Guidance for Industry 
and FDA Staff: 
 
Application User Fees for 
Combination Products 
 
 
 
 
 
 
 
 
 
 
 
For questions regarding this document, contact: 
 Mark D. Kramer, Office of Combination Products, at 301-427-1934. 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Office of the Commissioner 
Office of Combination Products 
 
 
April 2005   
Guidance for Industry 
and FDA Staff: 
 
Application User Fees for 
Combination Products 
 
 
 
 
 
 
 
 
Additional copies are available from: 
 
Office of Combination Products, HFG-3 
Office of the Commissioner 
Food and Drug Administration 
15800 Crabbs Branch Way, Suite 200 
Rockville, MD 20855 
(Tel) 301-427-1934 
(Fax) 301-427-1935 
http://www.fda.gov/oc/combination  
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Office of the Commissioner 
Office of Combination Products 
April 2005  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
I.  PURPOSE..........................................................................................................................1 
 
II.  BACKGROUND INFORMATION................................................................................2 
A. What is a combination product?........................................................................................2 
B. How are combination products assigned for review and what type of marketing 
applications should be used?....................................................................................................2 
C.  What are user fees?.............................................................................................................3 
 
III.  USER FEES FOR COMBINATION PRODUCTS.......................................................4 
A.  How are application user fees determined for combination products?.........................4 
B.  What user fee waivers are available under MDUFMA?.................................................5 
C.  What user fee waivers are available under PDUFA?......................................................6 
D.   How might the PDUFA barrier to innovation waiver apply to innovative 
combination products for which two applications may be appropriate?............................7 
E.  What factors may be considered in determining whether a product is eligible for an 
Innovative Combination Product waiver?.........................................................................7 
F.  When would a combination product be considered innovative for the purposes of the 
Innovative Combination Product waiver?.........................................................................8 
G. How does FDA expect to reduce application fees under the Innovative Combination 
Product waiver for innovative combination products for which two applications are 
required?....................................................................................................................................9 
H.  My product qualifies for an Innovative Combination Product waiver.  How does this 
affect product and establishment fees payable under PDUFA?.........................................12 
I. I am submitting two marketing applications for my innovative combination product, 
but FDA has determined that only a single marketing application is necessary.  By 
submitting two applications, do I forfeit my eligibility for the PDUFA barrier to 
innovation waiver?..................................................................................................................12 
J.  A MDUFMA application is required for the approval of a new use for my 
combination product (e.g., a drug delivery device), but the vast majority of the review is  Contains Nonbinding Recommendations 
 
covered by the PDUFA application for the drug product.  Whether my combination 
product is innovative or not, do I have to pay a full MDUFMA fee?................................13 
K.  Will other waivers be available for combination products for which two applications 
are required?...........................................................................................................................13 
 
IV. PROCEDURES FOR REQUESTING WAIVERS FOR USER FEES FOR 
COMBINATION PRODUCTS..................................................................................................14 
A. How do I request a small business waiver under MDUFMA?......................................14 
B. How do I request a waiver for a PDUFA application, establishment, or product fee?14 
C. Where can I get more information about combination products?................................15  1  Guidance for Industry and FDA Staff1 
2  Application User Fees for Combination Products 
3   
4   
5   
6  This guidance represents the Food and Drug Administration's (FDA's) current thinking on this 
7  topic.  It does not create or confer any rights for or on any person and does not operate to bind 
8  FDA or the public.  You can use an alternative approach if the approach satisfies the requirements 
9  of the applicable statutes and regulations.  If you want to discuss an alternative approach, contact 
10  the FDA staff responsible for implementing this guidance.  If you cannot identify the appropriate 
11  FDA staff, call the appropriate number listed on the title page of this guidance.  
12   
13   
14   
15  I.     PURPOSE  
16   
17  This document provides guidance to industry and FDA staff on marketing application user fees for 
18  combination products as defined under 21 CFR 3.2(e).  The guidance document explains that 
19  combination products for which a single marketing application is submitted should be assessed the 
20  user fee associated with that particular type of marketing application.  The document explains that, 
21  in the infrequent situation where FDA requires two marketing applications for a combination 
22  product, two application fees would ordinarily be assessed.  The guidance also describes how the 
23  barrier to innovation waiver provision2 under the prescription drug user fee provisions of the 
24  Federal Food, Drug, and Cosmetic Act (the Act) may be applied to innovative combination 
25  products for which FDA requires the submission of two applications.  Such a waiver would 
26  provide a reduction in application user fees equivalent to the additional fee burden associated with 
27  the submission of two marketing applications. 
28   
29  FDA's guidance documents, including this guidance, do not establish legally enforceable 
30  responsibilities.  Instead, guidances describe the Agency's current thinking on a topic and should 
31  be viewed only as recommendations, unless specific regulatory or statutory requirements are cited.  
32  The use of the word should in Agency guidances means that something is suggested or 
33  recommended, but not required. 
34   
35   
36   
37   
38   
39   
                                                 
1 This guidance was prepared by the Office of Combination Products in the Office of the Commissioner in cooperation 
with the Center for Biologics Evaluation and Research, the Center for Drug Evaluation and Research, and the Center 
for Devices and Radiological Health at the Food and Drug Administration.  
2 Section 736(d)(1)(B) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 379h(d)(1)(B)).  Contains Nonbinding Recommendations 
 
40  II. BACKGROUND INFORMATION 
41   
42   A. What is a combination product? 
43   
44  A combination product is a product comprised of any combination of a drug and a device; a 
45  biological product and a device; a drug and a biological product; or a drug, device, and a 
46  biological product.  Under 21 CFR 3.2 (e), a combination product is defined to include:  
47   
48  (1) A product comprised of two or more regulated components; i.e., drug/device, 
49  biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, 
50  or otherwise combined or mixed and produced as a single entity; 
51   
52  (2) Two or more separate products packaged together in a single package or as a unit and 
53  comprised of drug and device products, device and biological products, or biological 
54  and drug products;  
55   
56  (3) A drug, device, or biological product packaged separately that according to its 
57  investigational plan or proposed labeling is intended for use only with an approved 
58  individually specified drug, device, or biological product where both are required to 
59  achieve the intended use, indication, or effect and where upon approval of the proposed 
60  product the labeling of the approved product would need to be changed; e.g., to reflect 
61  a change in intended use, dosage form, strength, route of administration, or significant 
62  change in dose; or  
63   
64  (4) Any investigational drug, device, or biological product packaged separately that 
65  according to its proposed labeling is for use only with another individually specified 
66  investigational drug, device, or biological product where both are required to achieve 
67  the intended use, indication, or effect. 
68   
69  Drug-drug, device-device, or biologic-biologic products do not meet the definition of a 
70  combination product as defined in 21 CFR 3.2 (e), and are outside the scope of this guidance.   
71   
72   
73  B. How are combination products assigned for review and what type of marketing 
74  applications should be used?  
75   
76  A combination product is assigned to an Agency center3 that will have primary jurisdiction for 
77  its premarket review and regulation.  Under section 503(g) of the Act, the assignment of a 
78  lead center is based upon a determination of the primary mode of action (PMOA) of the 
79  combination product.4  For example, if the PMOA of a combination product is that of a 
80  biological product, then the combination product would be assigned to the Agency component 
                                                 
3 Section 503(g) of the Act defines the term agency center as a center or alternative organizational component of the 
Food and Drug Administration. 
4 A proposed rule defining the primary mode of action of a combination product was published in the May 7, 2004, 
Federal Register (69 FR 25527), and is available at http://www.fda.gov/oc/combination/default.htm. 
  2 Contains Nonbinding Recommendations 
 
81  responsible for premarket review of that biological product.  A combination products PMOA 
82  does not automatically determine the type of marketing application that will be used for the 
83  products approval, clearance, or licensure.  Depending upon the type of combination product, 
84  approval, clearance or licensure may be obtained through submission of a single marketing 
85  application, or through separate marketing applications for the individual constituent parts of 
86  the combination product.   
87   
88  For most combination products, a single marketing application is sufficient for the products 
89  approval, clearance or licensure.  In some cases, however, a sponsor may choose to submit two 
90  marketing applications for a combination product when one application would suffice.  For 
91  example, a sponsor may choose to submit two applications in order to receive some benefit that 
92  accrues only from approval under a particular type of application (e.g., new drug product 
93  exclusivity, orphan status, or proprietary data protection when two firms are involved).  In 
94  other cases, FDA may determine that two marketing applications are necessary.  For example, 
95  when one of the individual constituent parts of a combination product is already approved for 
96  another use, and where the labeling of the already approved product will need to be changed to 
97  reflect its new intended use in the combination product, FDA may determine that two 
98  applications are necessary if the labeling of the already approved product is subject to legal 
99  requirements different from those that will apply to the combination product.  A guidance 
100  addressing the factors FDA expects to consider in determining whether a single or multiple 
101  marketing applications should be submitted for a combination product is in development and 
102  will be provided separately for public review and comment.  FDA encourages applicants who 
103  are uncertain as to whether a single or multiple marketing applications should be submitted for 
104  a combination product to discuss the issue with the lead reviewing Division and/or the Office 
105  of Combination Products.  
106   
107   
108  C.  What are user fees?  
109   
110  In 1992, Congress passed the Prescription Drug User Fee Act (PDUFA), P.L. 102-571. The 
111  user fee amendments were reauthorized by the Food and Drug Administration Modernization 
112  Act of 1997 and again by the Public Health Security and Bioterrorism Preparedness and 
113  Response Act of 2002.  PDUFA authorized FDA to collect fees from companies that produce 
114  certain human drug and biological products. When a company requests approval of a new drug 
115  or biological product prior to marketing, it must submit an application (e.g., new drug 
116  application (NDA) or biologics license application (BLA)) along with a fee to support the 
117  review process. In addition, companies pay annual fees for each prescription drug product 
118  marketed and for the establishment where the prescription drug product is manufactured.   
119  More information about PDUFA is available at http://www.fda.gov/oc/pdufa/ and 
120  http://www.fda.gov/cder/pdufa/default.htm . 
121   
122  The Medical Device User Fee and Modernization Act of 2002 (MDUFMA), P.L. 107-250, 
123  amended the Act to provide for user fees for device reviews.  The fees apply to certain 
124  premarket reviews of premarket approval applications (PMAs), product development protocols 
125  (PDPs), premarket reports (PMRs), biologics license applications (BLAs), certain supplements, 
  3 Contains Nonbinding Recommendations 
 
126  and premarket notifications (510(k)s).   More information about MDUFMA is available at 
127  http://www.fda.gov/oc/mdufma/. 
128   
129   
130  III. USER FEES FOR COMBINATION PRODUCTS 
131   
132  A.  How are application user fees determined for combination products? 
133   
134  As explained in the document Assessing User Fees: PMA Supplement Definitions, Modular 
135  PMA Fees, BLA and Efficacy Supplement Definitions, Bundling Multiple Devices in a Single 
136  Application, and Fees for Combination Products; Guidance for Industry and FDA, available at 
137  http://www.fda.gov/cdrh/mdufma/guidance/1201.pdf, a combination product with a device 
138  component (e.g., a drug-device or biologic-device product) should be subject to the fee 
139  associated with the type of application required for the product's premarket approval, 
140  clearance, or licensure. For example, a biologic-device or a drug-device combination product 
141  for which a PMA is required should be subject to the PMA fee under MDUFMA, while a 
142  biologic-device or a drug-device combination product for which a 510(k) is required should be 
143  subject to the 510(k) fee under MDUFMA.  
144   
145  A biologic-device product regulated under section 351 of the PHS Act will be subject to the 
146  BLA fee under MDUFMA, if the biological component meets the definition of a device. Other 
147  biologic-device combination products (those with biologic components that do not meet the 
148  definition of a device) or drug-biologic combination products regulated under section 351 of 
149  the PHS Act, or drug-device or drug-biologic combination products regulated under section 
150  505(b) of the Act, that are human drug applications as defined in section 735 of the Act, will be 
151  subject to prescription drug user fees. Prescription drug user fees may include application and 
152  yearly product and establishment fees.  More information about prescription drug user fees is 
153  available at http://www.fda.gov/cder/pdufa/default.htm.  
154   
155  Therefore, combination products for which a single marketing application is submitted should 
156  be subject to the fee associated with that type of application.  Sponsors may be eligible for fee 
157  waivers or reductions (e.g., for small businesses) under PDUFA and MDUFMA.  More 
158  information on available waiver options is provided below.   
159   
160  In some circumstances, a sponsor may choose to submit two applications covering the various 
161  components of a combination product when one application would suffice.  In such cases, two 
162  application fees would be assessed, i.e., one fee for each application.  For example, a sponsor 
163  may choose to submit two applications when one would suffice in order to receive some 
164  benefit from having two applications (e.g., new drug product exclusivity, orphan status, or 
165  proprietary data protection when two firms are involved).  Although sponsors may still be 
166  eligible for existing fee waivers or reductions in this circumstance, the sponsor receives benefit 
167  by submitting two applications.  Review of two applications when one would suffice places 
168  extra burden on FDA resources, and a user fee for each application would ordinarily be 
169  assessed.   
170   
  4 Contains Nonbinding Recommendations 
 
171  Likewise, when FDA requires two applications for a combination product, two application fees 
172  would be assessed.  Sponsors may be eligible for existing waivers or reductions under PDUFA 
173  or MDUFMA.  In particular, as explained below, the Agency intends to look closely at whether 
174  a PDUFA barrier to innovation waiver may be appropriate to reduce the additional fee 
175  burden associated with FDAs requirement for two marketing applications.   
176   
177   
178  B.  What user fee waivers are available under MDUFMA?5 
179   
180  MDUFMA provides more limited user fee waiver options than are provided for under PDUFA.  
181  Other than specific situations identified in Table 1 below for which no application fee is 
182  required, standard MDUFMA fees are required for all device applications other than those 
183  from small businesses.  Under MDUFMA, a small business is defined as one whose annual 
184  gross sales and revenues (for the firm and its affiliates) is  $30 million. Under MDUFMA, 
185  small businesses pay 38% of the standard PMA and BLA fee and 80% of the standard 510(k) 
186  fee.  MDUFMA also provides a one-time waiver for the first premarket application from a 
187  qualified small business.   
188   
189   
Table 1: MDUFMA Fee Exemptions and Waivers (No Fee for These)  
Category   Exemption or Waiver 
Humanitarian Device Exemption (HDE)   Exempt from any fee. 
BLA for a product licensed for further 
Exempt from any fee. 
manufacturing use only  
First premarket application (PMA, PDP, 
One-time waiver of the fee that would 
BLA, or premarket report) from a small 
otherwise apply. 
business  
Exempt from any FDA fee; however, the 
Third-party 510(k)  
third-party may charge a fee for its review.  
Exempt from any fee. If an applicant obtains 
an exemption under this provision, and later 
Any application for a device intended 
submits a supplement for adult use, that 
solely for pediatric use. 
supplement is subject to the fee then in effect 
for an original premarket application. 
Any application from a State or Federal  Exempt from any fee unless the device is to 
Government entity.  be distributed commercially. 
190   
191   
192   
193   
194   
195   
196   
                                                 
5 MDUFMA waivers are described in Section 738 of the Act. 
  5 Contains Nonbinding Recommendations 
 
197   
198  C.  What user fee waivers are available under PDUFA?6 
199   
200  PDUFA provides for a waiver of the fee for the first human drug application from a small 
201  business.7  The criteria for qualifying as a small business under PDUFA are different than 
202  those under MDUFMA.8  Under PDUFA, small business means an entity that has fewer than 
203  500 employees for the small business and its affiliates.9   
204   
205  PDUFA also provides for waivers or reductions of fees where: 
206   
207  (cid:131)  such waiver or reduction is necessary to protect the public health;  
208   
209  (cid:131)  the assessment of the fee would present a significant barrier to innovation because of 
210  limited resources available to such person or other circumstances; or 
211   
212  (cid:131)  the fees to be paid by such person will exceed the anticipated present and future costs 
213  incurred by the Secretary in conducting the process for the review of human drug 
214  applications for such person. 
215   
216  The document Interim Guidance Document for Waivers of and Reductions in User Fees, 
217  available at http://www.fda.gov/cder/pdufa/default.htm, provides information for requesting, 
218  and the criteria for evaluating, a waiver of PDUFA application, establishment, or product 
219  fees.10  In addition, the document Fees-Exceed-The-Costs Waivers Under the Prescription 
220  Drug User Fee Act, available at http://www.fda.gov/cder/pdufa/default.htm, provides further 
221  explanation of the waiver option described in the third bullet above. 
222   
223  It should be noted that PDUFA applications (NDA or BLA) not requiring clinical data for 
224  approval are assessed half the fee that is assessed for applications that do require clinical data 
225  for approval.11  NDA or BLA supplements that require clinical data for approval are assessed 
226  half the full application fee; however NDA or BLA supplements that do not require clinical 
227  data for approval are not assessed a fee.   
228   
229   
230   
231   
232   
                                                 
6 PDUFA waivers are described in Section 736(d) of the Act (21 U.S.C. 379h(d)). 
7 See section 736(d)(1)(D) of the Act (21 U.S.C. 379h(d)(1)(D)). 
8 Qualifying sponsors could receive a waiver from one or both application fees for their first PDUFA and MDUFMA 
premarket applications.  Given the different criteria for small businesses, however, some companies may qualify for 
one waiver but not the other.   
9 See section 736(d)(3) of the Act (21 U.S.C. 379h(d)(3)). 
10 The current mailing addresses for submitting PDUFA waiver requests can be found on the Internet at 
http://www.fda.gov/cder/pdufa/addresses.htm. 
11 For FY 2005, the full NDA or BLA fee is $672,000, and the fee for an NDA or BLA that does not require clinical 
data for approval is $336,000. 
  6 Contains Nonbinding Recommendations 
 
233  D.   How might the PDUFA barrier to innovation waiver apply to innovative combination 
234  products for which two applications may be appropriate? 
235   
236  Combination products may incorporate cutting edge, innovative technologies that hold great 
237  promise for advancing patient care.  For example, by combining two different types of 
238  regulated components, treatment may be made safer or more effective than it would be using 
239  either or both of the components independently.   
240  FDA believes that the assessment of two marketing application fees for an innovative 
241  combination product could represent a significant barrier to its development.   
242  After reviewing the various waiver options available under PDUFA and MDUFMA, FDA 
243  believes that the PDUFA barrier to innovation waiver allows the Agency to reduce the 
244  additional fee burden associated with the requirement for two marketing applications for an 
245  innovative combination product.  In particular, PDUFA provides for a fee waiver or reduction 
246  when the assessment of the fee would present a significant barrier to innovation because of 
247  limited resources available to such person or other circumstances.  FDA believes such other 
248  circumstances may exist in the infrequent case where two marketing applications are required.  
249  FDA expects to consider the factors discussed below in determining whether a particular 
250  innovative combination product is eligible for this fee reduction.   
251   
252   
253  E.  What factors may be considered in determining whether a product is eligible for an 
254  Innovative Combination Product waiver? 
255   
256  To be eligible for the Innovative Combination Product waiver under PDUFAs barrier to 
257  innovation because of...other circumstances provision, FDA expects to consider the following 
258  factors: 
259   
260  (cid:131)  The combination product (as defined in 21 CFR 3.2(e)) as a whole is innovative (see 
261  Section F below for factors FDA expects to consider in determining whether a 
262  combination product is innovative); 
263   
264  (cid:131)  FDA is requiring two fee-eligible12 marketing applications13 for the combination 
265  product; 
266   
267  (cid:131)  The applications only request approval of the two components of the combination 
268  product for use together.  Applications that include independent uses of one or both 
269  components outside the combination product generally would not be eligible for this 
270  waiver.  However, applications for combinations of already approved, independent 
                                                 
12 Orphan product applications exempt from fees under 736(a)(1)(E) of the Act, BLAs for further manufacturing use 
only, HDEs, pediatric device applications, and other applications where a fee is not assessed would not qualify.  This 
waiver is specifically intended to reduce the additional fee burden associated with the requirement of two fee-paying 
applications.  In these cases, only one application would be assessed a fee. 
13 The two applications could be any combination of fee-eligible original or supplemental applications (e.g., two 
original applications, an original application and a supplemental application, or two supplemental applications). 
  7 Contains Nonbinding Recommendations 
 
271  products generally would be eligible if two applications are required for approval of the 
272  new combined use. 
273   
274  (cid:131)  The applicant does not qualify for a PDUFA small business waiver or have limited 
275  resources.  Applicants who qualify for a PDUFA small business waiver receive a full 
276  waiver of their first PDUFA application fee.  In addition, applicants with an innovative 
277  combination product who do not qualify for a PDUFA small business waiver, but who 
278  have limited resources, may be eligible for a standard PDUFA barrier to innovation 
279  waiver, which may provide a full waiver of the PDUFA application fee because of the 
280  applicants financial need.  More information about the standard barrier to innovation 
281  waiver is available at http://www.fda.gov/cder/pdufa/default.htm.  Applicants who 
282  believe they qualify are encouraged to explore their eligibility for the PDUFA small 
283  business or barrier to innovation waivers first.   
284   
285   
286  F.  When would a combination product be considered innovative for the purposes of the 
287  Innovative Combination Product waiver? 
288   
289  FDA expects to consider the following factors14 in determining whether a combination product 
290  is innovative for the purposes of this waiver: 
291   
292  (cid:131)  The product addresses an unmet medical need in the treatment, diagnosis or prevention 
293  of disease, as demonstrated by one of the following: 
294   
295    No approved alternative treatment or means of diagnosis exists; or 
296   
297    The combination product offers significant, meaningful advantages over 
298  existing approved alternative treatments.  The combination product 
299  should provide for clinically important earlier or more accurate 
300  diagnosis or offer important therapeutic advantages in safety and/or 
301  effectiveness or patient compliance over existing alternatives.  Such 
302  advantages may include demonstrated superiority over current 
303  treatments for effects on serious outcomes (e.g., morbidity), ability to 
304  provide clinical benefit for those patients unable to tolerate current 
305  treatments, or ability to provide clinical benefit without the serious side 
306  effects associated with current treatments.  Innovative combination 
307  products may also provide these types of significant, meaningful 
308  advantages over existing approved alternative treatments by providing 
309  greater convenience or ease of use for patients and/or healthcare 
310  providers.  For example, an innovative combination product 
311  distinguished by its ease of use or convenience may significantly 
                                                 
14 These factors are largely derived from the Agency's approach to determining the eligibility of a product for 
expedited or priority review, where such factors are relevant to a determination of a combination products 
innovativeness.  FDA notes that a product need not be life-saving or for use in critical conditions to satisfy these 
factors, although the benefits of such innovation are sometimes more evident in these circumstances. 
  8 Contains Nonbinding Recommendations 
 
312  improve safety by resulting in fewer adverse events, or may significantly 
313  improve effectiveness by providing better patient compliance or more 
314  effective dosing.15   
315   
316  (cid:131)  Factors such as whether one of the two applications includes a new molecular 
317  entity, has been designated as a priority drug16 or eligible for expedited device 
318  review, or has been granted fast track status,17 may also be considered in 
319  determining whether a product is considered innovative for the purposes of this 
320  waiver.   
321   
322  (cid:131)  The existence of treatment alternatives would weigh against deciding that a 
323  product is innovative. 
324   
325   
326  G. How does FDA expect to reduce application fees under the Innovative Combination 
327  Product waiver for innovative combination products for which two applications are 
328  required? 
329    
330  In evaluating how the PDUFA barrier to innovation waiver provision may apply to innovative 
331  combination products, FDAs goal would be to reduce the additional fee burden associated 
332  with the requirement for two marketing applications.  As noted above, waiver options under 
333  MDUFMA are limited, and the only fee reduction under MDUFMA is for small businesses.  
334  Therefore, for innovative combination products requiring two marketing applications, in 
335  appropriate situations FDA would expect to reduce PDUFA application fees as follows: 
336   
337  (cid:131)  Products requiring a MDUFMA application and a PDUFA application.  FDA would expect 
338  to reduce the PDUFA fee by the amount of the MDUFMA fee.  Thus, a sponsor would pay 
339  the full MDUFMA fee associated with the type of MDUFMA application, and a PDUFA 
340  fee reduced by the paid MDUFMA fee.  The total amount paid would be equivalent to one 
341  PDUFA fee. 
342   
343   
344  (cid:131)  Products requiring two PDUFA applications.  FDA would expect to reduce each PDUFA 
345  fee by half.  In the case where two full PDUFA fees would otherwise be required, the total 
346  amount paid under this waiver would be equivalent to one PDUFA fee.   
347   
                                                 
15 Innovative Combination Product Waiver Requests that are based on convenience or ease of use should describe how 
the convenience or ease of use results in significant, meaningful advantages as described here. 
16 Further information on FDAs policies in determining priority status of drugs can be found in CDERs Manual of 
Policies and Procedures (MAPP) 6020.3, Priority Review Policy, available on the Internet at www.fda.gov/cder, or 
CBERs Manual of Standard Operating Procedures and Policies (SOPP) 8405, Complete Review and Issuance of 
Actions Letters, available on the Internet at www.fda.gov/cber/regsopp/regsopp.htm. 
17 Further information on FDAs policies regarding designation of fast track status can be found in FDAs guidance for 
industry on Fast Track Drug Development Programs  Designation, Development, and Application Review, available 
on the Internet at www.fda.gov/cder/guidance. 
  9 Contains Nonbinding Recommendations 
 
348  Table 2 below illustrates how, in a variety of scenarios, FDA would expect to reduce fees for 
349  innovative combination products for which two marketing applications are required.  The 
350  actual fee amounts are based on the FY 2005 fee structure, and are subject to change in 
351  subsequent fiscal years.  
352   
353   
354   
Table 2: Examples of Fees Under Innovative Combination Product Waiver (FY05 Fees) 
Application #1  Standard  Application #2 Standard Fee  Total Fee for  Proposed 
Fee for  for   both   Total Fee 
Application  Application  Applications   (With Waiver) 
#1  #2  (Without 
Waivers) 
PMA, PMA  $239,237  NDA/BLA  $672,000  $911,237  $672,000: 
Panel-Track   
Supplement or  $239,237 
MDUFMA  MDUFMA, 
BLA or BLA  $432,763 PDUFA 
Efficacy 
Supplement 
180-Day PMA  $51,436  NDA/BLA  $672,000  $723,436  $672,000: 
Supplement   
$51,436 
MDUFMA, 
$620,564 PDUFA 
PMA, PMA  $239,237  NDA/BLA  $336,000  $575,237  $336,000: 
Panel-Track  Efficacy   
Supplement or  Supplement  $239,237 
MDUFMA  MDUFMA,  
BLA or BLA  $96,763 PDUFA 
Efficacy 
Supplement 
First Small  $0  NDA/BLA  $672,000  $672,000  $672,000: 
Business18   
PMA, PMA  $0 MDUFMA 
Panel-Track  $672,000 PDUFA 
Supplement or 
MDUFMA 
BLA or BLA 
Efficacy 
Supplement 
                                                 
18 Assumes sponsor qualifies as a small business under MDUFMA but not PDUFA. 
  10 Contains Nonbinding Recommendations 
 
Table 2: Examples of Fees Under Innovative Combination Product Waiver (FY05 Fees) 
Application #1  Standard  Application #2 Standard Fee  Total Fee for  Proposed 
Fee for  for   both   Total Fee 
Application  Application  Applications   (With Waiver) 
#1  #2  (Without 
Waivers) 
Small  $90,910  NDA/BLA  $672,000  $762,910  $672,000: 
Business19   
PMA, PMA  $90,910 MDUFMA
Panel-Track  $581,090 PDUFA 
Supplement or 
MDUFMA 
BLA or BLA 
Efficacy 
Supplement 
Real-Time  $17,225  NDA/BLA  $672,000  $689,225  $672,000: 
PMA   
Supplement  $17,225 MDUFMA
$654,775 PDUFA 
Real-Time  $17,225  NDA/BLA  $336,000  $353,225  $336,000: 
PMA  Efficacy   
Supplement  Supplement   
$17,225 MDUFMA 
$318,775 PDUFA 
510(k)  $3,502  NDA/BLA  $672,000  $675,502  $672,000: 
 
$3,502 MDUFMA, 
$668,498 PDUFA 
510(k)  $3,502  NDA/BLA  $336,000  $339,502  $336,000: 
Efficacy   
Supplement  $3,502 MDUFMA, 
$332,498 PDUFA 
 
Original  $672,000  Original  $672,000  $1,344,000  $672,000: 
PDUFA  PDUFA   
Application  Application  $672,000 PDUFA 
(NDA)  (BLA) 
Original  $672,000  PDUFA  $336,000  $1,008,000  $672,000: 
PDUFA  Efficacy   
Application  Supplement  $672,000 PDUFA 
(NDA)  (BLA) 
PDUFA  $336,000  PDUFA  $336,000  $672,000  $336,000: 
Efficacy  Efficacy   
Supplement  Supplement  $336,000 PDUFA 
(NDA)  (BLA) 
355   
                                                 
19 Assumes sponsor qualifies as a small business under MDUFMA but not PDUFA. 
  11 Contains Nonbinding Recommendations 
 
356   
357  H.  My product qualifies for an Innovative Combination Product waiver.  How does this 
358  affect product and establishment fees payable under PDUFA? 
359   
360  The Innovative Combination Product waiver would only provide for a reduction of application 
361  fees equivalent to the additional fee burden associated with the requirement for two marketing 
362  applications.  This use of the PDUFA barrier to innovation waiver is not applicable to the 
363  yearly product and establishment fees. FDA intends to review requests for waivers of PDUFA 
364  product and/or establishment fees for combination products, including innovative combination 
365  products, under existing criteria established for the review of such waivers, which are 
366  applicable to both combination and non-combination products.20   
367   
368  I. I am submitting two marketing applications for my innovative combination product, 
369  but FDA has determined that only a single marketing application is necessary.  By 
370  submitting two applications, do I forfeit my eligibility for the PDUFA barrier to 
371  innovation waiver? 
372   
373  No.  As described in Section III.A above, sponsors may still be eligible for existing fee waivers 
374  or reductions under both PDUFA and MDUFMA when submitting two applications covering 
375  the various components of a combination product, even when one application would suffice.  
376  For example, sponsors may qualify for small business waivers or fee reductions under PDUFA 
377  and/or MDUFMA, or other waivers provided under PDUFA, such as the barrier to innovation 
378  waiver.   
379   
380  In the particular case of the PDUFA barrier to innovation waiver, as described in the document 
381  Interim Guidance Document for Waivers of and Reductions in User Fees, available at 
382  http://www.fda.gov/cder/pdufa/default.htm, FDA ordinarily considers a variety of factors, 
383  including the applicants financial status, to determine whether the submission of an 
384  application presents a barrier to innovation because of limited resources available to the 
385  applicant.  FDA believes it is also appropriate to use these criteria in the case where an 
386  applicant chooses to submit two applications when one would suffice because the sponsor 
387  receives some benefit by submitting two applications (e.g., new drug product exclusivity, 
388  orphan designation, or proprietary data protection when two firms are involved).   
389   
390  In contrast, for the Innovative Combination Product Waiver, when FDA requires the 
391  submission of two marketing applications for an innovative combination product meeting the 
392  criteria outlined in this document, FDA expects to reduce the total application fee burden (i.e., 
393  grant a partial waiver) as described in this document, regardless of the applicants financial 
394  status.  FDA believes this approach is reasonable because of the other circumstances 
395  associated with FDAs requirement for two marketing applications.  
396   
                                                 
20 It should be noted that only PDUFA NDA and BLA holders are assessed product and establishment fees under 
PDUFA.  In general, NDA products without generic competition are assessed product fees.  If you are assessed a 
product fee, then you would likely be assessed an establishment fee. Please note that if multiple applicants share the 
same establishment, under PDUFA, the establishment fee is shared equally among the user fee paying applicants. 
  12 Contains Nonbinding Recommendations 
 
397  Applicants with an innovative combination product who qualify for a standard PDUFA barrier 
398  to innovation waiver (because the applicant has limited resources) may qualify for a full waiver 
399  of the PDUFA application fee as compared to the partial fee reduction provided by the 
400  Innovative Combination Product Waiver.     
401   
402   
403  J.  A MDUFMA application is required for the approval of a new use for my 
404  combination product (e.g., a drug delivery device), but the vast majority of the review is 
405  covered by the PDUFA application for the drug product.  Whether my combination 
406  product is innovative or not, do I have to pay a full MDUFMA fee?  
407   
408  Under MDUFMA, the user fee assessed for a particular type of marketing application is related 
409  to the resources required for the review of that specific type of application.  FDA believes that 
410  under appropriate circumstances, as described below, changes to approved devices, such as use 
411  of an existing drug delivery device with a new drug product where in-depth review of such use 
412  is being evaluated under a PDUFA application, should be handled under a device application 
413  appropriate to the level of review required.   
414   
415  For example, while most new indications for PMA products require panel-track PMA 
416  supplements or original PMA applications, submission of a real-time or 180-day PMA 
417  supplement may be appropriate when only a minor change is being made to the device and the 
418  review of the new use is being conducted as part of the PDUFA application.  Such an approach 
419  would also provide for lower device application user fees, since real-time and 180-day PMA 
420  supplements have lower fees than those for panel-track supplements or original PMAs.  FDA 
421  encourages applicants to discuss the appropriate type of device application in such 
422  circumstances.  
423   
424   
425  K.  Will other waivers be available for combination products for which two applications 
426  are required? 
427   
428  FDA has considered the various options available under PDUFA and MDUFMA, and believes 
429  the Innovative Combination Product waiver would appropriately address the additional fee 
430  burden associated with any FDA requirement for the submission of two marketing applications 
431  for an innovative combination product.  FDA will evaluate its experience in working with this 
432  guidance document, and the impact of the Innovative Combination Product waiver on the user 
433  fee program as a whole.   
434   
435   
436   
437   
438   
439   
440   
441   
  13 Contains Nonbinding Recommendations 
 
442  IV. PROCEDURES FOR REQUESTING WAIVERS FOR USER FEES FOR 
443  COMBINATION PRODUCTS  
444   
445   
446  A. How do I request a small business waiver under MDUFMA? 
447   
448  Each fiscal year, FDA publishes a document titled Guidance for Industry and FDA: 
449  MDUFMA Small Business Qualification Worksheet and Certification (see 
450  http://www.fda.gov/cdrh/mdufma/guidance), which provides instructions for obtaining an FDA 
451  decision that a business qualifies as a small business and is eligible for reduced or waived 
452  MDUFMA application fees. 
453   
454  If you submit an application before FDA has determined you qualify as a small business, you 
455  must pay the standard (full) amount of any fee that applies.  FDA will not refund the difference 
456  between the standard (full) fee and the small business fee if you later qualify as a small 
457  business.21  If you want to pay the small business fee for an application, do not submit it until 
458  you obtain your Small Business Decision number from FDA.  FDA expects to make its 
459  decision about whether you qualify as a small business within 60 days of receiving your 
460  Certification and supporting materials.  Therefore, applicants are encouraged to submit 
461  MDUFMA small business waiver requests/certifications at least 60 days before the required 
462  fees are expected to be paid.   
463   
464   
465  B. How do I request a waiver for a PDUFA application, establishment, or product fee? 
466   
467  The document Interim Guidance Document for Waivers of and Reductions in User Fees, 
468  available at http://www.fda.gov/cder/pdufa/default.htm provides instructions for requesting a 
469  waiver of application, establishment, or product fees under PDUFA.22   
470   
471  The same instructions should be followed for requesting the Innovative Combination Product 
472  waiver described above.  The request should be clearly identified as an Innovative 
473  Combination Product Waiver Request, and be accompanied by a statement of reasons the 
474  applicant believes the Innovative Combination Product Waiver should be applied.  To facilitate 
475  FDAs consideration of the request, FDA encourages sponsors to fully address and substantiate 
476  each of the criteria outlined in Section III above.  Current mailing addresses for submitting 
477  PDUFA waiver requests, including an Innovative Combination Product waiver, are provided at 
478  http://www.fda.gov/cder/pdufa/addresses.htm.   
479   
480  Persons are encouraged to submit requests for fee waivers or reductions at least 90 days before 
481  the required fees are expected to be paid.  In addition, under section 736(i) of the Act, to 
482  qualify for a refund of any fee collected under the user fee provisions of the Act, you must 
483  submit a written request for a refund within 180 days after such fee is due.   
484   
                                                 
21  See Sections 738(d)(2)(D) and 738(e)(2)(D) of the Act. 
22 See particularly pages 23-24 of that interim guidance document. 
  14 Contains Nonbinding Recommendations 
 
485  C. Where can I get more information about combination products? 
486   
487  The Office of Combination Products is available as a resource to sponsors and review staff 
488  throughout the development of a combination product.  The Office may be reached at (301) 
489  427-1934 or by email at combination@fda.gov.  In addition, the Office maintains an updated 
490  website with information on the regulation of combination products at 
491  http://www.fda.gov/oc/combination. 
  15