,,ii #aadth ,,congress #ast ,session ,s4 #agfg ,,in ,,the ,,senate ,,of ,,the ,,united ,,states ,july #ae1 #bjae,mr4 ,isakson 7for himself1 ,mr4 ,casey1 and ,mr4 ,roberts7 introduced the following bill2 which was read twice and referred to the ,committee on ,health1 ,education1 ,labor1 and ,pensions ,a ,,bill ,to amend the ,federal ,food1 ,drug1 and ,cosmetic ,act with respect to combination products1 and for other purposes4 #a4 ,short title ,this ,act may be cited as the ,combination ,product ,regulatory ,fairness ,act of #bjae4 #b4 ,device definition ,section #bja7;h7 of the ,federal ,food1 ,drug1 and ,cosmetic ,act 7#ba ,u4,s4,c4 #cba7;h77 is amended-- 7#a7 by redesignating subparagraphs 7#a71 7#b71 and 7#c7 as clauses 7,a71 7,b71 and 7,c71 respectively2 7#b7 by striking 7h7 and inserting 7h77#a72 and 7#c7 by adding at the end the following3 7#b7 7,a7 ,before determining that an article does not meet the definition of a device under this paragraph1 the ,secretary shall provide to the sponsor of the article competent and reliable scientific rationale that-- 7i7 cites any scientific evidence relied upon to support the rationale2 and 7ii7 supports such determination4 7,b7 ,if the ,secretary makes a determination described in clause 7,a7-- 7i7 the sponsor of the article may propose a nonclinical or clinical study1 limited to not more data than necessary to establish the significance1 if any1 of the chemical action in achieving the primary intended purpose of the article2 and 7ii7 the ,secretary and the sponsor of the article shall collaborate in good faith to reach agreement1 within a reasonable time not to exceed #ij days1 on the design of such study4 7,c7 ,the data resulting from a study conducted under clause 7,b7 shall inform the classification of the article4 4 #c4 ,combination products ,section #ejc7;g7 of the ,federal ,food1 ,drug1 and ,cosmetic ,act 7#ba ,u4,s4,c4 #cec7;g77 is amended-- 7#a7 by redesignating paragraphs 7#b7 through 7#e7 as paragraphs 7#f7 through 7#i71 respectively2 7#b7 by striking 7g77#a7 and all that follows through the end of paragraph 7#a7 and inserting the following3 7g7 7#a7 7,a7 ,the ,secretary shall1 in accordance with this subsection1 assign an agency center to regulate products that constitute a combination of a drug1 device1 or biological product 7referred to in this subsection as the lead center74 7,b7 ,the ,secretary shall conduct the premarket review of any combination product1 whenever possible1 under a single application using existing premarket review authorities4 7,c7 ,the ,secretary shall determine the primary mode of action of the combination product4 ,if the ,secretary determines that the primary mode of action is that of-- 7i7 a drug 7other than a biological product71 the agency center charged with premarket review of drugs shall have primary jurisdiction2 7ii7 a device1 the agency center charged with premarket review of devices shall have primary jurisdiction2 or 7iii7 a biological product1 the agency center charged with premarket review of biological products shall have primary jurisdiction4 7,d7 ,in determining the primary mode of action of a combination product1 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 body4 7,e7 ,if the ,secretary disagrees with the conclusions of the sponsor on the primary mode of action of the combination product1 the ,secretary shall provide a competent and reliable scientific rationale to the product sponsor that cites any scientific evidence relied upon to support the decision4 7,f7 ,for purposes of this paragraph-- 7i7 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 product2 and 7ii7 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 product4 7#b7 7,a7 ,the sponsor of a combination product may submit a combination product review plan 7referred to in this subsection as a ,,cprp7 for the combination product1 and may request a meeting prior to submission of the ,,cprp1 to establish clarity and certainty for the sponsor regarding the standards and requirements applicable to-- 7i7 the review of safety and effectiveness1 or substantial equivalence1 of the combination product2 7ii7 a postmarket modification of the combination product2 or 7iii7 good manufacturing practices for the combination product4 7,b7 ,not later than #fj days after the sponsor of a combination product submits a proposed ,,cprp1 including a revision to a previously proposed or approved ,,cprp1 the ,secretary shall review the ,,cprp and-- 7i7 if the ,secretary determines that the ,,cprp is appropriate to ensure adequate review of the safety and effectiveness1 or substantial equivalence1 of the combination product-- 7,i7 approve the ,,cprp2 and 7,,ii7 issue to the sponsor a response indicating such approval2 or 7ii7 if the ,secretary finds that the ,,cprp does not meet the standard specified in clause 7i7-- 7,i7 decline to approve the ,,cprp2 and 7,,ii7 issue to the sponsor a response indicating that the ,secretary has declined such approval and specifying any deficiencies in the proposed ,,cprp4 7,c7 7i7 ,in the case of a ,,cprp that the ,secretary declines to approve under subparagraph 7,b77ii71 unless the sponsor submitting such ,,cprp determines a meeting is not necessary1 the ,secretary shall1 not later than #cj days after submitting a response under such subparagraph1 meet with such sponsor to discuss the ,,cprp4 7ii7 ,a meeting under clause 7i7 shall-- 7,i7 include any necessary experts from the relevant agency centers2 and 7,,ii7 coordinate the advice of such experts4 7,d7 ,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 effectiveness1 or substantial equivalence1 of the combination product4 7,e7 ,not later than #cj days after the date on which a meeting is held under subparagraph 7,a77i71 the minutes of such meeting shall be prepared by the sponsor and made available to the ,secretary4 7,f7 ,any agreement that is reached between the ,secretary and a sponsor or applicant through a meeting held under subparagraph 7,a77i7 shall be reduced to writing by the sponsor or applicant1 and1 once approved by the ,secretary1 made part of the administrative record by the ,secretary within #fj days of such meeting4 7,g7 ,an agreement described in subparagraph 7,f7 shall not be changed after approval of the agreement1 except-- 7i7 with the written agreement of the sponsor or applicant2 or 7ii7 pursuant to a decision1 made in accordance with subparagraph 7,h7 by the director of the reviewing division of the lead center1 in consultation with consulting centers and the ,office1 that a substantial scientific issue essential to determining the safety or effectiveness1 or substantial equivalence1 of the combination product has been identified4 7,h7 ,with respect to a decision under subparagraph 7,g77ii71 the ,secretary shall provide notice1 within #b business days of such decision1 to the sponsor of the combination product and an opportunity for a meeting to take place not later than #ad calendar days after issuing such notice1 at which-- 7i7 the director of the reviewing division of the lead center1 staff from the consulting agency centers1 representatives of the ,office1 and the sponsor will be present2 and 7ii7 the director of the reviewing division of the lead center will document the scientific issue involved4 7#c7 ,for purposes of conducting the premarket review of a combination product that contains an approved constituent product described in paragraph 7#d71 the ,secretary may require only that the sponsor of such combination product submit to the ,secretary data or information that-- 7,a7 the ,secretary determines is necessary to assess the specific safety and effectiveness questions and incremental risks posed by the combination product1 using a risk-based approach and taking into account any prior finding of safety and efficacy or substantial equivalence for the approved constituent product2 and 7,b7 is not duplicative of data or information included in an application or other material submitted to the ,secretary in connection with the approved constituent product4 7#d7 ,for purposes of paragraph 7#c71 an approved constituent product is-- 7,a7 a drug constituent part of a combination product being reviewed in a single application under section #eae or #eaj7k71 provided such drug constituent part was previously approved under section #eje and such application complies with subparagraph 7,a7 of paragraph 7#e7 and is subject to subparagraphs 7,d7 and 7,e7 of such paragraph2 7,b7 a device constituent part approved under section #eae that is referenced by the sponsor and which is available for use by the ,secretary under section #ebj7;h77#d72 or 7,c7 any constituent part that was previously approved1 cleared1 or licensed under section #eje1 #eaj7k71 or #eae of this ,act or section #cea of the ,public ,health ,service ,act1 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 ,act4 7#e7 7,a7 ,if an application is submitted under section #eae or #eaj7k7 for a combination product containing as a constituent part an approved drug-- 7i7 the application shall include the certification or statement required pursuant section #eje7;b77#b72 and 7ii7 the applicant shall provide notice as required pursuant to section #eje7;b77#c74 7,b7 ,for purposes of this paragraph1 the term approved drug means a drug-- 7i7 that was previously approved under section #eje2 7ii7 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-- 7,i7 are relied upon by the applicant submitting the application described in subparagraph 7,a72 and 7,,ii7 were not conducted by or for such applicant2 and 7iii7 with respect to which1 the applicant submitting the application described in subparagraph 7,a7 has not obtained a right of reference or use from the person by or for whom the investigations were conducted4 7,c7 ,the following provisions shall apply with respect an application described in subparagraph 7,a73 7i7 ,subparagraphs 7,a71 7,b71 7,c71 and 7,d7 of section #eje7;c77#c74 7ii7 ,clauses 7ii71 7iii71 and 7iv7 of section #eje7;c77#c77;,e74 7iii7 ,paragraphs 7b7 and 7c7 of section #eje;,a4 7iv7 ,section #eje;,e7a74 7v7 ,section #ebg7;a74 7,d7 ,notwithstanding section #ebj7;h77#d77;,a77i71 information contained in an application for premarket approval filed with the ,secretary pursuant to section #eae7;c7 may not be used to approve any application submitted under section #eae or #eaj7k7 for a combination product containing as a constituent part a drug previously approved under section #eje unless-- 7i7 the application includes the certification or statement referenced in subparagraph 7,a72 7ii7 the applicant provides notice as described in subparagraph 7,a72 and 7iii7 the ,secretary's approval of such application is subject to the provisions specified in subparagraph 7,c74 7,e7 ,an application for a combination product described in subparagraph 7,a7 or 7,d7 shall be considered an application submitted under ,section #eje7;b77#b7 solely for purposes of section #bga7;e77#b77;,a7 of the ,patent ,act4 2 7#c7 in paragraph 7#h7 7as redesignated by paragraph 7#a77-- 7,a7 in subparagraph 7,c7-- 7i7 by amending clause 7i7 to read as follows3 7i7 ,in carrying out this subsection1 the ,office shall ensure timely and effective premarket reviews involving more than one agency center by-- 7,i7 overseeing the timeliness and alignment of reviews2 and 7,,ii7 coordinating reviews4 2 7ii7 in clause 7ii71 by inserting and alignment after the timeliness each place it appears2 and 7iii7 by adding at the end the following new clauses3 7iii7 ,the ,office shall ensure that the lead center be the primary point of contact for the sponsor of the product4 ,the ,office shall also coordinate communications to and from any consulting agency center involved in such premarket review4 ,agency communications and commitments1 to the extent consistent with other provisions of law and the requirements of all affected agency centers1 from the lead center shall be binding on all other centers involved in the review4 7iv7 ,the ,office shall1 with respect to the premarket review of a combination product-- 7,i7 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 review1 as appropriate2 7,,ii7 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 #b1 #c1 #g1 and #h1 as applicable1 of subchapter ,c of title ,,vii2 and 7,,iii7 ensure that each consulting agency center complies with the guidance described in clause 7vi7 and other relevant regulations1 guidances1 and policies4 7v7 ,not later than #aj days after the receipt by an agency center of an application under section #eje1 #eaj7k71 or #ebj of this ,act1 or under section #cea of the ,public ,health ,service ,act1 for a combination product or an application for investigational use of a combination product under section #eje7;i7 or #ebj7;g71 the agency center shall inform the ,office of such receipt4 7vi7 ,not later than #b years after the date of enactment of the ,combination ,product ,regulatory ,fairness ,act of #bjae1 the ,secretary shall issue final guidance that describes the responsibilities of each agency center regarding its review of combination products1 including each center's role in evaluating evidence development and review under a risk-based approach1 dispute resolution1 labeling1 product usability assessments1 and human factors testing4 ,the ,office shall1 after soliciting public comment1 review and update the guidance at least biannually and specify in such updated guidance the reasons for updates4 2 7,b7 in subparagraph 7,e7-- 7i7 by striking clause 7i7 and inserting the following new clause3 7i7 ,during the review process1 any dispute regarding the substance1 timeliness1 review process1 requirements1 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 #ij days after the date on which the ,office receives written notice of such conflicts4 2 and 7ii7 in clause 7ii71 by striking ,during the review process1 any dispute regarding the substance of the premarket review and inserting ,any remaining dispute2 7,c7 in subparagraph 7,f71 in the first sentence-- 7i7 by inserting or which involves determining the safety or efficacy of a component of a combination product after assignment of combination products to agency centers2 and 7ii7 by inserting and with the guidance described in subparagraph 7,c77vi74 before the period at the end2 and 7,d7 in subparagraph 7,g7-- 7i7 in clause 7ii71 by striking and at the end2 7ii7 in clause 7iii71 by striking the period at the end and inserting a semicolon2 and 7iii7 by adding at the end the following new clauses3 7iv7 identifying the percentage of combination products for which a dispute resolution1 with respect to premarket review1 was requested by the combination product's sponsor2 and 7v7 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 attendance1 in accordance with subparagraph 7,c77iv77,i74 2 7#d7 in paragraph 7#i7 7as redesignated by paragraph 7#a771 by adding at the end the following3 7,d7 ,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 #eje1 #eaj7k71 #eae1 or #ebj of this ,act or under section #cea of the ,public ,health ,service ,act1 including with respect to investigational use of the product4 2 and 7#e7 by adding at the end the following3 7#aj7 ,rule of construction ,nothing in this subsection shall be construed as prohibiting a sponsor1 at the sponsor's discretion1 from submitting separate applications for the constituent parts of a combination product1 unless the ,secretary determines that a single application is necessary to ensure the safety and effectiveness1 or substantial equivalence1 as applicable1 of the combination product4 4