Guidance for Industry and FDA Staff: 
Submissions for Postapproval Modifications 
to a Combination Product Approved Under a 
BLA, NDA, or PMA 
 
 
DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 90 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit written comments to the Division of Dockets Management (HFA-305), Food 
and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, MD  20852.  Submit 
electronic comments to http://www.regulations.gov.  All comments should be identified with the 
docket number listed in the notice of availability that publishes in the Federal Register. 
Additional copies are available from: 
Office of Combination Products  
Food and Drug Administration  
WO32, Hub/Mail Room #5129  
10903 New Hampshire Avenue 
Silver Spring, MD 20993 
(Tel) 301-796-8930 
 (Fax) 301-847-8619 
http://www.fda.gov/CombinationProducts/default.htm. 
For questions regarding this draft document contact the Office of Combination Products, Office 
of Special Medical Programs in the Office of the Commissioner, Dr. Patricia Love, 301-796-
8933 or combination@fda.gov. 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Office of Combination Products 
 Office of Special Medical Programs 
Office of the Commissioner 
 
January 2013 
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
Guidance for Industry and FDA Staff: 
Submissions for Postapproval Modifications 
to a Combination Product Approved Under a 
BLA, NDA, or PMA 
 
Additional Copies are available from: 
Food and Drug Administration  
WO32, Hub/Mail Room #5129  
10903 New Hampshire Avenue 
Silver Spring, MD 20993 
(Tel) 301-796-8930 
 (Fax) 301-847-8619 
http://www.fda.gov/oc/combination 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Office of Combination Products 
Office of Special Medical Programs 
 Office of the Commissioner 
 
 January 2013 
  ii Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
 
I.  INTRODUCTION.............................................................................................................1 
II.  BACKGROUND...............................................................................................................2 
III.  WHAT TYPE OF SUBMISSION TO PROVIDE WHEN MAKING A CHANGE 
TO AN APPROVED COMBINATION PRODUCT?...................................................3 
IV.  ILLUSTRATIONS BY TYPE OF CHANGE BEING MADE.....................................8 
V.  HOW CAN I DISCUSS MY OPTIONS WITH FDA?................................................10 
VI.  WHERE CAN I OBTAIN ADDITIONAL INFORMATION?..................................11 
  iii 1
Guidance for Industry and FDA Staff:  
1 
Submissions for Postapproval Modifications to a 
2 
Combination Product Approved Under a BLA, NDA, or PMA 
3 
(Draft) 
4 
5   
6  This draft guidance, when finalized, will represent the Food and Drug Administrations (FDAs) 
7  current thinking on this topic.  It does not create or confer any rights for or on any person and 
8  does not operate to bind FDA or the public.  You can use an alternative approach if the approach 
9  satisfies the requirements of the applicable statutes and regulations.  If you want to discuss an 
10  alternative approach, contact the FDA staff responsible for implementing this guidance.  If you 
11  cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of 
12  this guidance.  
13   
14   
15  I.  INTRODUCTION  
16  This document provides guidance to industry and FDA staff on the underlying principles 
17  to determine the type of marketing submission that may be required for postapproval 
18  changes to a combination product, as defined in 21 CFR 3.2(e), that is approved under 
19  one marketing application, i.e., a biologics license application (BLA), a new drug 
20  application (NDA), or a device premarket approval application (PMA).   
21  This guidance supplements existing guidance documents developed by the Center for 
22  Biologics Evaluation and Research (CBER), the Center for Devices and Radiological 
23  Health (CDRH), the Center for Drug Evaluation and Research (CDER), and the Office of 
24  Combination Products (OCP).   
25  This guidance does not address changes to combination products that are not approved 
26  under a BLA, NDA or PMA (e.g., those cleared solely under a device premarket 
27  notification submission2 or those marketed under an over-the-counter drug monograph3).  
28  Nor does this guidance address changes to combination products that were approved 
29  under more than one marketing application.  Further, while this guidance does address 
30  the type of submission to provide when making a change to a constituent part of a 
31  combination product approved under one marketing application, it does not address the 
32  scientific or technical content to provide in any such submission.   
33  FDAs guidance documents, including this guidance, do not establish legally enforceable 
34  responsibilities.  Instead, guidances describe the Agencys current thinking on a topic and 
35  should be viewed only as recommendations, unless specific regulatory or statutory 
                                                 
1 This guidance has been prepared by the Office of Combination Products (OCP) in the Office of Special 
Medical Programs, Office of the Commissioner, in cooperation with the Center for Biologics Evaluation 
and Research (CBER), the Center for Drug Evaluation and Research (CDER), and the Center for Devices 
and Radiological Health (CDRH) at the Food and Drug Administration.  
2 Device premarket notification submissions are also referred to as 510(k) submissions. 
3 See 21 CFR Part 330. 
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
36  requirements are cited.  The use of the word should in Agency guidances means that 
37  something is suggested or recommended, but not required.  
38   
39   
40  II.  BACKGROUND 
41   
42  As defined in 21 CFR 3.2(e), a combination product is a product comprised of any 
43  combination of a drug and a device; a biological product and a device; a drug and a 
44  biological product; or a drug, device, and a biological product.4  Under Section 503(g)(1) 
45  of the Federal Food, Drug, and Cosmetic Act (FD&C Act), a combination product is 
46  assigned to a center (CBER, CDER, or CDRH) with primary jurisdiction (the lead center) 
47  for premarket review and postmarket regulation.  The lead center assignment is based on 
48  a determination of the primary mode of action (PMOA) of the combination product or 
49  other defined regulatory criteria when the PMOA cannot be determined with reasonable 
50  certainty.5  Regardless of center assignment, in most instances FDA may regulate the 
51  entire combination product under one type of marketing application (e.g., one BLA, 
52  NDA, or PMA).6  This one application would include all necessary information to 
53  support the approval of the combination product as a whole, including each of its 
54  constituent parts (drug, device, and/or biological product).7   
55   
56  For a combination product that is approved under one application, there may be 
57  uncertainty on the part of the application holder in determining the appropriate regulatory 
58  pathway for submitting a postmarket submission for a change to a constituent part or to 
59  the combination product as a whole.8  The FD&C Act,9 the Public Health Service Act 
60  (PHS Act),10 and FDAs associated regulations11 contain provisions describing when a 
                                                 
4 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 physically, chemically, or 
otherwise combined 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 products; (3) A drug, device, or biological product 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 
administration, or significant change in dose; or (4) Any investigational drug, device, or biological product 
packaged separately 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.  21 CFR 3.2(e). 
5 21 CFR 3.2(m) and 3.4(a), (b).  See also Final Rule for Definition of Primary Mode of Action of a 
Combination Product, published August 25, 2005, 70 Fed. Reg. 49848, accessible at 
http://www.fda.gov/OHRMS/DOCKETS/98fr/05-16527.pdf.  
6 In some instances FDA may require two or more marketing applications for a combination product.  21 
CFR 3.4(c).  Further, as appropriate, FDA may accept two marketing applications upon request by the 
applicant(s).  
7 See Section 503(g)(2) of the FD&C Act. 
8 For purposes of this document, changes to the combination product are assumed to not affect the primary 
mode of action, the lead center assignment or the underlying type of marketing application for the 
combination product.   
9 Sections 505, 506A, and 515(d) of the FD&C Act. 
10 Section 351 of the PHS Act. 
  2 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
61  postmarket submission is required for a change to an approved, stand-alone12 drug, 
62  device, or biological product or its manufacturing process.13  As a general matter, these 
63  provisions set forth similar criteria for determining when a postapproval submission is 
64  required; e.g., a prior approval submission is generally required for a product change that 
65  could affect safety or effectiveness.14  These provisions do not, however, expressly 
66  address the criteria for when, how, and what type of submission to submit for a change to 
67  a constituent part of an approved combination product.  The intent of this guidance 
68  document is to provide clarity in the postapproval change requirements and consistency 
69  in the type of postmarket submission to provide for a change to a combination product 
70  approved under one application (BLA, NDA, or PMA), regardless of which agency 
71  center has lead jurisdiction for the combination product. 
72    
73   
74  III.  WHAT TYPE OF SUBMISSION TO PROVIDE WHEN MAKING A 
75  CHANGE TO AN APPROVED COMBINATION PRODUCT?  
76   
77  As stated above, a combination product is comprised of different constituent parts.  These 
78  constituent parts retain their regulatory identity as a drug, device or biological product. 
79  Therefore, if a change is made to any constituent part of the combination product that 
80  would have required a postmarket submission to FDA if the constituent part were a stand-
81  alone product, then a postmarket submission is required for the combination product.  In 
82  addition, a postmarket submission would also be required for the combination product if 
83  a change to any of the constituent parts would otherwise trigger the requirements 
84  associated with the application type used for approval of the combination product.  In 
85  cases where the regulatory identity of the constituent part differs from the approved 
86  application type for the combination product, and a change is made that would require a 
87  postmarket submission to FDA, the requirement for submitting information about the 
88  change to the agency is generally satisfied with one postmarket submission to the original 
89  application.  The type of submission to provide for the change will depend on the type of 
90  application used to obtain approval of the combination product.  For example, a change to 
91  the device constituent part of a combination product approved under an NDA should be 
92  reflected in the appropriate postmarket NDA submission and be submitted to that NDA.  
93  In some cases, it may be easier to first identify the type of submission typically associated 
94  with the constituent part before determining what type of submission is required to the 
95  original application that was used for approval of the combination product.  To aid in this 
96  determination, tables are provided in this document to generally align the corresponding 
97  postmarket submissions for changes to a constituent part of a combination product 
98  approved under a BLA, NDA, or PMA. 
99   
                                                                                                                                                 
11 21 CFR 314.70, 601.12, and 814.39. 
12 For purposes of this document, the term stand-alone refers to an individual drug, device, or biological 
product that is not part of a combination product. 
13 The types of submissions describing a change to an approved product include, but are not limited to, a 
new original application, a prior approval supplement, a changes being effected supplement, and an annual 
or periodic report. 
14 For purposes of this document, the term change or modification is used interchangeably to apply to a 
postapproval or postmarket change to an approved application or approved product. 
  3 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
100  The following steps outline the process for determining which type of submission to 
101  provide for a postmarket change to a constituent part of a combination product approved 
102  under a BLA, NDA, or PMA.  
103   
104  1.  Identify the type of premarket application used to obtain approval of the 
105  combination product (NDA, BLA, or PMA). 
106   
107  2.  Identify the type of postapproval submission that ordinarily would have been 
108  submitted for the modification(s), if the constituent part(s) were marketed as a 
109  stand-alone product.  For a device constituent part, apply the appropriate device 
110  criteria in determining what type of submission to FDA would ordinarily have 
111  been submitted because of a change to the device constituent part.15  For a 
112  biological product or drug constituent part, apply the appropriate biological 
113  product and drug criteria, respectively.   
114   
115  3.  If the original application type used for approval of the combination product (step 
116  1 above) is the same as that customarily used for the constituent part being 
117  changed, then submit the postapproval submission identified in step 2.  If not, 
118  then proceed to step 4. 
119   
120  4.  Use the tables below as guidance in determining the appropriate postapproval 
121  change submission type for the combination product.  The tables correlate the 
122  submission type typically used for the changed constituent part as identified in 
123  step 2 with the appropriate submission type for the combination product based on 
124  the original application under which the combination product was approved. 
125   
126  Table 1, page 6 identifies the types of NDA or BLA submissions to submit when making 
127  a change to a device constituent part of a combination product approved under an NDA 
128  or BLA.  Column 1 identifies the type of PMA submission that would customarily be 
129  submitted for a change in the device constituent part if it were a stand-alone device 
130  approved under a PMA.16  Column 2 identifies the types of NDA or BLA submissions to 
131  submit for the change in the device constituent part of the combination product.17 
132   
133  Table 2, page 7 identifies the types of PMA submissions to submit when making a 
134  change to a biological product/drug constituent part of a combination product approved 
135  under a PMA.  Column 1 provides information on both BLA and NDA submissions.  
136  Specifically, it identifies the types of NDA submissions that would customarily be 
                                                 
15 For example, if the stent material of a PMA-approved drug eluting stent is changed, determine whether 
such a change would require a real-time PMA supplement, a 180-day PMA supplement, a panel-track PMA 
supplement, or an original PMA. 
16 See sections 515 and 737 of the FD&C Act, 21 CFR 814.39, and FDA Guidance for Modifications to 
Devices Subject to Premarket Approval (PMA) - The PMA Supplement Decision-Making Process (2008), at 
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UC
M089360.pdf). 
17 This document does not address combination products approved with an ANDA under Section 505(j) of 
the FD&C Act. For such products, applicants should consider whether a postmarket change to a device 
constituent part would be permissible under the ANDA.   
  4 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
137  submitted for a change if the drug constituent part were a stand-alone drug approved 
138  under an NDA.18  It also identifies the types of BLA submissions that would customarily 
139  be submitted for a change to the biological product constituent part if it were a stand-
140  alone biological product licensed under a BLA.19  Column 2 identifies the types of PMA 
141  submissions to submit when the change is in the biological product/drug constituent part 
142  of a combination product approved under a PMA.   
143   
144  To use these tables, first refer to relevant provisions in the FD&C Act, FDA regulations, 
145  and FDA guidance on the type of postmarket change being made to the constituent part to 
146  help you determine the type of submission ordinarily required for such a change.  For a 
147  list of potentially applicable guidance documents, see Section VI of this document.  You 
148  can then use the tables to identify the type of corresponding submission to provide for the 
149  combination product. 
150   
151   
152   
153   
154  (Continue to next page)
                                                 
18 See FD&C Act Section 505, 21 CFR 314.70, and FDA Guidance for Changes to an Approved NDA or 
ANDA (2004), at http://www.fda.gov/downloads/Drugs/ 
GuidanceComplianceRegulatoryInformation/Guidances/ucm077097.pdf).  Also, see FDA Guidance for 
Contents of a Complete Submission for the Evaluation of Proprietary Names (2010), at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM07506
8.pdf. 
19 See 21 CFR 601.12 and FDA Guidance for Changes to an Approved Application: Biological Products 
(1997), at http://www.fda.gov/downloads/BiologicsBloodVaccines/ 
GuidanceComplianceRegulatoryInformation/Guidances/Blood/UCM170166.pdf. 
  5 Contains Nonbinding Recommendations 
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155   
Table 1: Type of NDA/BLA Submission for a Change in a Device Constituent Part of a  
Combination Product Approved under an NDA/BLA 
If the Device Constituent Part Were a   Then Submit Information on the Device 
Stand-Alone Device Approved under a PMA  Change Using This Type of NDA/BLA* 
and the Change Would Have Required the  Submission for the Combination 
Following Submission  Product 
PMA Original   NDA/BLA Original 
PMA Panel-Track Supplement    Prior Approval Supplement (Efficacy)  
(New indication/population, without any other 
change to the constituent parts, supported by new 
clinical data and the original preclinical data) 
PMA 180-day  Design change and labeling  Prior Approval Supplement (Efficacy)  
Supplement   change supported by new 
      preclinical and/or limited 
  Design   confirmatory clinical data 
  Manufacturing  Changes supported by limited  Prior Approval Supplement 
site change  confirmatory data (i.e., clinical  (Manufacturing) 
  Labeling  bioequivalence or   
change  bioavailability data)  (With or without labeling changes) 
including  Manufacturing site change not 
nomenclature  requiring any clinical data 
 
(And with a  Significant labeling change  Prior Approval Supplement (Labeling)  
change from the  that does not qualify for a   
next column)  Special PMA Supplement - 
Changes Being Effected, does 
not change the indication, and 
does not include a design 
change 
PMA Real-Time Supplement   Prior Approval Supplement 
(Design or labeling change that does not require  (Manufacturing or Labeling) 
clinical data and for which the data provided fall 
within only one scientific discipline, e.g., electrical 
engineering, microbiology, or sterilization) 
30-day Notice (Manufacturing process or method  30-day Changes Being Effected 
change only) 
Special PMA Supplement - Changes Being  Changes Being Effected 
Effected 
PMA Periodic Report  Annual Report 
*Time lines and FDA-industry interactive procedures will be those of the NDA/BLA 
156   
  6 Contains Nonbinding Recommendations 
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Table 2: Type of PMA Submission for a Change in a Biological Product/Drug 
Constituent Part of a Combination Product Approved under a PMA 
If the Biological Product/Drug Constituent Part  Then Submit Information on the 
Were a Stand-Alone Biological Product/Drug  Biological Product/Drug Change 
Approved under a BLA/NDA and the Change  Using This Type of PMA* 
Would Have Required the Following Submission Submission for the Combination 
Product 
BLA Original; NDA Original (Section 505(b)(1) or  PMA Original  
(b)(2)) (New biological product, new drug, or new   
formulation with new clinical data and new 
preclinical data)  
New indication/population, without  Panel-Track Supplement  
 
al  any other change to the constituent 
ovnt y   parts, supported by new clinical data 
prmeac
Apeic  and the original preclinical data 
lf
 pf Same indication with manufacturing  180-day Supplement  
orpE
PriSu change in drug/biological product 
requiring clinical data 
Drug/biological product  180-day Supplement 
manufacturing change requiring only 
roval nt  uring  bcliioneiqcuali vdaaltean ce or bioavailability 
pet Drug/biological product  180-day Supplement or Real-Time 
pmc
Aefa manufacturing and related labeling  Supplement 
rior upplManu change that does not require any type  (depending on amount and 
PS of clinical or preclinical (animal) data  complexity of data) 
Prior Approval Supplement  Labeling   180-day Supplement or  Real-Time 
(When the labeling change does not rely on a  Supplement 
clinical trial and is not related to a manufacturing  (depending on amount and 
change)   complexity of data) 
30-day Changes Being Effected (Manufacturing  PMA 30-day Notice  
process or method change only) 
Changes Being Effected (Manufacturing or  Special PMA Supplement - Changes 
Labeling)  Being Effected 
 
Annual Report  PMA Periodic Report 
*Time lines and FDA-industry interactive procedures will be those of the PMA 
157   
  7 Contains Nonbinding Recommendations 
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158  IV.  ILLUSTRATIONS BY TYPE OF CHANGE BEING MADE 
159   
160  This section provides examples of some of the more significant changes that may be 
161  made to constituent parts of a combination product (i.e., changes that may require prior 
162  approval from FDA).  The types of submissions that such changes may require, 
163  depending upon the submission type used to obtain approval of the combination product, 
164  are identified.  These recommendations are based on relevant statutory and regulatory 
165  provisions as well as relevant CDER, CDRH, and CBER guidance documents (see 
166  Section VI of this document). 
167   
168  1.  Certain changes in the combination product device constituent part (e.g., 
169  those that result in a combination product new indication for use, new 
170  clinical effects, or in a modified analyte and indication/patient population 
171  for an in vitro diagnostic) customarily require new preclinical and clinical 
172  data to provide support for safety and effectiveness.20  Generally, for any 
173  such changes that do not affect the primary mode of action, select the 
174  submission type to match the application type used to obtain approval of 
175  the combination product: 
176   
177  a.  PMA Original21   
178  b.  NDA Original22   
179  c.  BLA Original  
180   
181  2.  Changes in the drug constituent part substance, drug constituent part 
182  production process, quality controls, equipment, or facilities that affect 
183  controlled release or drug particle size or have a substantial potential to 
184  have an adverse effect on the identity, strength, quality, purity, or potency 
185  of the drug constituent part.23  Such changes include those that may affect 
186  the sterility assurance of the drug constituent part, such as process changes 
187  for sterile drug substances and sterile packaging components.24  Generally, 
188  for any such change, select the submission type to match the application 
189  type used to obtain approval of the combination product: 
190   
191  a.  NDA Prior Approval Supplement  
                                                 
20 In some instances the change in the device constituent part may result in a new combination product.   
21 Ordinarily, changes to a device that require new preclinical and clinical data are submitted in an original 
PMA as explained in FDA guidance.  FDA Guidance, Modifications to Devices Subject to Premarket 
Approval (PMA) - The PMA Supplement Decision-Making Process (2008) (see Section IV.A), at 
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UC
M089360.pdf. 
22 For more information on the type of original NDA submissions, you may wish to refer to the FDA Draft 
Guidance, Applications Covered by Section 505(b)(2), at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079345.
pdf.  
23 21 CFR 314.70(b). 
24 FDA Guidance, Changes to an Approved NDA or ANDA (2004) (see Section VII.B), at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm077097.
pdf. 
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192  b.  BLA Prior Approval Supplement  
193  c.  PMA 180-day Supplement 
194   
195  3.  Modified chemical formulation of the device constituent part (not a 
196  chemical that would be considered a drug constituent part of the 
197  combination product), hardware or software modification of the device 
198  constituent part, or other design modification to the device constituent part 
199  (without also changing the indication or patient population) for which only 
200  new preclinical testing and/or limited confirmatory clinical data are 
201  necessary to demonstrate reasonable assurance of safety and effectiveness 
202  of the modified device constituent part.25  Generally, for any such change, 
203  select the submission type to match the application type used to obtain 
204  approval for the combination product:  
205   
206  a.  PMA 180-day Supplement  
207  b.  BLA Prior Approval Supplement   
208  c.  NDA Prior Approval Supplement 
209   
210  4.  Changes in the biological product constituent part, production process, 
211  quality controls, equipment, facilities, or responsible personnel that have a 
212  substantial potential to have an adverse effect on the identity, strength, 
213  quality, purity, or potency of the product.26  Generally, for any such 
214  change, select the submission type to match the application type used to 
215  obtain approval for the combination product:  
216   
217  a.  BLA Prior Approval Supplement 
218  b.  NDA Prior Approval Supplement 
219  c.  PMA 180-day Supplement 
220   
221  5.  Changes in indication or in patient population (without any other change 
222  to the combination product itself or to any constituent part, except for 
223  relevant changes to the labeling) that require substantial clinical data to 
224  provide reasonable assurance of safety and effectiveness for the change 
225  but either no or very limited new preclinical testing.  Generally, for any 
226  such change, select the submission type to match the application type used 
227  to obtain approval for the combination product: 
228   
229  a.  PMA Panel-Track27  
                                                 
25 See Section 737(4)(C) of the FD&C Act and 21 CFR 814.39(a)(6); see also FDA Guidance, 
Modifications to Devices Subject to Premarket Approval (PMA) - The PMA Supplement Decision-Making 
Process (2008) (see Section IV.C), at 
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UC
M089360.pdf. 
26 21 CFR 601.12(b). 
27 See Section 737(4)(B) of the FD&C Act and 21 CFR 814.39(a)(1); see also FDA Guidance, 
Modifications to Devices Subject to Premarket Approval (PMA) - The PMA Supplement Decision-Making 
Process (2008) (see Section IV.B), at 
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230  b.  NDA Prior Approval Supplement 
231  c.  BLA Prior Approval Supplement 
232   
233  The preceding tables and illustrations provide correlations between NDA, BLA, and 
234  PMA submissions for a change to a single constituent part of a combination product 
235  approved under a single application.  When changes are made to multiple constituent 
236  parts, the recommendations in Section III, above, still apply for each change.  If the 
237  applicable submission requirements for each change do not match (e.g., one change 
238  requires a prior approval supplement and another requires a changes being effected 
239  supplement), then the type of submission should be that associated with the most 
240  significant change being submitted.  For example, a manufacturer of a drug eluting stent 
241  approved under a PMA would like to modify the design of the stent and delete a test for 
242  the drug to comply with an official compendium that is consistent with FDA statutory 
243  and regulatory requirements.  In isolation, the change in the design of the stent would 
244  generally require the submission of a PMA 180-day supplement, whereas the change in 
245  the test to comply with an official compendium for the drug would generally be 
246  submitted in an NDA Changes Being Effected-30 day supplement.  In this case, when 
247  submitted together, the manufacturer should submit the PMA 180-day supplement for 
248  both changes.  
249   
250  FDA cautions that this document provides information only on the type of submission 
251  that should be made by the application holder when making a change to a constituent part 
252  of a combination product approved under a BLA, NDA, or PMA.  It does not address the 
253  type and amount of information to include in each submission.  Finally, FDA reminds 
254  industry that the recommendations in this guidance document do not affect other 
255  requirements that may apply to the application type used to obtain approval of a 
256  particular combination product.   
257   
258   
259  V.  HOW CAN I DISCUSS MY OPTIONS WITH FDA? 
260   
261  FDA recognizes that this guidance provides general recommendations and that the tables 
262  provided above are intended as useful tools, but may not provide the applicable 
263  correlation in all cases.  There may be added complexity based on certain types of 
264  combination products.  Further, FDA recognizes that it may not be possible to isolate the 
265  change of one constituent part from another constituent part (e.g., those meeting the 
266  definition in 21 CFR 3.2(e)(1) or if one constituent part activates or changes the other 
267  constituent part).  FDA encourages applicants to anticipate the type of postapproval 
268  changes that they wish to make and to develop protocols to help establish comparability 
269  of the modifications in methodology or products to the original approved combination 
270  product.  Further, FDA encourages industry to discuss with FDA the type of information 
271  that may be necessary to address the change to the constituent part, including whether 
272  and how this change may affect the other constituent part(s) and the combination product 
                                                                                                                                                 
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UC
M089360.pdf.  
  10 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
273  as a whole; and any alternative approaches for submission types the applicant may 
274  propose.   
275   
276  To discuss possible postmarket changes to combination products, as well as the type of 
277  information and type of submission to provide to FDA, applicants should request a 
278  meeting with the intercenter review team.  The meeting request should be sent to the lead 
279  center that approved the original application, with a cover letter requesting inclusion of 
280  representatives from the consulting center(s).  OCP may attend such a meeting as well.  
281  The meeting request should include background material to support any proposed 
282  approach.   
283   
284   
285  VI.  WHERE CAN I OBTAIN ADDITIONAL INFORMATION? 
286   
287  OCP is available as a resource to industry and FDA review staff throughout the lifecycle 
288  (assignment, development, premarket review and postmarket regulation) of a 
289  combination product.  OCP can be reached at (301) 427-1934 or by email at 
290  combination@fda.gov.  In addition, OCP maintains an updated list of FDA guidance 
291  documents that industry may find helpful in the development of their products.  The list is 
292  available at OCPs Internet Website at 
293  http://www.fda.gov/CombinationProducts/default.htm.  Each center also maintains a 
294  webpage for guidance documents and information on the types of submissions addressed 
295  in this guidance document.   
296   
297  In considering possible changes to constituent parts and their potential to affect the safety 
298  and effectiveness of the approved combination product, the following FDA webpages 
299  may be useful.  These webpages include information on requesting meetings with FDA:   
300   
301    BLA Therapeutic Biologic Applications; 
302  http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelope
303  dandApproved/ApprovalApplications/TherapeuticBiologicApplications/default.ht
304  m 
305   
306    NDA webpage; 
307  http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelope
308  dandApproved/ApprovalApplications/NewDrugApplicationNDA/default.htm 
309   
310    PMA webpage;  
311  http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarke
312  tYourDevice/PremarketSubmissions/PremarketApprovalPMA/default.htm  
313   
314    BLA webpage; 
315  http://www.fda.gov/BiologicsBloodVaccines/DevelopmentApprovalProcess/Biol
316  ogicsLicenseApplicationsBLAProcess/default.htm 
317   
  11 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
318    Drug and Therapeutic Biologic Labeling website; 
319  http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/LawsActs
320  andRules/ucm084159.htm 
321   
322    PDUFA reauthorization performance Goals and Procedures Fiscal Years 2012 
323  through 2017; 
324  http://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/U
325  CM270412.pdf 
326   
327    FDA and Industry Actions on Premarket Approval Applications (PMAs): Effect 
328  on FDA Review Clock and Goals, October 15, 2012;  
329  http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDo
330  cuments/ucm089733.htm 
331   
332  In addition, the following FDA guidance documents, which focus on postmarket 
333  modifications to regulated articles, may help applicants in assessing which type of 
334  postapproval submission is typically required for various types of changes and may be 
335  helpful when applying Tables 1 and 2 of this document: 
336      
337    Changes to an Approved Application: Biological Products; 
338  http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRe
339  gulatoryInformation/Guidances/Blood/UCM170166.pdf 
340   
341    Modifications to Devices Subject to Premarket Approval (PMA) - The PMA 
342  Supplement Decision-Making Process (2008);  
343  http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/G
344  uidanceDocuments/UCM089360.pdf 
345   
346    Real-Time Premarket Approval Application (PMA) Supplements (2006); 
347  http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/G
348  uidanceDocuments/ucm089612.pdf 
349   
350    30-day Notices, 135-Day Premarket Approval (PMA) Supplements and 75-Day 
351  Humanitarian Device Exemption (HDE) Supplements for Manufacturing Method 
352  or Process Changes (2011); 
353  http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/G
354  uidanceDocuments/UCM080194.pdf 
355   
356    Changes to an Approved NDA or ANDA (2004); 
357  http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio
358  n/Guidances/ucm077097.pdf 
359   
360    Changes to an Approved Application: Biological Products: Human Blood and 
361  Blood Components Intended for Transfusion or for Further Manufacture (2001); 
362  http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInf
363  ormation/Guidances/Blood/ucm076729.htm 
  12 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
364   
365    Demonstration of Comparability of Human Biological Products, Including 
366  Therapeutic Biotechnology-derived Products (1996); 
367  http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
368  s/ucm122879.htm 
369   
370    Changes to an Approved Application for Specified Biotechnology and Specified 
371  Synthetic Biological Products (1997); 
372  http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio
373  n/Guidances/UCM124805.pdf 
374   
375    Q10 Pharmaceutical Quality System (2009); 
376  http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio
377  n/Guidances/ucm073517.pdf 
378   
379    Q8, Q9, and Q10  Questions and Answers(R4) (2010); 
380  http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio
381  n/Guidances/UCM210822.pdf 
382   
383    Cooperative Manufacturing Arrangements for Licensed Biologics (2008); 
384  http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRe
385  gulatoryInformation/Guidances/General/UCM069908.pdf    
386   
387  Finally, applicants may refer to the following FDA draft guidance documents for 
388  additional information.  When finalized, these will provide FDA policy on these subjects. 
389    
390    CMC Postapproval Manufacturing Changes Reportable in Annual Reports; 
391  (Draft 2010); 
392  http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio
393  n/Guidances/UCM217043.pdf 
394   
395    Annual Reports for Approved Premarket Approval Applications (PMA) (Draft 
396  2006);  
397  http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/G
398  uidanceDocuments/ucm089398.pdf 
399   
400    Public Availability of Labeling Changes in Changes Being Effected 
401  Supplements (Draft 2006); 
402  http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio
403  n/Guidances/ucm075091.pdf 
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