Product jurisdiction (21 CFR 3.1-3.10)

111 Food and Drug Administration, HHS Pt. 3 (1) If the petition is to add use of a noninvestigational product, the peti tioner must submit compelling evi dence that: (i) Substantial technical barriers exist to formulating the product with out ODSs; (ii) The product will provide an un available important public health ben efit; and (iii) Use of the product does not re lease cumulatively significant amounts of ODSs into the atmosphere or the re lease is warranted in view of the un available important public health ben efit. (2) If the petition is to add use of an investigational product, the petitioner must submit compelling evidence that: (i) Substantial technical barriers exist to formulating the investiga tional product without ODSs; (ii) A high probability exists that the investigational product will provide an unavailable important public health benefit; and (iii) Use of the investigational prod uct does not release cumulatively sig nificant amounts of ODSs into the at mosphere or the release is warranted in view of the high probability of an un available important public health ben efit. (g) Any person may file a petition under part 10 of this chapter to request that FDA initiate rulemaking to amend paragraph (e) of this section to remove an essential use. FDA may ini tiate notice-and-comment rulemaking to remove an essential use on its own initiative or in response to a petition, if granted. If the petition is to remove an essential use from paragraph (e) of this section, the petitioner must sub mit compelling evidence of any one of the following criteria: (1) The product using an ODS is no longer being marketed; or (2) After January 1, 2005, FDA deter mines that the product using an ODS no longer meets the criteria in para graph (f) of this section after consulta tion with a relevant advisory com mittee(s) and after an open public meeting; or (3) For individual active moieties marketed as ODS products and rep resented by one new drug application (NDA): (i) At least one non-ODS product with the same active moiety is mar keted with the same route of adminis tration, for the same indication, and with approximately the same level of convenience of use as the ODS product containing that active moiety; (ii) Supplies and production capacity for the non-ODS product(s) exist or will exist at levels sufficient to meet pa tient need; (iii) Adequate U.S. postmarketing use data is available for the non-ODS product(s); and (iv) Patients who medically required the ODS product are adequately served by the non-ODS product(s) containing that active moiety and other available products; or (4) For individual active moieties marketed as ODS products and rep resented by two or more NDAs: (i) At least two non-ODS products that contain the same active moiety are being marketed with the same route of delivery, for the same indica tion, and with approximately the same level of convenience of use as the ODS products; and (ii) The requirements of paragraphs (g)(3)(ii), (g)(3)(iii), and (g)(3)(iv) of this section are met. [67 FR 48384, July 24, 2002, as amended at 71 FR 70873, Dec. 7, 2006; 70 FR 17192, Apr. 4, 2005; 75 FR 19241, Apr. 14, 2010; 73 FR 69552, Nov. 19, 2008; 75 FR 19241, Apr. 14, 2010] PART 3—PRODUCT JURISDICTION Subpart A—Assignment of Agency Com ponent for Review of Premarket Appli cations Sec. 3.1 Purpose. 3.2 Definitions. 3.3 Scope. 3.4 Designated agency component. 3.5 Procedures for identifying the des ignated agency component. 3.6 Product jurisdiction officer. 3.7 Request for designation. 3.8 Letter of designation. 3.9 Effect of letter of designation. 3.10 Stay of review time. Subpart B [Reserved] AUTHORITY: 21 U.S.C. 321, 351, 353, 355, 360, 360c–360f, 360h–360j, 360gg–360ss, 360bbb–2, 371(a), 379e, 381, 394; 42 U.S.C. 216, 262, 264. VerDate Sep<11>2014 14:18 Apr 18, 2016 Jkt 238070 PO 00000 Frm 00121 Fmt 8010 Sfmt 8010 Q:\21\21V1.TXT 31lp o w e ll o n D S K 5 4 D X V N 1 O F R w ith $ $ JO B 112 21 CFR Ch. I (4–1–16 Edition) § 3.1 SOURCE: 56 FR 58756, Nov. 21, 1991, unless otherwise noted. Subpart A—Assignment of Agen cy Component for Review of Premarket Applications § 3.1 Purpose. This regulation relates to agency management and organization and has two purposes. The first is to implement section 503(g) of the act, as added by section 16 of the Safe Medical Devices Act of 1990 (Public Law 101–629) and amended by section 204 of the Medical Device User Fee and Modernization Act of 2002 (Public Law 107–250), by speci fying how FDA will determine the or ganizational component within FDA designated to have primary jurisdic tion for the premarket review and reg ulation of products that are comprised of any combination of a drug and a de vice; a device and a biological; a bio logical and a drug; or a drug, a device and a biological. This determination will eliminate, in most cases, the need to receive approvals from more than one FDA component for such combina tion products. The second purpose of this regulation is to enhance the effi ciency of agency management and op erations by providing procedures for determining which agency component will have primary jurisdiction for any drug, device, or biological product where such jurisdiction is unclear or in dispute. Nothing in this section pre vents FDA from using any agency re sources it deems necessary to ensure adequate review of the safety and effec tiveness of any product, or the substan tial equivalence of any device to a predicate device. [56 FR 58756, Nov. 21, 1991, as amended at 68 FR 37077, June 23, 2003] § 3.2 Definitions. For the purpose of this part: (a) Act means the Federal Food, Drug, and Cosmetic Act. (b) Agency component means the Cen ter for Biologics Evaluation and Re search, the Center for Devices and Ra diological Health, the Center for Drug Evaluation and Research, or alter native organizational component of the agency. (c) Applicant means any person who submits or plans to submit an applica tion to the Food and Drug Administra tion for premarket review. For pur poses of this section, the terms ‘‘spon sor’’ and ‘‘applicant’’ have the same meaning. (d) Biological product has the meaning given the term in section 351(a) of the Public Health Service Act (42 U.S.C. 262(a)). (e) Combination product includes: (1) A product comprised of two or more regulated components, i.e., drug/ device, biologic/device, drug/biologic, or drug/device/biologic, that are phys ically, chemically, or otherwise com bined or mixed and produced as a single entity; (2) Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug prod ucts; (3) A drug, device, or biological prod uct packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of admin istration, or significant change in dose; or (4) Any investigational drug, device, or biological product packaged sepa rately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect. (f) Device has the meaning given the term in section 201(h) of the act. (g) Drug has the meaning given the term in section 201(g)(1) of the act. (h) FDA means Food and Drug Ad ministration. (i) Letter of designation means the written notice issued by the product jurisdiction officer specifying the agen cy component with primary jurisdic tion for a combination product. VerDate Sep<11>2014 14:18 Apr 18, 2016 Jkt 238070 PO 00000 Frm 00122 Fmt 8010 Sfmt 8010 Q:\21\21V1.TXT 31lp o w e ll o n D S K 5 4 D X V N 1 O F R w ith $ $ JO B 113 Food and Drug Administration, HHS § 3.4 (j) Letter of request means an appli cant’s written submission to the prod uct jurisdiction officer seeking the des ignation of the agency component with primary jurisdiction. (k) Mode of action is the means by which a product achieves an intended therapeutic effect or action. For pur poses of this definition, ‘‘therapeutic’’ action or effect includes any effect or action of the combination product in tended to diagnose, cure, mitigate, treat, or prevent disease, or affect the structure or any function of the body. When making assignments of combina tion products under this part, the agen cy will consider three types of mode of action: The actions provided by a bio logical product, a device, and a drug. Because combination products are comprised of more than one type of regulated article (biological product, device, or drug), and each constituent part contributes a biological product, device, or drug mode of action, com bination products will typically have more than one identifiable mode of ac tion. (1) A constituent part has a biologi cal product mode of action if it acts by means of a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product applica ble to the prevention, treatment, or cure of a disease or condition of human beings, as described in section 351(i) of the Public Health Service Act. (2) A constituent part has a device mode of action if it meets the defini tion of device contained in section 201(h)(1) to (h)(3) of the act, it does not have a biological product mode of ac tion, and it does not achieve its pri mary intended purposes through chem ical action within or on the body of man or other animals and is not de pendent upon being metabolized for the achievement of its primary intended purposes. (3) A constituent part has a drug mode of action if it meets the defini tion of drug contained in section 201(g)(1) of the act and it does not have a biological product or device mode of action. (l) Premarket review includes the ex amination of data and information in an application for premarket review described in sections 505, 510(k), 513(f), 515, or 520(g) or 520(l) of the act or sec tion 351 of the Public Health Service Act of data and information contained in any investigational new drug (IND) application, investigational device ex emption (IDE), new drug application (NDA), biologics license application, device premarket notification, device reclassification petition, and pre market approval application (PMA). (m) Primary mode of action is the sin gle mode of action of a combination product that provides the most impor tant therapeutic action of the com bination product. The most important therapeutic action is the mode of ac tion expected to make the greatest contribution to the overall intended therapeutic effects of the combination product. (n) Product means any article that contains any drug as defined in section 201(g)(1) of the act; any device as de fined in section 201(h) of the act; or any biologic as defined in section 351(a) of the Public Health Service Act (42 U.S.C. 262(a)). (o) Product jurisdiction officer is the person or persons responsible for desig nating the component of FDA with pri mary jurisdiction for the premarket re view and regulation of a combination product or any product requiring a ju risdictional designation under this part. (p) Sponsor means ‘‘applicant’’ (see § 3.2(c)). [56 FR 58756, Nov. 21, 1991, as amended at 64 FR 398, Jan. 5, 1999; 64 FR 56447, Oct. 20, 1999; 68 FR 37077, June 23, 2003; 70 FR 49861, Aug. 25, 2005] § 3.3 Scope. This section applies to: (a) Any combination product, or (b) Any product where the agency component with primary jurisdiction is unclear or in dispute. § 3.4 Designated agency component. (a) To designate the agency compo nent with primary jurisdiction for the premarket review and regulation of a combination product, the agency shall determine the primary mode of action of the product. Where the primary mode of action is that of: VerDate Sep<11>2014 14:18 Apr 18, 2016 Jkt 238070 PO 00000 Frm 00123 Fmt 8010 Sfmt 8010 Q:\21\21V1.TXT 31lp o w e ll o n D S K 5 4 D X V N 1 O F R w ith $ $ JO B 114 21 CFR Ch. I (4–1–16 Edition) § 3.5 (1) A drug (other than a biological product), the agency component charged with premarket review of drugs shall have primary jurisdiction; (2) A device, the agency component charged with premarket review of de vices shall have primary jurisdiction; (3) A biological product, the agency component charged with premarket re view of biological products shall have primary jurisdiction. (b) In some situations, it is not pos sible to determine, with reasonable certainty, which one mode of action will provide a greater contribution than any other mode of action to the overall therapeutic effects of the com bination product. In such a case, the agency will assign the combination product to the agency component that regulates other combination products that present similar questions of safety and effectiveness with regard to the combination product as a whole. When there are no other combination prod ucts that present similar questions of safety and effectiveness with regard to the combination product as a whole, the agency will assign the combination product to the agency component with the most expertise related to the most significant safety and effectiveness questions presented by the combina tion product. (c) The designation of one agency component as having primary jurisdic tion for the premarket review and reg ulation of a combination product does not preclude consultations by that component with other agency compo nents or, in appropriate cases, the re quirement by FDA of separate applica tions. [56 FR 58756, Nov. 21, 1991, as amended at 70 FR 49861, Aug. 25, 2005] § 3.5 Procedures for identifying the designated agency component. (a)(1) The Center for Biologics Eval uation and Research, the Center for Devices and Radiological Health, and the Center for Drug Evaluation and Re search have entered into agreements clarifying product jurisdictional issues. These guidance documents are on dis play in the Division of Dockets Man agement (HFA–305), Food and Drug Ad ministration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852, and are enti tled ‘‘Intercenter Agreement Between the Center for Drug Evaluation and Re search and the Center for Devices and Radiological Health;’’ ‘‘Intercenter Agreement Between the Center for De vices and Radiological Health and the Center for Biologics Evaluation and Research;’’ ‘‘Intercenter Agreement Between the Center for Drug Evalua tion and Research and the Center for Biologics Evaluation and Research.’’ The availability of any amendments to these intercenter agreements will be announced by FEDERAL REGISTER no tice. (2) These guidance documents de scribe the allocation of responsibility for categories of products or specific products. These intercenter agree ments, and any amendments thereto, are nonbinding determinations de signed to provide useful guidance to the public. (3) The sponsor of a premarket appli cation or required investigational fil ing for a combination or other product covered by these guidance documents may contact the designated agency component identified in the inter center agreement before submitting an application of premarket review or to confirm coverage and to discuss the ap plication process. (b) For a combination product not covered by a guidance document or for a product where the agency component with primary jurisdiction is unclear or in dispute, the sponsor of an applica tion for premarket review should fol low the procedures set forth in § 3.7 to request a designation of the agency component with primary jurisdiction before submitting the application. [56 FR 58756, Nov. 21, 1991, as amended at 68 FR 24879, May 9, 2003] § 3.6 Product jurisdiction officer. The Office of Combination Products (Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 32, rm. 5129, Silver Spring, MD 20993–0002, 301–796– 8930,, e-mail: combination@fda.gov, is the designated product jurisdiction of ficer. [68 FR 37077, June 23, 2003, as amended at 71 FR 16033, Mar. 30, 2006; 75 FR 13678, Mar. 23, 2010] VerDate Sep<11>2014 14:18 Apr 18, 2016 Jkt 238070 PO 00000 Frm 00124 Fmt 8010 Sfmt 8010 Q:\21\21V1.TXT 31lp o w e ll o n D S K 5 4 D X V N 1 O F R w ith $ $ JO B 115 Food and Drug Administration, HHS § 3.8 § 3.7 Request for designation. (a) Who should file: the sponsor of: (1) Any combination product the sponsor believes is not covered by an intercenter agreement; or (2) Any product where the agency component with primary jurisdiction is unclear or in dispute. (b) When to file: a sponsor should file a request for designation before filing any application for premarket review, whether an application for marketing approval or a required investigational notice. Sponsors are encouraged to file a request for designation as soon as there is sufficient information for the agency to make a determination. (c) What to file: an original and two copies of the request for designation must be filed. The request for designa tion must not exceed 15 pages, includ ing attachments, and must set forth: (1) The identity of the sponsor, in cluding company name and address, es tablishment registration number, com pany contact person and telephone number. (2) A description of the product, in cluding: (i) Classification, name of the prod uct and all component products, if ap plicable; (ii) Common, generic, or usual name of the product and all component prod ucts; (iii) Proprietary name of the product; (iv) Identification of any component of the product that already has re ceived premarket approval, is mar keted as not being subject to pre market approval, or has received an in vestigational exemption, the identity of the sponsors, and the status of any discussions or agreements between the sponsors regarding the use of this prod uct as a component of a new combina tion product. (v) Chemical, physical, or biological composition; (vi) Status and brief reports of the re sults of developmental work, including animal testing; (vii) Description of the manufac turing processes, including the sources of all components; (viii) Proposed use or indications; (ix) Description of all known modes of action, the sponsor’s identification of the single mode of action that pro vides the most important therapeutic action of the product, and the basis for that determination. (x) Schedule and duration of use; (xi) Dose and route of administration of drug or biologic; (xii) Description of related products, including the regulatory status of those related products; and (xiii) Any other relevant informa tion. (3) The sponsor’s recommendation as to which agency component should have primary jurisdiction based on the mode of action that provides the most important therapeutic action of the combination product. If the sponsor cannot determine with reasonable cer tainty which mode of action provides the most important therapeutic action of the combination product, the spon sor’s recommendation must be based on the assignment algorithm set forth in § 3.4(b) and an assessment of the as signment of other combination prod ucts the sponsor wishes FDA to con sider during the assignment of its com bination product. (d) Where to file: all communications pursuant to this subpart shall be ad dressed to the attention of the product jurisdiction officer. Such a request, in its mailing cover should be plainly marked ‘‘Request for Designation.’’ Concurrent submissions of electronic copies of Requests for Designation may be addressed to combination@fda.gov. [56 FR 58756, Nov. 21, 1991, as amended at 68 FR 37077, June 23, 2003; 70 FR 49861, Aug. 25, 2005] § 3.8 Letter of designation. (a) Each request for designation will be reviewed for completeness within 5 working days of receipt. Any request for designation determined to be in complete will be returned to the appli cant with a request for the missing in formation. The sponsor of an accepted request for designation will be notified of the filing date. (b) Within 60 days of the filing date of a request for designation, the product jurisdiction officer will issue a letter of designation to the sponsor, with copies to the centers, specifying the agency component designated to have primary jurisdiction for the premarket review and regulation of the product at issue, VerDate Sep<11>2014 14:18 Apr 18, 2016 Jkt 238070 PO 00000 Frm 00125 Fmt 8010 Sfmt 8010 Q:\21\21V1.TXT 31lp o w e ll o n D S K 5 4 D X V N 1 O F R w ith $ $ JO B 116 21 CFR Ch. I (4–1–16 Edition) § 3.9 and any consulting agency compo nents. The product jurisdiction officer may request a meeting with the spon sor during the review period to discuss the request for designation. If the prod uct jurisdiction officer has not issued a letter of designation within 60 days of the filing date of a request for designa tion, the sponsor’s recommendation of the center with primary jurisdiction, in accordance with § 3.7(c)(3), shall be come the designated agency compo nent. (c) Request for reconsideration by sponsor: If the sponsor disagrees with the designation, it may request the product jurisdiction officer to recon sider the decision by filing, within 15 days of receipt of the letter of designa tion, a written request for reconsider ation not exceeding 5 pages. No new in formation may be included in a request for reconsideration. The product juris diction officer shall review and act on the request in writing within 15 days of its receipt. § 3.9 Effect of letter of designation. (a) The letter of designation con stitutes an agency determination that is subject to change only as provided in paragraph (b) of this section. (b) The product jurisdiction officer may change the designated agency component with the written consent of the sponsor, or without its consent to protect the public health or for other compelling reasons. A sponsor shall be given 30 days written notice of any pro posed nonconsensual change in des ignated agency component. The spon sor may request an additional 30 days to submit written objections, not to ex ceed 15 pages, to the proposed change, and shall be granted, upon request, a timely meeting with the product juris diction officer and appropriate center officials. Within 30 days of receipt of the sponsor’s written objections, the product jurisdiction officer shall issue to the sponsor, with copies to appro priate center officials, a written deter mination setting forth a statement of reasons for the proposed change in des ignated agency component. A non consensual change in the designated agency component requires the concur rence of the Principal Associate Com missioner. [56 FR 58756, Nov. 21, 1991, as amended at 68 FR 37077, June 23, 2003] § 3.10 Stay of review time. Any filing with or review by the product jurisdiction officer stays the review clock or other established time periods for agency action for an appli cation for marketing approval or re quired investigational notice during the pendency of the review by the prod uct jurisdiction officer. Subpart B [Reserved] PART 4—REGULATION OF COMBINATION PRODUCTS Subpart A—Current Good Manufacturing Practice Requirements for Combina tion Products Sec. 4.1 What is the scope of this subpart? 4.2 How does FDA define key terms and phrases in this subpart? 4.3 What current good manufacturing prac tice requirements apply to my combina tion product? 4.4 How can I comply with these current good manufacturing practice require ments for a co-packaged or single-entity combination product? Subpart B [Reserved] AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360b–360f, 360h–360j, 360l, 360hh–360ss, 360aaa–360bbb, 371(a), 372–374, 379e, 381, 383, 394; 42 U.S.C. 216, 262, 263a, 264, 271. SOURCE: 78 FR 4321, Jan. 22, 2013, unless otherwise noted. Subpart A—Current Good Manu facturing Practice Require ments for Combination Prod ucts § 4.1 What is the scope of this subpart? This subpart applies to combination products. It establishes which current good manufacturing practice require ments apply to these products. This subpart clarifies the application of cur rent good manufacturing practice regu lations to combination products, and provides a regulatory framework for VerDate Sep<11>2014 14:18 Apr 18, 2016 Jkt 238070 PO 00000 Frm 00126 Fmt 8010 Sfmt 8010 Q:\21\21V1.TXT 31lp o w e ll o n D S K 5 4 D X V N 1 O F R w ith $ $ JO B