II 

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. 

1 Be it enacted by the Senate and House of Representa2 tives of the United States of America in Congress assembled, 

3 SECTION 1. SHORT TITLE. 

4 This Act may be cited as the ‘‘Combination Product 

5 Regulatory Fairness Act of 2015’’. 


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1 SEC. 2. DEVICE DEFINITION. 

2 Section 201(h) of the Federal Food, Drug, and Cos3 metic Act (21 U.S.C. 321(h)) is amended— 

4 (1) by redesignating subparagraphs (1), (2), 

5 and (3) as clauses (A), (B), and (C), respectively; 

6 (2) by striking ‘‘(h)’’ and inserting ‘‘(h)(1)’’; 

7 and 

8 (3) by adding at the end the following: 

9 ‘‘(2)(A) Before determining that an article does not 

10 meet the definition of a device under this paragraph, the 

11 Secretary shall provide to the sponsor of the article com12 petent and reliable scientific rationale that— 

13 ‘‘(i) cites any scientific evidence relied upon to 

14 support the rationale; and 

15 ‘‘(ii) supports such determination. 

16 ‘‘(B) If the Secretary makes a determination de17 scribed in clause (A)— 

18 ‘‘(i) the sponsor of the article may propose a 

19 nonclinical or clinical study, limited to not more data 

20 than necessary to establish the significance, if any, 

21 of the chemical action in achieving the primary in22 tended purpose of the article; and 

23 ‘‘(ii) the Secretary and the sponsor of the arti24 cle shall collaborate in good faith to reach agree25 ment, within a reasonable time not to exceed 90 

26 days, on the design of such study. 


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1 ‘‘(C) The data resulting from a study conducted 

2 under clause (B) shall inform the classification of the arti3 cle.’’. 

4 SEC. 3. COMBINATION PRODUCTS. 

5 Section 503(g) of the Federal Food, Drug, and Cos6 metic Act (21 U.S.C. 353(g)) is amended— 

7 (1) by redesignating paragraphs (2) through 

8 (5) as paragraphs (6) through (9), respectively; 

9 (2) by striking ‘‘(g)(1)’’ and all that follows 

10 through the end of paragraph (1) and inserting the 

11 following: 

12 ‘‘(g)(1)(A) The Secretary shall, in accordance with 

13 this subsection, assign an agency center to regulate prod14 ucts that constitute a combination of a drug, device, or 

15 biological product (referred to in this subsection as the 

16 ‘lead center’). 

17 ‘‘(B) The Secretary shall conduct the premarket re18 view of any combination product, whenever possible, under 

19 a single application using existing premarket review au20 thorities. 

21 ‘‘(C) The Secretary shall determine the primary mode 

22 of action of the combination product. If the Secretary de23 termines that the primary mode of action is that of— 


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1 ‘‘(i) a drug (other than a biological product), 

2 the agency center charged with premarket review of 

3 drugs shall have primary jurisdiction; 

4 ‘‘(ii) a device, the agency center charged with 

5 premarket review of devices shall have primary juris6 diction; or 

7 ‘‘(iii) a biological product, the agency center 

8 charged with premarket review of biological products 

9 shall have primary jurisdiction. 

10 ‘‘(D) In determining the primary mode of action of 

11 a combination product, the Secretary shall not determine 

12 that the primary mode of action is that of a drug or bio13 logical product solely because the combination product has 

14 any chemical action within or on the human body. 

15 ‘‘(E) If the Secretary disagrees with the conclusions 

16 of the sponsor on the primary mode of action of the com17 bination product, the Secretary shall provide a competent 

18 and reliable scientific rationale to the product sponsor that 

19 cites any scientific evidence relied upon to support the de20 cision. 

21 ‘‘(F) For purposes of this paragraph— 

22 ‘‘(i) the term ‘primary mode of action’ means 

23 the single mode of action of a combination product 

24 that provides the most important therapeutic action 

25 of the combination product; and 


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1 ‘‘(ii) the term ‘most important therapeutic ac2 tion’ means the mode of action expected to make the 

3 greatest contribution to the overall intended thera4 peutic effects of the combination product. 

5 ‘‘(2)(A) The sponsor of a combination product may 

6 submit a combination product review plan (referred to in 

7 this subsection as a ‘CPRP’) for the combination product, 

8 and may request a meeting prior to submission of the 

9 CPRP, to establish clarity and certainty for the sponsor 

10 regarding the standards and requirements applicable to— 

11 ‘‘(i) the review of safety and effectiveness, or 

12 substantial equivalence, of the combination product; 

13 ‘‘(ii) a postmarket modification of the combina14 tion product; or 

15 ‘‘(iii) good manufacturing practices for the com16 bination product. 

17 ‘‘(B) Not later than 60 days after the sponsor of a 

18 combination product submits a proposed CPRP, including 

19 a revision to a previously proposed or approved CPRP, 

20 the Secretary shall review the CPRP and— 

21 ‘‘(i) if the Secretary determines that the CPRP 

22 is appropriate to ensure adequate review of the safe23 ty and effectiveness, or substantial equivalence, of 

24 the combination product— 

25 ‘‘(I) approve the CPRP; and 


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1 ‘‘(II) issue to the sponsor a response indi2 cating such approval; or 

3 ‘‘(ii) if the Secretary finds that the CPRP does 

4 not meet the standard specified in clause (i)— 

5 ‘‘(I) decline to approve the CPRP; and 

6 ‘‘(II) issue to the sponsor a response indi7 cating that the Secretary has declined such ap8 proval and specifying any deficiencies in the 

9 proposed CPRP. 

10 ‘‘(C)(i) In the case of a CPRP that the Secretary de11 clines to approve under subparagraph (B)(ii), unless the 

12 sponsor submitting such CPRP determines a meeting is 

13 not necessary, the Secretary shall, not later than 30 days 

14 after submitting a response under such subparagraph, 

15 meet with such sponsor to discuss the CPRP. 

16 ‘‘(ii) A meeting under clause (i) shall— 

17 ‘‘(I) include any necessary experts from the rel18 evant agency centers; and 

19 ‘‘(II) coordinate the advice of such experts. 

20 ‘‘(D) The sponsor or applicant shall provide informa21 tion necessary for discussion and agreement on the level 

22 of evidence necessary to ensure adequate review of the 

23 safety and effectiveness, or substantial equivalence, of the 

24 combination product. 


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1 ‘‘(E) Not later than 30 days after the date on which 

2 a meeting is held under subparagraph (A)(i), the minutes 

3 of such meeting shall be prepared by the sponsor and 

4 made available to the Secretary. 

5 ‘‘(F) Any agreement that is reached between the Sec6 retary and a sponsor or applicant through a meeting held 

7 under subparagraph (A)(i) shall be reduced to writing by 

8 the sponsor or applicant, and, once approved by the Sec9 retary, made part of the administrative record by the Sec10 retary within 60 days of such meeting. 

11 ‘‘(G) An agreement described in subparagraph (F) 

12 shall not be changed after approval of the agreement, ex13 cept— 

14 ‘‘(i) with the written agreement of the sponsor 

15 or applicant; or 

16 ‘‘(ii) pursuant to a decision, made in accordance 

17 with subparagraph (H) by the director of the review18 ing division of the lead center, in consultation with 

19 consulting centers and the Office, that a substantial 

20 scientific issue essential to determining the safety or 

21 effectiveness, or substantial equivalence, of the com22 bination product has been identified. 

23 ‘‘(H) With respect to a decision under subparagraph 

24 (G)(ii), the Secretary shall provide notice, within 2 busi25 ness days of such decision, to the sponsor of the combinaVerDate Sep 11 2014 20:57 Apr 05, 2016 Jkt 059200 PO 00000 Frm 00007 Fmt 6652 Sfmt 6401 E:\BILLS\S1767.RS S1767

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1 tion product and an opportunity for a meeting to take 

2 place not later than 14 calendar days after issuing such 

3 notice, at which— 

4 ‘‘(i) the director of the reviewing division of the 

5 lead center, staff from the consulting agency centers, 

6 representatives of the Office, and the sponsor will be 

7 present; and 

8 ‘‘(ii) the director of the reviewing division of the 

9 lead center will document the scientific issue in10 volved. 

11 ‘‘(3) For purposes of conducting the premarket re12 view of a combination product that contains an approved 

13 constituent product described in paragraph (4), the Sec14 retary may require only that the sponsor of such combina15 tion product submit to the Secretary data or information 

16 that— 

17 ‘‘(A) the Secretary determines is necessary to 

18 assess the specific safety and effectiveness questions 

19 and incremental risks posed by the combination 

20 product, using a risk-based approach and taking into 

21 account any prior finding of safety and efficacy or 

22 substantial equivalence for the approved constituent 

23 product; and 

24 ‘‘(B) is not duplicative of data or information 

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1 mitted to the Secretary in connection with the ap2 proved constituent product. 

3 ‘‘(4) For purposes of paragraph (3), an approved con4 stituent product is— 

5 ‘‘(A) a drug constituent part of a combination 

6 product being reviewed in a single application under 

7 section 515 or 510(k), provided such drug con8 stituent part was previously approved under section 

9 505 and such application complies with subpara10 graph (A) of paragraph (5) and is subject to sub11 paragraphs (D) and (E) of such paragraph; 

12 ‘‘(B) a device constituent part approved under 

13 section 515 that is referenced by the sponsor and 

14 which is available for use by the Secretary under 

15 section 520(h)(4); or 

16 ‘‘(C) any constituent part that was previously 

17 approved, cleared, or licensed under section 505, 

18 510(k), or 515 of this Act or section 351 of the 

19 Public Health Service Act, for which the sponsor has 

20 a right of reference or which is otherwise available 

21 for consideration by the Secretary under this Act or 

22 the Public Health Service Act. 

23 ‘‘(5)(A) If an application is submitted under section 

24 515 or 510(k) for a combination product containing as 

25 a constituent part an approved drug— 


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1 ‘‘(i) the application shall include the certifi2 cation or statement required pursuant section 

3 505(b)(2); and 

4 ‘‘(ii) the applicant shall provide notice as re5 quired pursuant to section 505(b)(3). 

6 ‘‘(B) For purposes of this paragraph, the term ‘ap7 proved drug’ means a drug— 

8 ‘‘(i) that was previously approved under section 

9 505; 

10 ‘‘(ii) for which full reports of investigations that 

11 have been made to show whether such drug is safe 

12 for use and whether such drug is effective in use— 

13 ‘‘(I) are relied upon by the applicant sub14 mitting the application described in subpara15 graph (A); and 

16 ‘‘(II) were not conducted by or for such 

17 applicant; and 

18 ‘‘(iii) with respect to which, the applicant sub19 mitting the application described in subparagraph 

20 (A) has not obtained a right of reference or use from 

21 the person by or for whom the investigations were 

22 conducted. 

23 ‘‘(C) The following provisions shall apply with respect 

24 an application described in subparagraph (A): 


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1 ‘‘(i) Subparagraphs (A), (B), (C), and (D) of 

2 section 505(c)(3). 

3 ‘‘(ii) Clauses (ii), (iii), and (iv) of section 

4 505(c)(3)(E). 

5 ‘‘(iii) Paragraphs (b) and (c) of section 505A. 

6 ‘‘(iv) Section 505E(a). 

7 ‘‘(v) Section 527(a). 

8 ‘‘(D) Notwithstanding section 520(h)(4)(A)(i), infor9 mation contained in an application for premarket approval 

10 filed with the Secretary pursuant to section 515(c) may 

11 not be used to approve any application submitted under 

12 section 515 or 510(k) for a combination product con13 taining as a constituent part a drug previously approved 

14 under section 505 unless— 

15 ‘‘(i) the application includes the certification or 

16 statement referenced in subparagraph (A); 

17 ‘‘(ii) the applicant provides notice as described 

18 in subparagraph (A); and 

19 ‘‘(iii) the Secretary’s approval of such applica20 tion is subject to the provisions specified in subpara21 graph (C). 

22 ‘‘(E) An application for a combination product de23 scribed in subparagraph (A) or (D) shall be considered 

24 an application submitted under Section 505(b)(2) solely 

25 for purposes of section 271(e)(2)(A) of the Patent Act.’’; 


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1 (3) in paragraph (8) (as redesignated by para2 graph (1))— 

3 (A) in subparagraph (C)— 

4 (i) by amending clause (i) to read as 

5 follows: 

6 ‘‘(i) In carrying out this subsection, the Office shall 

7 ensure timely and effective premarket reviews involving 

8 more than one agency center by— 

9 ‘‘(I) overseeing the timeliness and alignment of 

10 reviews; and 

11 ‘‘(II) coordinating reviews.’’; 

12 (ii) in clause (ii), by inserting ‘‘and 

13 alignment’’ after ‘‘the timeliness’’ each 

14 place it appears; and 

15 (iii) by adding at the end the fol16 lowing new clauses: 

17 ‘‘(iii) The Office shall ensure that the lead center be 

18 the primary point of contact for the sponsor of the prod19 uct. The Office shall also coordinate communications to 

20 and from any consulting agency center involved in such 

21 premarket review. Agency communications and commit22 ments, to the extent consistent with other provisions of 

23 law and the requirements of all affected agency centers, 

24 from the lead center shall be binding on all other centers 

25 involved in the review. 


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1 ‘‘(iv) The Office shall, with respect to the premarket 

2 review of a combination product— 

3 ‘‘(I) ensure that any meeting between the Food 

4 and Drug Administration and the sponsor of the 

5 product is attended by each agency center involved 

6 in the review, as appropriate; 

7 ‘‘(II) require that each consulting agency center 

8 has completed its premarket review and provided the 

9 results of such review to the lead center within time10 frames that allow the lead center to meet the review 

11 goals established pursuant to the most recent au12 thorization or reauthorization of parts 2, 3, 7, and 

13 8, as applicable, of subchapter C of title VII; and 

14 ‘‘(III) ensure that each consulting agency cen15 ter complies with the guidance described in clause 

16 (vi) and other relevant regulations, guidances, and 

17 policies. 

18 ‘‘(v) Not later than 10 days after the receipt by an 

19 agency center of an application under section 505, 510(k), 

20 or 520 of this Act, or under section 351 of the Public 

21 Health Service Act, for a combination product or an appli22 cation for investigational use of a combination product 

23 under section 505(i) or 520(g), the agency center shall 

24 inform the Office of such receipt. 


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1 ‘‘(vi) Not later than 2 years after the date of enact2 ment of the Combination Product Regulatory Fairness Act 

3 of 2015, the Secretary shall issue final guidance that de4 scribes the responsibilities of each agency center regarding 

5 its review of combination products, including each center’s 

6 role in evaluating evidence development and review under 

7 a risk-based approach, dispute resolution, labeling, prod8 uct usability assessments, and human factors testing. The 

9 Office shall, after soliciting public comment, review and 

10 update the guidance at least biannually and specify in 

11 such updated guidance the reasons for updates.’’; 

12 (B) in subparagraph (E)— 

13 (i) by striking clause (i) and inserting 

14 the following new clause: 

15 ‘‘(i) During the review process, any dispute regarding 

16 the substance, timeliness, review process, requirements, or 

17 alignment of the premarket review may be presented to 

18 the Office for resolution and the Office shall convene the 

19 relevant parties and resolve conflicts not later than 90 

20 days after the date on which the Office receives written 

21 notice of such conflicts.’’; and 

22 (ii) in clause (ii), by striking ‘‘During 

23 the review process, any dispute regarding 

24 the substance of the premarket review’’ 

25 and inserting ‘‘Any remaining dispute’’; 


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1 (C) in subparagraph (F), in the first sen2 tence— 

3 (i) by inserting ‘‘or which involves de4 termining the safety or efficacy of a com5 ponent of a combination product’’ after 

6 ‘‘assignment of combination products to 

7 agency centers’’; and 

8 (ii) by inserting ‘‘and with the guid9 ance described in subparagraph (C)(vi).’’ 

10 before the period at the end; and 

11 (D) in subparagraph (G)— 

12 (i) in clause (ii), by striking ‘‘and’’ at 

13 the end; 

14 (ii) in clause (iii), by striking the pe15 riod at the end and inserting a semicolon; 

16 and 

17 (iii) by adding at the end the fol18 lowing new clauses: 

19 ‘‘(iv) identifying the percentage of combination 

20 products for which a dispute resolution, with respect 

21 to premarket review, was requested by the combina22 tion product’s sponsor; and 

23 ‘‘(v) identifying the percentage of meetings be24 tween the Food and Drug Administration and the 

25 sponsor of a combination product at which all of the 


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1 centers participating in the review of the combina2 tion product were in attendance, in accordance with 

3 subparagraph (C)(iv)(I).’’; 

4 (4) in paragraph (9) (as redesignated by para5 graph (1)), by adding at the end the following: 

6 ‘‘(D) The terms ‘premarket review’ and ‘re7 views’ include all activities of the Food and Drug 

8 Administration conducted prior to approval or clear9 ance of an application or notification submitted 

10 under section 505, 510(k), 515, or 520 of this Act 

11 or under section 351 of the Public Health Service 

12 Act, including with respect to investigational use of 

13 the product.’’; and 

14 (5) by adding at the end the following: 

15 ‘‘(10) RULE OF CONSTRUCTION.—Nothing in this 

16 subsection shall be construed as prohibiting a sponsor, at 

17 the sponsor’s discretion, from submitting separate applica18 tions for the constituent parts of a combination product, 

19 unless the Secretary determines that a single application 

20 is necessary to ensure the safety and effectiveness, or sub21 stantial equivalence, as applicable, of the combination 

22 product.’’. 

23 SECTION 1. SHORT TITLE. 

24 This Act may be cited as the ‘‘Combination Product 

25 Regulatory Fairness Act of 2016’’. 


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1 SEC. 2. COMBINATION PRODUCTS. 

2 (a) IN GENERAL.—Section 503(g) of the Federal Food, 

3 Drug, and Cosmetic Act (21 U.S.C. 353(g)) is amended— 

4 (1) by striking paragraph (3); 

5 (2) by redesignating paragraph (2) as para6 graph (7); 

7 (3) by redesignating paragraphs (4) and (5) as 

8 paragraphs (8) and (9), respectively; and 

9 (4) by striking ‘‘(g)(1)’’ and all that follows 

10 through the end of paragraph (1) and inserting the 

11 following: 

12 ‘‘(g)(1)(A) The Secretary shall, in accordance with this 

13 subsection, assign a primary agency center to regulate 

14 products that constitute a combination of a drug, device, 

15 or biological product. 

16 ‘‘(B) The Secretary shall conduct the premarket review 

17 of any combination product under a single application, 

18 whenever appropriate. 

19 ‘‘(C) For purposes of this subsection, the term ‘primary 

20 mode of action’ means the single mode of action of a com21 bination product expected to make the greatest contribution 

22 to the overall intended therapeutic effects of the combination 

23 product. 

24 ‘‘(D) The Secretary shall determine the primary mode 

25 of action of the combination product. If the Secretary deter26 mines that the primary mode of action is that of— 


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1 ‘‘(i) a drug (other than a biological product), the 

2 agency center charged with premarket review of drugs 

3 shall have primary jurisdiction; 

4 ‘‘(ii) a device, the agency center charged with 

5 premarket review of devices shall have primary juris6 diction; or 

7 ‘‘(iii) a biological product, the agency center 

8 charged with premarket review of biological products 

9 shall have primary jurisdiction. 

10 ‘‘(E) In determining the primary mode of action of 

11 a combination product, the Secretary shall not determine 

12 that the primary mode of action is that of a drug or biologi13 cal product solely because the combination product has any 

14 chemical action within or on the human body. 

15 ‘‘(F) If a sponsor of a combination product disagrees 

16 with the determination under subparagraph (D)— 

17 ‘‘(i) such sponsor may request, and the Secretary 

18 shall provide, a substantive rationale to such sponsor 

19 that references scientific evidence provided by the 

20 sponsor and any other scientific evidence relied upon 

21 by the Secretary to support such determination; and 

22 ‘‘(ii)(I) the sponsor of the combination product 

23 may propose one or more studies (which may be non24 clinical, clinical, or both) to establish the relevance, if 


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1 any, of the chemical action in achieving the primary 

2 mode of action of such product; 

3 ‘‘(II) if the sponsor proposes any such studies, 

4 the Secretary and the sponsor of such product shall 

5 collaborate and seek to reach agreement, within a rea6 sonable time of such proposal, not to exceed 90 cal7 endar days, on the design of such studies; and 

8 ‘‘(III) if an agreement is reached under sub9 clause (II) and the sponsor conducts one or more of 

10 such studies, the Secretary shall consider the data re11 sulting from any such study when reevaluating the 

12 determination of the primary mode of action of such 

13 product, and unless and until such reevaluation has 

14 occurred and the Secretary issues a new determina15 tion, the determination of the Secretary under sub16 paragraph (D) shall remain in effect. 

17 ‘‘(2)(A)(i) To establish clarity and certainty for the 

18 sponsor, the sponsor of a combination product may submit 

19 a proposed combination product review plan with respect 

20 to such combination product, at any point following the 

21 Secretary’s determination of the primary mode of action 

22 pursuant to paragraph (1). 

23 ‘‘(ii) Such proposed combination product review plan 

24 may— 


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1 ‘‘(I) address the standards and requirements for 

2 market approval or clearance of the combination 

3 product; 

4 ‘‘(II) address other issues relevant to such com5 bination product, such as requirements related to 

6 postmarket modification of such combination product 

7 and good manufacturing practices applicable to such 

8 combination product; and 

9 ‘‘(III) identify elements under subclauses (I) and 

10 (II) that may be more appropriate for discussion and 

11 agreement with the Secretary at a later date given 

12 that scientific or other information is not available, 

13 or agreement is otherwise not feasible regarding such 

14 elements, at the time such plan is submitted. 

15 ‘‘(B) After the sponsor of a combination product sub16 mits a proposed combination product review plan under 

17 subparagraph (A), the Secretary shall review such plan 

18 and, in a written response to such sponsor— 

19 ‘‘(i) accept such plan in its entirety, which may 

20 include elements to be the subject of discussion and 

21 agreement between the sponsor and the Secretary at 

22 a later date, as described in subparagraph 

23 (A)(ii)(III); 

24 ‘‘(ii) accept the plan in part, which may include 

25 elements that have not been accepted at the time of the 


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1 response and are to be the subject of discussion and 

2 agreement between the sponsor and the Secretary at 

3 a later date, as described in subparagraph 

4 (A)(ii)(III), and elements that the Secretary declines 

5 to accept; or 

6 ‘‘(iii) deny such plan in its entirety. 

7 ‘‘(C) When reviewing a proposed combination product 

8 review plan under subparagraph (B), the Secretary shall 

9 accept such plan, or elements of such plan, if the Secretary 

10 determines that the data to be collected is appropriate— 

11 ‘‘(i) for market approval or clearance of the com12 bination product; or 

13 ‘‘(ii) to otherwise meet relevant standards under 

14 this Act, as applicable. 

15 ‘‘(D)(i) If the Secretary declines to accept a proposed 

16 combination product review plan under subparagraph 

17 (B)(iii), or elements of such a plan under subparagraph 

18 (B)(ii), the Secretary shall, in the written response to such 

19 sponsor— 

20 ‘‘(I) include a description of the deficiencies of 

21 such plan or such elements, as applicable; and 

22 ‘‘(II) clarify what elements may be suitable for 

23 discussion at a later date. 

24 ‘‘(ii) If the Secretary declines to accept a proposed 

25 combination product review plan under subparagraph 


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1 (B)(iii), or elements of such a plan under subparagraph 

2 (B)(ii), the sponsor of such plan may request a meeting 

3 with the Secretary. Upon the request of the sponsor, the Sec4 retary, including any necessary experts from the relevant 

5 agency centers, shall meet with the sponsor to discuss a pro6 posed combination product review plan or elements of a 

7 combination product review plan that the Secretary has de8 clined to accept, for the purpose of discussing the informa9 tion and requirements necessary to make the plan or ele10 ments of such plan acceptable. Minutes of such meeting shall 

11 be made part of the administrative record. 

12 ‘‘(iii) If the Secretary declines to accept a proposed 

13 combination product review plan under subparagraph 

14 (B)(iii), or elements of such a plan under subparagraph 

15 (B)(ii), a sponsor may resubmit a proposed combination 

16 product review plan for consideration by the Secretary 

17 under subparagraph (A). 

18 ‘‘(E) A combination product review plan accepted 

19 under subparagraph (B)(i), or the elements of a combina20 tion product review plan that are accepted under subpara21 graph (B)(ii), shall remain in effect, except— 

22 ‘‘(i) with the written agreement of the Secretary 

23 and the sponsor or applicant; or 

24 ‘‘(ii) pursuant to a decision, made in accordance 

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1 ing division of the primary agency center, or a per2 son more senior than such director, in consultation 

3 with consulting centers and the Office, that an impor4 tant, materially relevant scientific issue essential to 

5 determining the safety or effectiveness, or substantial 

6 equivalence, as applicable, of the combination product 

7 has been identified since a combination product re8 view plan or elements of a combination product re9 view plan were accepted, as applicable. 

10 ‘‘(F) If the Secretary makes a decision under subpara11 graph (E)(ii), the Secretary shall provide notice, within a 

12 reasonable time after such decision, to the sponsor of the 

13 combination product subject to such decision and provide 

14 an opportunity for a meeting with the Secretary, to take 

15 place within a reasonable time after issuing such notice, 

16 at which— 

17 ‘‘(i) the director of the reviewing division of the 

18 primary agency center, or a person more senior than 

19 such director, staff from the consulting centers, rep20 resentatives of the Office, and the sponsor shall be rep21 resented; and 

22 ‘‘(ii) the director of the reviewing division of the 

23 primary agency center, or a person more senior than 

24 the director, shall describe the important, materially 

25 relevant issue involved to such sponsor. 


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1 ‘‘(3) For purposes of conducting the premarket review 

2 of a combination product that contains an approved con3 stituent part described in paragraph (4), the Secretary may 

4 require that the sponsor of such combination product sub5 mit to the Secretary only data or information that the Sec6 retary determines is necessary to assess the safety and effec7 tiveness of the combination product, including any incre8 mental risks and benefits posed by such combination prod9 uct, using a risk-based approach and taking into account 

10 any prior finding of safety and effectiveness or substantial 

11 equivalence for the approved constituent part relied upon 

12 by the applicant in accordance with paragraph (5). 

13 ‘‘(4) For purposes of paragraph (3), an approved con14 stituent part is— 

15 ‘‘(A) a drug constituent part of a combination 

16 product being reviewed in a single application or re17 quest under section 515, 510(k), or 513(f)(2) (sub18 mitted in accordance with paragraph (5)), that is an 

19 approved drug, provided such application or request 

20 complies with paragraph (5); 

21 ‘‘(B) a device constituent part approved under 

22 section 515 that is referenced by the sponsor and that 

23 is available for use by the Secretary under section 

24 520(h)(4); or 


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1 ‘‘(C) any constituent part that was previously 

2 approved, cleared, or classified under section 505, 

3 510(k), 513(f)(2), or 515 of this Act for which the 

4 sponsor has a right of reference or any constituent 

5 part that is a nonprescription drug, as defined in sec6 tion 760(a)(2). 

7 ‘‘(5)(A) If an application is submitted under section 

8 515, 510(k), or a request is submitted under section 

9 513(f)(2), consistent with any determination made under 

10 paragraph (1)(D), for a combination product containing as 

11 a constituent part an approved drug— 

12 ‘‘(i) the application or request shall include the 

13 certification or statement described in section 

14 505(b)(2); and 

15 ‘‘(ii) the applicant or requester shall provide no16 tice as described in section 505(b)(3). 

17 ‘‘(B) For purposes of this paragraph and paragraph 

18 (4), the term ‘approved drug’ means an active ingredient— 

19 ‘‘(i) that was in an application previously ap20 proved under section 505(c); 

21 ‘‘(ii) where such application is relied upon by 

22 the applicant submitting the application or request 

23 described in subparagraph (A); 

24 ‘‘(iii) for which full reports of investigations that 

25 have been made to show whether such drug is safe for 


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1 use and whether such drug is effective in use were not 

2 conducted by or for the applicant submitting the ap3 plication or request described in subparagraph (A); 

4 and 

5 ‘‘(iv) for which the applicant submitting the ap6 plication or request described in subparagraph (A) 

7 has not obtained a right of reference or use from the 

8 person by or for whom the investigations described in 

9 clause (iii) were conducted. 

10 ‘‘(C) The following provisions shall apply with respect 

11 to an application or request described in subparagraph (A) 

12 to the same extent and in the same manner as if such appli13 cation or request were an application described in section 

14 505(b)(2) that referenced the approved drug: 

15 ‘‘(i) Subparagraphs (A), (B), (C), and (D) of 

16 section 505(c)(3). 

17 ‘‘(ii) Clauses (ii), (iii), and (iv) of section 

18 505(c)(3)(E). 

19 ‘‘(iii) Subsections (b) and (c) of section 505A. 

20 ‘‘(iv) Section 505E(a). 

21 ‘‘(v) Section 527(a). 

22 ‘‘(D) Notwithstanding any other provision of this sub23 section, an application or request for classification for a 

24 combination product described in subparagraph (A) shall 

25 be considered an application submitted under section 


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1 505(b)(2) for purposes of section 271(e)(2)(A) of title 35, 

2 United States Code. 

3 ‘‘(6) Nothing in this subsection shall be construed as 

4 prohibiting a sponsor from submitting separate applica5 tions for the constituent parts of a combination product, 

6 unless the Secretary determines that a single application 

7 is necessary.’’; 

8 (5) in paragraph (8) (as redesignated by para9 graph (3))— 

10 (A) in subparagraph (C)— 

11 (i) by amending clause (i) to read as 

12 follows: 

13 ‘‘(i) In carrying out this subsection, the Office shall 

14 help to ensure timely and effective premarket review that 

15 involves more than one agency center by coordinating such 

16 reviews, overseeing the timeliness of such reviews, and over17 seeing the alignment of feedback regarding such reviews.’’; 

18 (ii) in clause (ii), by inserting ‘‘and 

19 alignment’’ after ‘‘the timeliness’’ each place 

20 it appears; and 

21 (iii) by adding at the end the following 

22 new clauses: 

23 ‘‘(iii) The Office shall ensure that, with respect to a 

24 combination product, a designated person or persons in the 

25 primary agency center be the primary point or points of 


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1 contact for the sponsor of such combination product. The 

2 Office shall also coordinate communications to and from 

3 any consulting center involved in such premarket review, 

4 if requested by such primary agency center or any such con5 sulting center. Agency communications and commitments, 

6 to the extent consistent with other provisions of law and 

7 the requirements of all affected agency centers, from the pri8 mary agency center shall be considered as communication 

9 from the Food and Drug Administration on behalf of all 

10 agency centers involved in the review. 

11 ‘‘(iv) The Office shall, with respect to the premarket 

12 review of a combination product— 

13 ‘‘(I) ensure that any meeting between the Food 

14 and Drug Administration and the sponsor of such 

15 product is attended by each agency center involved in 

16 the review, as appropriate; 

17 ‘‘(II) ensure that each consulting agency center 

18 has completed its premarket review and provided the 

19 results of such review to the primary agency center in 

20 a timely manner; and 

21 ‘‘(III) ensure that each consulting center follows 

22 the guidance described in clause (vi) and advises, as 

23 appropriate, on other relevant regulations, guidances, 

24 and policies. 


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1 ‘‘(v) In seeking agency action with respect to a com2 bination product, the sponsor of such product— 

3 ‘‘(I) shall identify the product as a combination 

4 product; and 

5 ‘‘(II) may request in writing the participation of 

6 representatives of the Office in meetings related to 

7 such combination product, or to have the Office other8 wise engage on such regulatory matters concerning 

9 the combination product. 

10 ‘‘(vi) Not later than 4 years after the date of enactment 

11 of the Combination Product Regulatory Fairness Act of 

12 2016, and after a public comment period of not less than 

13 60 calendar days, the Secretary shall issue a final guidance 

14 that describes— 

15 ‘‘(I) the responsibilities of each agency center re16 garding its review of combination products, including 

17 each center’s role in evaluating evidence development 

18 and review under a risk-based approach, dispute reso19 lution, labeling, product usability assessments, and 

20 human factors testing; 

21 ‘‘(II) the structured process for managing pre22 submission interactions with sponsors developing 

23 combination products; 

24 ‘‘(III) the best practices for ensuring that the 

25 feedback in such pre-submission interactions repVerDate Sep 11 2014 20:57 Apr 05, 2016 Jkt 059200 PO 00000 Frm 00029 Fmt 6652 Sfmt 6203 E:\BILLS\S1767.RS S1767

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1 resents the Agency’s best advice based on the informa2 tion provided during such pre-submission inter3 actions; 

4 ‘‘(IV) the best practices regarding submissions by 

5 sponsors, and review by the Secretary, of combination 

6 product review plans under paragraph (2), including 

7 the appropriate timing for discussion and agreement 

8 of such plans, and the various elements of such plans, 

9 based on scientific and technical understanding dur10 ing product development; 

11 ‘‘(V) the Secretary’s processes for ensuring input 

12 from experts from each relevant agency center in such 

13 pre-submission interactions with sponsors developing 

14 combination products and in fulfilling the require15 ments of this subsection; 

16 ‘‘(VI) the timelines associated with responding 

17 to, and holding meetings regarding, combination 

18 product review plans under paragraph (2); and 

19 ‘‘(VII) disputes appropriate for presentation to 

20 the Office as described in subparagraph (E)(i).’’. 

21 (B) in subparagraph (E)— 

22 (i) by striking clause (i) and inserting 

23 the following new clause: 

24 ‘‘(i) During the review process, disputes between dif25 ferent agency centers regarding the substance, timeliness, reVerDate Sep 11 2014 20:57 Apr 05, 2016 Jkt 059200 PO 00000 Frm 00030 Fmt 6652 Sfmt 6203 E:\BILLS\S1767.RS S1767

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1 view process, requirements, or alignment of the premarket 

2 review with respect to a combination product, including 

3 conflicting feedback, responses, and decisions from such 

4 agency centers, may be presented to the Office by the spon5 sor of such combination product for resolution and the Of6 fice shall convene the relevant parties and seek to resolve 

7 such conflicts.’’; and 

8 (ii) in clause (ii), by striking ‘‘During 

9 the review process, any dispute regarding 

10 the substance of the premarket review’’ and 

11 inserting ‘‘Any dispute remaining after the 

12 process under clause (i) is completed’’; 

13 (C) in subparagraph (F), in the first sen14 tence— 

15 (i) by inserting ‘‘or that involves deter16 mining the safety or efficacy, reasonable as17 surance of safety and efficacy, or substan18 tial equivalence of a component of a com19 bination product’’ after ‘‘assignment of 

20 combination products to agency centers’’; 

21 and 

22 (ii) by inserting ‘‘and with the guid23 ance described in subparagraph (C)(vi)’’ be24 fore the period at the end; and 

25 (D) in subparagraph (G)— 


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1 (i) in clause (ii), by striking ‘‘and’’ at 

2 the end; 

3 (ii) in clause (iii), by striking the pe4 riod at the end and inserting a semicolon; 

5 and 

6 (iii) by adding at the end the following 

7 new clauses: 

8 ‘‘(iv) identifying the percentage of combination 

9 products for which a dispute resolution, with respect 

10 to premarket review, was requested by the combina11 tion product’s sponsor; 

12 ‘‘(v) stating the average, median, and range of 

13 response times to combination product review plans 

14 under paragraph (2); 

15 ‘‘(vi) identifying the percentage of meetings be16 tween the Food and Drug Administration and the 

17 sponsor of a combination product at which all of the 

18 agency centers participating in the review of the com19 bination product were in attendance, in accordance 

20 with subparagraph (C)(iv)(I); and 

21 ‘‘(vii) for the report submitted in 2017, and in 

22 a report at least once every 5 years thereafter, regard23 ing any recommendations to streamline premarket re24 view of combination products.’’; and 


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1 (6) in paragraph (9) (as redesignated by para2 graph (3))— 

3 (A) in subparagraph (C)— 

4 (i) in clause (ii), by striking ‘‘and’’; 

5 (ii) in clause (iii), by striking the pe6 riod and inserting ‘‘, and’’; and 

7 (iii) by adding at the end the fol8 lowing: 

9 ‘‘(iv) de novo classification under sec10 tion 513(a)(1).’’; and 

11 (B) by adding at the end the following: 

12 ‘‘(D) The terms ‘premarket review’ and ‘reviews’ 

13 include all activities of the Food and Drug Adminis14 tration conducted prior to approval or clearance of 

15 an application, notification, or request for classifica16 tion submitted under section 505, 510(k), 513(f)(2), 

17 515, or 520 of this Act or under section 351 of the 

18 Public Health Service Act, including with respect to 

19 investigational use of the product.’’. 

20 (b) INFORMATION FOR APPROVAL OF COMBINATION

21 PRODUCTS.—Section 520(h)(4) of the Federal Food, Drug, 

22 and Cosmetic Act (21 U.S.C. 360j) is amended— 

23 (1) in subparagraph (A), by striking ‘‘Any infor24 mation’’ and inserting ‘‘Subject to subparagraph (C), 

25 any information’’; and 


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1 (2) by adding at the end the following new sub2 paragraph: 

3 ‘‘(C) No information contained in an appli4 cation for premarket approval filed with the Sec5 retary pursuant to section 515(c) may be used to 

6 approve or clear any application submitted 

7 under section 515 or 510(k) or to classify a prod8 uct under section 513(f)(2) for a combination 

9 product containing as a constituent part an 

10 ‘‘approved drug’’ as defined in section 

11 503(g)(5)(B) unless— 

12 ‘‘(i) the application includes the cer13 tification or statement referenced in section 

14 503(g)(5)(A); 

15 ‘‘(ii) the applicant provides notice as 

16 described in Section 503(g)(5)(A); and 

17 ‘‘(iii) the Secretary’s approval of such 

18 application is subject to the provisions in 

19 section 503(g)(5)(C).’’. 

20 (c) VARIATIONS FROM CGMP STREAMLINED AP21 PROACH.—Not later than 18 months after the date of enact22 ment of this Act, the Secretary shall identify types of com23 bination products that the Secretary proposes may adopt 

24 good manufacturing practices that vary from the require25 ments set forth in section 4.4 of title 21, Code of Federal 


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1 Regulations (or any successor regulations). The Secretary 

2 shall identify such types, and identify variations from such 

3 requirements, in a proposed list published in the Federal 

4 Register. After a public comment period regarding the ap5 propriate good manufacturing practices for such types, the 

6 Secretary shall publish a final list in the Federal Register, 

7 notwithstanding section 553 of title 5, United States Code. 

8 The Secretary shall evaluate such types and such appro9 priate variations using a risk-based approach. The Sec10 retary shall periodically review such types on such final 

11 list, including whether additional types of combination 

12 products are appropriate for such final list. 


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Calendar No. 414 

114TH CONGRESS 

2D SESSION S. 1767 

A BILL 

To amend the Federal Food, Drug, and Cosmetic 

for other purposes. Act with respect to combination products, and 

APRIL 5, 2016 

Reported with an amendment 


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