sponsor of a combination product disagrees with the 
determination under subparagraph (D)--
            ``(i) such sponsor may request, and the Secretary shall 
        provide, a substantive rationale to such sponsor that 
        references scientific evidence provided by the sponsor and any 
        other scientific evidence relied upon by the Secretary to 
        support such determination; and
            ``(ii)(I) the sponsor of the combination product may 
        propose one or more studies (which may be nonclinical, 
        clinical, or both) to establish the relevance, if any, of the 
        chemical action in achieving the primary mode of action of such 
        product;
            ``(II) if the sponsor proposes any such studies, the 
        Secretary and the sponsor of such product shall collaborate and 
        seek to reach agreement, within a reasonable time of such 
        proposal, not to exceed 90 calendar days, on the design of such 
        studies; and
            ``(III) if an agreement is reached under subclause (II) and 
        the sponsor conducts one or more of such studies, the Secretary 
        shall consider the data resulting from any such study when 
        reevaluating the determination of the primary mode of action of 
        such product, and unless and until such reevaluation has 
        occurred and the Secretary issues a new determination, the 
        determination of the Secretary under subparagraph (D) shall 
        remain in effect.
    ``(2)(A)(i) To establish clarity and certainty for the sponsor, the 
sponsor of a combination product may submit a proposed combination 
product review plan with respect to such combination product, at any 
point following the Secretary's determination of the primary mode of 
action pursuant to paragraph (1).
    ``(ii) Such proposed combination product review plan may--
            ``(I) address the standards and requirements for market 
        approval or clearance of the combination product;
            ``(II) address other issues relevant to such combination 
        product, such as requirements related to postmarket 
        modification of such combination product and good manufacturing 
        practices applicable to such combination product; and
            ``(III) identify elements under subclauses (I) and (II) 
        that may be more appropriate for discussion and agreement with 
        the Secretary at a later date given that scientific or other 
        information is not available, or agreement is otherwise not 
        feasible regarding such elements, at the time such plan is 
        submitted.
    ``(B) After the sponsor of a combination product submits a proposed 
combination product review plan under subparagraph (A), the Secretary 
shall review such plan and, in a written response to such sponsor--
            ``(i) accept such plan in its entirety, which may include 
        elements to be the subject of discussion and agreement between 
        the sponsor and the Secretary at a later date, as described in 
        subparagraph (A)(ii)(III);
            ``(ii) accept the plan in part, which may include elements 
        that have not been accepted at the time of the response and are 
        to be the subject of discussion and agreement between the 
        sponsor and the Secretary at a later date, as described in 
        subparagraph (A)(ii)(III), and elements that the Secretary 
        declines to accept; or
            ``(iii) deny such plan in its entirety.
    ``(C) When reviewing a proposed combination product review plan 
under subparagraph (B), the Secretary shall accept such plan, or 
elements of such plan, if the Secretary determines that the data to be 
collected is appropriate--
            ``(i) for market approval or clearance of the combination 
        product; or
            ``(ii) to otherwise meet relevant standards under this Act, 
        as applicable.
    ``(D)(i) If the Secretary declines to accept a proposed combination 
product review plan under subparagraph (B)(iii), or elements of such a 
plan under subparagraph (B)(ii), the Secretary shall, in the written 
response to such sponsor--
            ``(I) include a description of the deficiencies of such 
        plan or such elements, as applicable; and
            ``(II) clarify what elements may be suitable for discussion 
        at a later date.
    ``(ii) If the Secretary declines to accept a proposed combination 
product review plan under subparagraph (B)(iii), or elements of such a 
plan under subparagraph (B)(ii), the sponsor of such plan may request a 
meeting with the Secretary. Upon the request of the sponsor, the 
Secretary, including any necessary experts from the relevant agency 
centers, shall meet with the sponsor to discuss a proposed combination 
product review plan or elements of a combination product review plan 
that the Secretary has declined to accept, for the purpose of 
discussing the information and requirements necessary to make the plan 
or elements of such plan acceptable. Minutes of such meeting shall be 
made part of the administrative record.
    ``(iii) If the Secretary declines to accept a proposed combination 
product review plan under subparagraph (B)(iii), or elements of such a 
plan under subparagraph (B)(ii), a sponsor may resubmit a proposed 
combination product review plan for consideration by the Secretary 
under subparagraph (A).
    ``(E) A combination product review plan accepted under subparagraph 
(B)(i), or the elements of a combination product review plan that are 
accepted under subparagraph (B)(ii), shall remain in effect, except--
            ``(i) with the written agreement of the Secretary and the 
        sponsor or applicant; or
            ``(ii) pursuant to a decision, made in accordance with 
        subparagraph (F) by the director of the reviewing division of 
        the primary agency center, or a person more senior than such 
        director, in consultation with consulting centers and the 
        Office, that an important, materially relevant scientific issue 
        essential to determining the safety or effectiveness, or 
        substantial equivalence, as applicable, of the combination 
        product has been identified since a combination product review 
        plan or elements of a combination product review plan were 
        accepted, as applicable.
    ``(F) If the Secretary makes a decision under subparagraph (E)(ii), 
the Secretary shall provide notice, within a reasonable time after such 
decision, to the sponsor of the combination product subject to such 
decision and provide an opportunity for a meeting with the Secretary, 
to take place within a reasonable time after issuing such notice, at 
which--
            ``(i) the director of the reviewing division of the primary 
        agency center, or a person more senior than such director, 
        staff from the consulting centers, representatives of the 
        Office, and the sponsor shall be represented; and
            ``(ii) the director of the reviewing division of the 
        primary agency center, or a person more senior than the 
        director, shall describe the important, materially relevant 
        issue involved to such sponsor.
    ``(3) For purposes of conducting the premarket review of a 
combination product that contains an approved constituent part 
described in paragraph (4), the Secretary may require that the sponsor 
of such combination product submit to the Secretary only data or 
information that the Secretary determines is necessary to assess the 
safety and effectiveness of the combination product, including any 
incremental risks and benefits posed by such combination product, using 
a risk-based approach and taking into account any prior finding of 
safety and effectiveness or substantial equivalence for the approved 
constituent part relied upon by the applicant in accordance with 
paragraph (5).
    ``(4) For purposes of paragraph (3), an approved constituent part 
is--
            ``(A) a drug constituent part of a combination product 
        being reviewed in a single application or request under section 
        515, 510(k), or 513(f)(2) (submitted in accordance with 
        paragraph (5)), that is an approved drug, provided such 
        application or request complies with paragraph (5);
            ``(B) a device constituent part approved under section 515 
        that is referenced by the sponsor and that is available for use 
        by the Secretary under section 520(h)(4); or
            ``(C) any constituent part that was previously approved, 
        cleared, or classified under section 505, 510(k), 513(f)(2), or 
        515 of this Act for which the sponsor has a right of reference 
        or any constituent part that is a nonprescription drug, as 
        defined in section 760(a)(2).
    ``(5)(A) If an application is submitted under section 515, 510(k), 
or a request is submitted under section 513(f)(2), consistent with any 
determination made under paragraph (1)(D), for a combination product 
containing as a constituent part an approved drug--
            ``(i) the application or request shall include the 
        certification or statement described in section 505(b)(2); and
            ``(ii) the applicant or requester shall provide notice as 
        described in section 505(b)(3).
    ``(B) For purposes of this paragraph and paragraph (4), the term 
`approved drug' means an active ingredient--
            ``(i) that was in an application previously approved under 
        section 505(c);
            ``(ii) where such application is relied upon by the 
        applicant submitting the application or request described in 
        subparagraph (A);
            ``(iii) for which full reports of investigations that have 
        been made to show whether such drug is safe for use and whether 
        such drug is effective in use were not conducted by or for the 
        applicant submitting the application or request described in 
        subparagraph (A); and
            ``(iv) for which the applicant submitting the application 
        or request described in subparagraph (A) has not obtained a 
        right of reference or use from the person by or for whom the 
        investigations described in clause (iii) were conducted.
    ``(C) The following provisions shall apply with respect to an 
application or request described in subparagraph (A) to the same extent 
and in the same manner as if such application or request were an 
application described in section 505(b)(2) that referenced the approved 
drug:
            ``(i) Subparagraphs (A), (B), (C), and (D) of section 
        505(c)(3).
            ``(ii) Clauses (ii), (iii), and (iv) of section 
        505(c)(3)(E).
            ``(iii) Subsections (b) and (c) of section 505A.
            ``(iv) Section 505E(a).
            ``(v) Section 527(a).
    ``(D) Notwithstanding any other provision of this subsection, an 
application or request for classification for a combination product 
described in subparagraph (A) shall be considered an application 
submitted under section 505(b)(2) for purposes of section 271(e)(2)(A) 
of title 35, United States Code.
    ``(6) Nothing in this subsection shall be construed as prohibiting 
a sponsor from submitting separate applications for the constituent 
parts of a combination product, unless the Secretary determines that a 
single application is necessary.'';
            (5) in paragraph (8) (as redesignated by paragraph (3))--
                    (A) in subparagraph (C)--
                            (i) by amending clause (i) to read as 
                        follows:
    ``(i) In carrying out this subsection, the Office shall help to 
ensure timely and effective premarket review that involves more than 
one agency center by coordinating such reviews, overseeing the 
timeliness of such reviews, and overseeing the alignment of feedback 
regarding such reviews.'';
                            (ii) in clause (ii), by inserting ``and 
                        alignment'' after ``the timeliness'' each place 
                        it appears; and
                            (iii) by adding at the end the following 
                        new clauses:
    ``(iii) The Office shall ensure that, with respect to a combination 
product, a designated person or persons in the primary agency center be 
the primary point or points of contact for the sponsor of such 
combination product. The Office shall also coordinate communications to 
and from any consulting center involved in such premarket review, if 
requested by such primary agency center or any such consulting center. 
Agency communications and commitments, to the extent consistent with 
other provisions of law and the requirements of all affected agency 
centers, from the primary agency center shall be considered as 
communication from the Food and Drug Administration on behalf of all 
agency centers involved in the review.
    ``(iv) The Office shall, with respect to the premarket review of a 
combination product--
            ``(I) ensure that any meeting between the Food and Drug 
        Administration and the sponsor of such product is attended by 
        each agency center involved in the review, as appropriate;
            ``(II) ensure that each consulting agency center has 
        completed its premarket review and provided the results of such 
        review to the primary agency center in a timely manner; and
            ``(III) ensure that each consulting center follows the 
        guidance described in clause (vi) and advises, as appropriate, 
        on other relevant regulations, guidances, and policies.
    ``(v) In seeking agency action with respect to a combination 
product, the sponsor of such product--
            ``(I) shall identify the product as a combination product; 
        and
            ``(II) may request in writing the participation of 
        representatives of the Office in meetings related to such 
        combination product, or to have the Office otherwise engage on 
        such regulatory matters concerning the combination product.
    ``(vi) Not later than 4 years after the date of enactment of the 
Combination Product Regulatory Fairness Act of 2016, and after a public 
comment period of not less than 60 calendar days, the Secretary shall 
issue a final guidance that describes--
            ``(I) the responsibilities of each agency center regarding 
        its review of combination products, including each center's 
        role in evaluating evidence development and review under a 
        risk-based approach, dispute resolution, labeling, product 
        usability assessments, and human factors testing;
            ``(II) the structured process for managing pre-submission 
        interactions with sponsors developing combination products;
            ``(III) the best practices for ensuring that the feedback 
        in such pre-submission interactions represents the Agency's 
        best advice based on the information provided during such pre-
        submission interactions;
            ``(IV) the best practices regarding submissions by 
        sponsors, and review by the Secretary, of combination product 
        review plans under paragraph (2), including the appropriate 
        timing for discussion and agreement of such plans, and the 
        various elements of such plans, based on scientific and 
        technical understanding during product development;
            ``(V) the Secretary's processes for ensuring input from 
        experts from each relevant agency center in such pre-submission 
        interactions with sponsors developing combination products and 
        in fulfilling the requirements of this subsection;
            ``(VI) the timelines associated with responding to, and 
        holding meetings regarding, combination product review plans 
        under paragraph (2); and
            ``(VII) disputes appropriate for presentation to the Office 
        as described in subparagraph (E)(i).''.
                    (B) in subparagraph (E)--
                            (i) by striking clause (i) and inserting 
                        the following new clause:
    ``(i) During the review process, disputes between different agency 
centers regarding the substance, timeliness, review process, 
requirements, or alignment of the premarket review with respect to a 
combination product, including conflicting feedback, responses, and 
decisions from such agency centers, may be presented to the Office by 
the sponsor of such combination product for resolution and the Office 
shall convene the relevant parties and seek to resolve such 
conflicts.''; and
                            (ii) in clause (ii), by striking ``During 
                        the review process, any dispute regarding the 
                        substance of the premarket review'' and 
                        inserting ``Any dispute remaining after the 
                        process under clause (i) is completed'';
                    (C) in subparagraph (F), in the first sentence--
                            (i) by inserting ``or that involves 
                        determining the safety or efficacy, reasonable 
                        assurance of safety and efficacy, or 
                        substantial equivalence of a component of a 
                        combination product'' after ``assignment of 
                        combination products to agency centers''; and
                            (ii) by inserting ``and with the guidance 
                        described in subparagraph (C)(vi)'' before the 
                        period at the end; and
                    (D) in subparagraph (G)--
                            (i) in clause (ii), by striking ``and'' at 
                        the end;
                            (ii) in clause (iii), by striking the 
                        period at the end and inserting a semicolon; 
                        and
                            (iii) by adding at the end the following 
                        new clauses:
            ``(iv) identifying the percentage of combination products 
        for which a dispute resolution, with respect to premarket 
        review, was requested by the combination product's sponsor;
            ``(v) stating the average, median, and range of response 
        times to combination product review plans under paragraph (2);
            ``(vi) identifying the percentage of meetings between the 
        Food and Drug Administration and the sponsor of a combination 
        product at which all of the agency centers participating in the 
        review of the combination product were in attendance, in 
        accordance with subparagraph (C)(iv)(I); and
            ``(vii) for the report submitted in 2017, and in a report 
        at least once every 5 years thereafter, regarding any 
        recommendations to streamline premarket review of combination 
        products.''; and
            (6) in paragraph (9) (as redesignated by paragraph (3))--
                    (A) in subparagraph (C)--
                            (i) in clause (ii), by striking ``and'';
                            (ii) in clause (iii), by striking the 
                        period and inserting ``, and''; and
                            (iii) by adding at the end the following:
                            ``(iv) de novo classification under section 
                        513(a)(1).''; and
                    (B) by adding at the end the following:
            ``(D) The terms `premarket review' and `reviews' include 
        all activities of the Food and Drug Administration conducted 
        prior to approval or clearance of an application, notification, 
        or request for classification submitted under section 505, 
        510(k), 513(f)(2), 515, or 520 of this Act or under section 351 
        of the Public Health Service Act, including with respect to 
        investigational use of the product.''.
    (b) Information for Approval of Combination Products.--Section 
520(h)(4) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360j) 
is amended--
            (1) in subparagraph (A), by striking ``Any information'' 
        and inserting ``Subject to subparagraph (C), any information''; 
        and
            (2) by adding at the end the following new subparagraph:
                    ``(C) No information contained in an application 
                for premarket approval filed with the Secretary 
                pursuant to section 515(c) may be used to approve or 
                clear any application submitted under section 515 or 
                510(k) or to classify a product under section 513(f)(2) 
                for a combination product containing as a constituent 
                part an ``approved drug'' as defined in section 
                503(g)(5)(B) unless--
                            ``(i) the application includes the 
                        certification or statement referenced in 
                        section 503(g)(5)(A);
                            ``(ii) the applicant provides notice as 
                        described in Section 503(g)(5)(A); and
                            ``(iii) the Secretary's approval of such 
                        application is subject to the provisions in 
                        section 503(g)(5)(C).''.
    (c) Variations From CGMP Streamlined Approach.--Not later than 18 
months after the date of enactment of this Act, the Secretary shall 
identify types of combination products that the Secretary proposes may 
adopt good manufacturing practices that vary from the requirements set 
forth in section 4.4 of title 21, Code of Federal Regulations (or any 
successor regulations). The Secretary shall identify such types, and 
identify variations from such requirements, in a proposed list 
published in the Federal Register. After a public comment period 
regarding the appropriate good manufacturing practices for such types, 
the Secretary shall publish a final list in the Federal Register, 
notwithstanding section 553 of title 5, United States Code. The 
Secretary shall evaluate such types and such appropriate variations 
using a risk-based approach. The Secretary shall periodically review 
such types on such final list, including whether additional types of 
combination products are appropriate for such final list.
                                                       Calendar No. 414

114th CONGRESS

  2d Session

                                S. 1767

_______________________________________________________________________

                                 A BILL

   To amend the Federal Food, Drug, and Cosmetic Act with respect to 
             combination products, and for other purposes.

_______________________________________________________________________

                             April 5, 2016

                       Reported with an amendment
```