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
Guidance for Industry and FDA Staff1 1 

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 

“barrier to innovation” waiver provision2 23 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 

2

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 

A combination product is assigned to an Agency center3 76 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 

combination product.4 79 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. 
Contains Nonbinding Recommendations 

3

81 responsible for premarket review of that biological product. A combination product’s PMOA 

82 does not automatically determine the type of marketing application that will be used for the 

83 product’s 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 product’s 

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, 
Contains Nonbinding Recommendations 

4

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 
Contains Nonbinding Recommendations 

5

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 FDA’s requirement for two marketing applications. 

176 

177 

B. What user fee waivers are available under MDUFMA?5 178 

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 

manufacturing use only Exempt from any fee. 

First premarket application (PMA, PDP, 

BLA, or premarket report) from a small 

business 

One-time waiver of the fee that would 

otherwise apply. 

Third-party 510(k) Exempt from any FDA fee; however, the 

third-party may charge a fee for its review. 

Any application for a device intended 

solely for pediatric use. 

Exempt from any fee. If an applicant obtains 

an exemption under this provision, and later 

submits a supplement for adult use, that 

supplement is subject to the fee then in effect 

for an original premarket application. 

Any application from a State or Federal 

Government entity. 

Exempt from any fee unless the device is to 

be distributed commercially. 

190 

191 

192 

193 

194 

195 

196 

 

5

 MDUFMA waivers are described in Section 738 of the Act. 
Contains Nonbinding Recommendations 

6

197 

C. What user fee waivers are available under PDUFA?6 198 

199 

200 PDUFA provides for a waiver of the fee for the first human drug application from a small 

business.7 201 The criteria for qualifying as a small business under PDUFA are different than 

those under MDUFMA.8 202 Under PDUFA, “small business” means an entity that has fewer than 

500 employees for the small business and its affiliates.9 203 

204 

205 PDUFA also provides for waivers or reductions of fees where: 

206 

207  such waiver or reduction is necessary to protect the public health; 

208 

209  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  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 

fees.10 219 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 

for approval.11 225 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. 
Contains Nonbinding Recommendations 

7

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 PDUFA’s “barrier to 

257 innovation because of...other circumstances” provision, FDA expects to consider the following 

258 factors: 

259 

260  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 

 FDA is requiring two fee-eligible12 marketing applications13 264 for the combination 

265 product; 

266 

267  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). 
Contains Nonbinding Recommendations 

8

271 products generally would be eligible if two applications are required for approval of the 

272 new combined use. 

273 

274  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 applicant’s 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 

FDA expects to consider the following factors14 289 in determining whether a combination product 

290 is innovative for the purposes of this waiver: 

291 

292  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 product’s 

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. 
Contains Nonbinding Recommendations 

9

312 improve safety by resulting in fewer adverse events, or may significantly 

313 improve effectiveness by providing better patient compliance or more 

effective dosing.15 314 

315 

316  Factors such as whether one of the two applications includes a new molecular 

entity, has been designated as a priority drug16 317 or eligible for expedited device 

review, or has been granted fast track status,17 318 may also be considered in 

319 determining whether a product is considered innovative for the purposes of this 

320 waiver. 

321 

322  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, FDA’s 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  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  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 FDA’s policies in determining priority status of drugs can be found in CDER’s Manual of 

Policies and Procedures (MAPP) 6020.3, Priority Review Policy, available on the Internet at www.fda.gov/cder, or 

CBER’s 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 FDA’s policies regarding designation of fast track status can be found in FDA’s guidance for 

industry on Fast Track Drug Development Programs — Designation, Development, and Application Review, available 

on the Internet at www.fda.gov/cder/guidance. 
Contains Nonbinding Recommendations 

10

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 

Fee for 

Application 

#1 

Application #2 Standard Fee 

for 

Application 

#2 

Total Fee for 

both 

Applications 

(Without 

Waivers) 

Proposed 

 Total Fee 

(With Waiver) 

PMA, PMA 

Panel-Track 

Supplement or 

MDUFMA 

BLA or BLA 

Efficacy 

Supplement 

$239,237 NDA/BLA $672,000 $911,237 $672,000: 

$239,237 

MDUFMA, 

$432,763 PDUFA 

180-Day PMA 

Supplement 

$51,436 NDA/BLA $672,000 $723,436 $672,000: 

$51,436 

MDUFMA, 

$620,564 PDUFA 

PMA, PMA 

Panel-Track 

Supplement or 

MDUFMA 

BLA or BLA 

Efficacy 

Supplement 

$239,237 NDA/BLA 

Efficacy 

Supplement 

$336,000 $575,237 $336,000: 

$239,237 

MDUFMA, 

$96,763 PDUFA 

First Small 

Business18

PMA, PMA 

Panel-Track 

Supplement or 

MDUFMA 

BLA or BLA 

Efficacy 

Supplement 

$0 NDA/BLA $672,000 $672,000 $672,000: 

$0 MDUFMA 

$672,000 PDUFA 

 

18 Assumes sponsor qualifies as a small business under MDUFMA but not PDUFA. 
Contains Nonbinding Recommendations 

11

Table 2: Examples of Fees Under Innovative Combination Product Waiver (FY05 Fees)

Application #1 Standard 

Fee for 

Application 

#1 

Application #2 Standard Fee 

for 

Application 

#2 

Total Fee for 

both 

Applications 

(Without 

Waivers) 

Proposed 

 Total Fee 

(With Waiver) 

Small 

Business19

PMA, PMA 

Panel-Track 

Supplement or 

MDUFMA 

BLA or BLA 

Efficacy 

Supplement 

$90,910 NDA/BLA $672,000 $762,910 $672,000: 

$90,910 MDUFMA

$581,090 PDUFA 

Real-Time 

PMA 

Supplement 

$17,225 NDA/BLA $672,000 $689,225 $672,000: 

$17,225 MDUFMA

$654,775 PDUFA 

Real-Time 

PMA 

Supplement 

$17,225 NDA/BLA 

Efficacy 

Supplement 

$336,000 $353,225 $336,000: 

$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 

Efficacy 

Supplement 

$336,000 $339,502 $336,000: 

$3,502 MDUFMA, 

$332,498 PDUFA 

Original 

PDUFA 

Application 

(NDA) 

$672,000 Original 

PDUFA 

Application 

(BLA) 

$672,000 $1,344,000 $672,000: 

$672,000 PDUFA 

Original 

PDUFA 

Application 

(NDA) 

$672,000 PDUFA 

Efficacy 

Supplement 

(BLA) 

$336,000 $1,008,000 $672,000: 

$672,000 PDUFA 

PDUFA 

Efficacy 

Supplement 

(NDA) 

$336,000 PDUFA 

Efficacy 

Supplement 

(BLA) 

$336,000 $672,000 $336,000: 

$336,000 PDUFA 

355 

 

19 Assumes sponsor qualifies as a small business under MDUFMA but not PDUFA. 
Contains Nonbinding Recommendations 

12

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 

applicable to both combination and non-combination products.20 366 

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 applicant’s 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 applicant’s financial 

394 status. FDA believes this approach is reasonable because of the “other circumstances” 

395 associated with FDA’s 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. 
Contains Nonbinding Recommendations 

13

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 
Contains Nonbinding Recommendations 

14

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 

business.21 457 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 

waiver of application, establishment, or product fees under PDUFA.22 469 

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 FDA’s 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. 
Contains Nonbinding Recommendations 

15

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.