Contains Nonbinding Recommendations 
 
Guidance for Industry  
and FDA Staff: 
 
Early Development 
Considerations for Innovative 
Combination Products  
 
 
 
 
 
 
 
 
 
 
 
 
For questions regarding this document, contact: 
Patricia Y. Love, MD, 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  
September 2006  Contains Nonbinding Recommendations 
Guidance for Industry 
and FDA Staff 
 
Early Development 
Considerations for Innovative 
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 (OCP) 
September  2006  Contains Nonbinding Recommendations 
 
 
 
Public Comment 
 
Written comments and suggestions may be submitted at any time for Agency consideration to the 
Division of Dockets Management, Food and Drug Administration, 5630 Fishers Lane, Room 
1061, (HFA-305), Rockville, MD 20852.  Submit electronic comments to 
http://www.fda.gov/dockets/ecomments. When submitting comments, please refer to the exact 
title of this guidance document.  Comments may not be acted upon by the Agency until the 
document is next revised or updated. 
 
 
  Contains Nonbinding Recommendations 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION.............................................................................................................1 
II.  BACKGROUND...............................................................................................................2 
A.  Definition...........................................................................................................................3 
B.  How are combination products regulated?....................................................................3 
III.  GENERAL DEVELOPMENT CONSIDERATIONS...................................................5 
IV.  CURRENTLY MARKETED PRODUCT CONSIDERATIONS................................6 
V.  PERSPECTIVES BY CONSTITUENT PART..............................................................7 
A.  Device constituent considerations....................................................................................7 
B.  Drug and biological product constituent considerations...............................................8 
VI.  ADDITIONAL PERSPECTIVES.................................................................................10 
A.  Clinical Investigation......................................................................................................10 
B.  Manufacturing considerations.......................................................................................11 
C.  Reliance on information not developed by the applicant............................................12 
VII.  EARLY INTERACTION AND COMMUNICATION WITH FDA..........................12 
A.        Where may I obtain additional information?...............................................................13  Guidance for Industry and FDA Staff1
1 
Early Development Considerations for  
2 
Innovative Combination Products 
3 
4   
5  This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic.  It 
6  does not create or confer any rights for or on any person and does not operate to bind FDA or the public.  
7  You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 
8  and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for 
9  implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
10  number listed on the title page of this guidance.  
11   
12  I.  INTRODUCTION 
13  This document provides guidance to industry and FDA staff on developmental considerations for 
14  innovative products that combine devices, drugs and/or biological products.  It is intended to 
15  provide a context for initial discussions on the type of scientific and technical information that 
16  may be necessary for investigational or marketing applications for these combination products. 
17  This guidance focuses on combination products as defined under 21 CFR 3.2(e).  The concepts 
18  may also be useful for the co-development of devices, drugs, and biological products that are 
19  used concomitantly but which do not meet the regulatory definition of a combination product.  
20  This information supplements existing guidance documents developed by the Center for 
21  Biologics Evaluation and Research (CBER), the Center for Devices and Radiological Health 
22  (CDRH), the Center for Drug Evaluation and Research (CDER), and the Office of Combination 
23  Products (OCP).   
24  FDA's guidance documents, including this guidance, do not establish legally enforceable 
25  responsibilities.  Instead, guidances describe the Agency's current thinking on a topic and should 
26  be viewed only as recommendations, unless specific regulatory or statutory requirements are 
27  cited.  The use of the word should in Agency guidances means that something is suggested or 
28  recommended, but not required.  
                                                 
1 This guidance has been prepared by the Center for Devices and Radiological Health, the Center for Biologics 
Evaluation and Research, the Center for Drug Evaluation and Research, and the Office of Combination Products in 
the Office of the Commissioner at the Food and Drug Administration.   Contains Nonbinding Recommendations 
29  II.  BACKGROUND 
30  FDA recognizes that innovative technologies may raise a spectrum of scientific and technical 
31  development issues.  Combination products are increasingly incorporating cutting edge, novel 
32  technologies that hold great promise for advancing patient care.  Innovative drug, biological 
33  product, device combinations have the potential to make treatments safer, more effective, or 
34  more convenient or acceptable to patients.  For example, drug-eluting cardiovascular stents may 
35  reduce the need for repeated surgery by helping to prevent the restenosis that may occur after 
36  stent implantation.  Drug and biologic products can be used in combination to potentially 
37  enhance the safety and/or effectiveness of either product used alone.  Proteins incorporated into 
38  novel orthopedic implants may facilitate the regeneration of bone required to permanently 
39  stabilize the implants.  Drug-device inhalation systems provide a new route of insulin delivery 
40  that may decrease the need for insulin injections.  Genomic-based diagnostic devices may be 
41  used to help determine whether certain patients are suitable candidates for a drug or biological 
42  product, or at risk for certain types of adverse events.2   
43  During an FDA workshop entitled, Innovative Systems for Delivery of Drugs and Biologics:  
44  Scientific, Clinical and Regulatory Challenges, industry and academic stakeholders requested 
45  that FDA provide guidance for the development of innovative technology that may challenge 
46  existing approaches.3  For example, what pre-clinical or animal studies are appropriate to begin 
47  human studies, or what types of clinical trial designs may be appropriate?  Further, FDA 
48  recognizes that combination product development may raise a number of Critical Path4 
49  challenges to progress from a novel concept to an innovative marketed product.   
50  Some of these developmental challenges may not be readily apparent.  For example, although a 
51  combination product may be comprised of an already approved drug and an already approved 
52  device, new scientific and technical issues may emerge when the drug and device are combined 
53  or used together.  New methodologies may need to be developed for manufacturing, evaluation 
54  of preclinical safety in targeted areas of the body, or clinical trial design to establish safety and 
55  effectiveness.  
56  FDA websites contain a wide variety of guidance documents for the development and testing of 
57  drugs, devices, and biological products.  These address drugs, devices, or biological products as 
58  individual products, but few guidance documents currently address the scientific and technical 
59  issues to consider when combining drug, device, and/or biological product constituent parts as a 
60  combination product..  
61  FDA believes it is important to address the scientific and technical issues raised by innovative 
62  combination products in order to develop efficient, appropriate techniques and methods to ensure 
63  the safety, effectiveness, and quality of the combination product. 
                                                 
2 Drug-pharmacogenomic test pairings may be considered combination products, depending how the products are 
intended for use and labeled.  FDA is developing separate guidance for the co-development of drug and genomic-
based diagnostic devices, and these types of products are not specifically addressed in this document. 
3 A summary of the workshop is available at http://www.fda.gov/oc/combination/workshop070803.html. 
A transcript is available at http://www.fda.gov/ohrms/dockets/dockets/03n0203/03n0203.htm. 
4 See The Critical Path to New Medical Products at http://www.fda.gov/oc/initiatives/criticalpath/. 
 
  2 Contains Nonbinding Recommendations 
64  A.  Definition 
65   
66  As defined in 21 CFR 3.2(e), a combination product is a product comprised of any combination 
67  of a drug and a device, a biological product and a device, a drug and a biological product, or a 
68  drug, device, and a biological product.  This includes: 
69   
70    A product comprised of two or more regulated components; i.e., drug/device, 
71  biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or 
72  otherwise combined or mixed and produced as a single entity; 
73   
74    Two or more separate products packaged together in a single package or as a unit and 
75  comprised of drug and device products, device and biological products, or biological and 
76  drug products;  
77   
78    A drug, device, or biological product packaged separately that according to its 
79  investigational plan or proposed labeling is intended for use only with an approved 
80  individually specified drug, device, or biological product where both are required to 
81  achieve the intended use, indication, or effect and where upon approval of the proposed 
82  product the labeling of the approved product would need to be changed; e.g., to reflect a 
83  change in intended use, dosage form, strength, route of administration, or significant 
84  change in dose; or  
85   
86    Any investigational drug, device, or biological product packaged separately that 
87  according to its proposed labeling is for use only with another individually specified 
88  investigational drug, device, or biological product where both are required to achieve the 
89  intended use, indication, or effect.  
90   
91  For purposes of this guidance, a constituent part of a combination product is an article in a 
92  combination product that can be distinguished by its regulatory identity as a drug, device, or 
93  biological product, as defined in section 21 U.S.C. 321, Federal Food, Drug, and Cosmetic Act 
94  (Act), and 42 U.S.C. 252 (i), Public Health Service Act, and as set forth in 21 CFR 3.2(k).  For 
95  example, a device coated or impregnated with a drug has two constituent parts, the device 
96  constituent and the drug constituent.  For simplicity, the concepts in this guidance are described 
97  in the context of a combination product composed of two constituent parts.  These concepts are 
98  also relevant for combination products with more than two constituent parts. 
99   
100   
101  B.  How are combination products regulated? 
102   
103  FDAs Office of Combination Products (OCP) was established in 2002 as required by the 
104  Medical Device User Fee and Modernization Act of 2002.  As set forth in section 503(g) of the 
105  Act, OCP is responsible for the prompt assignment of a lead Agency center that will have 
106  primary jurisdiction for the review and regulation of a combination product; ensuring timely and 
107  effective premarket review by overseeing the timeliness of and coordinating reviews involving 
108  more than one agency center; ensuring consistent and appropriate postmarket regulation of 
109  combination products; and resolving disputes regarding the timeliness of combination product 
  3 Contains Nonbinding Recommendations 
110  review.  OCP also works with agency centers to develop guidance and regulations to make the 
111  regulation of combination products as clear, consistent, and predictable as possible.   
112  Under section 503(g)(1) of the Act, a combination product is assigned to a center with primary 
113  jurisdiction, or a lead center, based on a determination of the primary mode of action (PMOA) of 
114  the combination product.  PMOA is defined as the single mode of action of a combination 
115  product that provides the most important therapeutic action of the combination product.  For 
116  example, if the PMOA of a device-biologic combination product were attributable to its 
117  biological product constituent, the Agency component responsible for premarket review of that 
118  biological product would have primary jurisdiction for the combination product.  The final 
119  regulation also includes an assignment algorithm that the Agency will use when the most 
120  important therapeutic action of a combination product cannot be determined with reasonable 
121  certainty.5  
122  A combination product is assigned to one of the Agencys three human medical product Centers: 
123  CBER, CDER, or CDRH.  The lead center has oversight responsibility for the review and 
124  regulation of the combination product.  The lead center often consults or collaborates with other 
125  agency components and OCP, as appropriate, to identify and evaluate the information needed for 
126  a regulatory submission (e.g., investigational application or marketing authorization).   
127  In streamlining the review of combination products, FDA established a Standard Operating 
128  Procedure for the Intercenter Consultative and Collaborative Review Process.6  The document 
129  provides the policies and procedures for FDA staff to follow when requesting, receiving, 
130  handling, processing, and tracking formal consultative and collaborative reviews of combination 
131  products, devices, drugs and biologics.  The objectives of the SOP are to ensure timely and 
132  effective intercenter communication on combination products, as well as the timeliness and 
133  consistency of intercenter consultations and collaborations.   
134  This guidance describes general information on developmental considerations for products that 
135  combine devices, drugs, and/or biological products.  Although details on the regulatory processes 
136  described in this section are beyond the scope of this guidance document, FDA encourages 
137  developers to contact OCP for assistance in determining the assignment of a lead center when 
138  jurisdiction is unclear or in dispute, the number and type of marketing applications7, the 
                                                 
5 See final rule for Definition of the Primary Mode of Action of a Combination Product, published August 25, 2005, 
Federal Register, http://www.fda.gov/OHRMS/DOCKETS/98fr/05-16527.pdf
6See Intercenter Consultative/Collaborative Review Process at 
http://www.fda.gov/oc/combination/consultative.html. 
7 For most combination products, a single marketing application is sufficient for the products approval, clearance or 
licensure.  In some cases, however, a sponsor may choose to submit two marketing applications for a combination 
product when one application would suffice.  For example, a sponsor may choose to submit two applications in 
order to receive some benefit that accrues only from approval under a particular type of application (e.g., new drug 
product exclusivity, orphan status, or proprietary data protection when two firms are involved).  In other cases, FDA 
may determine that two marketing applications are necessary.  For example, when one of the individual constituent 
parts of a combination product is already approved for another use, and where the labeling of the already approved 
product will need to be changed to reflect its new intended use in the combination product, FDA may determine that 
two applications are necessary if the labeling of the already approved product is subject to legal requirements 
different from those that will apply to the combination product.  FDA encourages applicants who are uncertain as to 
whether a single or multiple marketing applications should be submitted for a combination product to discuss the 
issue with the lead reviewing Division and/or OCP.  Information about the applicable time frames is provided in the 
  4 Contains Nonbinding Recommendations 
139  premarket review process, and the postmarket regulations such as adverse event reporting or 
140  good manufacturing practice requirements that may be appropriate for a combination product.  
141  OCP will work with the agency Centers as appropriate to facilitate a response.  Additional 
142  information on combination product regulation, guidance, and process is available on OCPs 
143  website.8   
144   
145   
146  III.  GENERAL DEVELOPMENT CONSIDERATIONS 
147   
148  As with other medical products, combination product development typically focuses on the 
149  scientific and technical issues raised by the particular product being developed.  For a 
150  combination product, these scientific/technical issues will ordinarily reflect the combination 
151  product itself as well as its constituent parts.  When combining products such as drugs or 
152  biologics and devices that are customarily developed using different regulatory paradigms, 
153  certain critical developmental issues, such as the interaction of the drug/biologic and device 
154  constituents, may not be readily apparent.  Further, because of the breadth, innovation and 
155  complexity of combination products, there is no single developmental paradigm appropriate for 
156  all combination products. 
157   
158  Existing guidance documents are generally excellent starting points for considering the types of 
159  issues raised by the constituent parts of a combination product, but often they will need 
160  adaptation to fully address the combined nature of a combination product.  For example, 
161  guidance for preclinical evaluation of drugs/biologics differs from the preclinical/non-clinical 
162  studies conducted for devices.  When developing a combination product, it is likely that neither 
163  isolated approach would fully address the relevant preclinical development questions for both 
164  constituents as well as for the combination product as a whole.  Instead, FDA recommends that 
165  developers consider the scientific and technical issues raised by the combination product and its 
166  constituents and propose an approach that appropriately addresses these issues without requiring 
167  duplicative or redundant studies.  
168   
169  In many circumstances, the development considerations depend on the type of combination 
170  product.  When the combination product is comprised of constituents that are chemically, 
171  physically or otherwise combined or mixed and produced as a single entity, developers should 
172  consider and, as appropriate, evaluate the potential for a broad range of drug/biologic/device 
173  interactions.  For example, for a drug eluting stent, the mechanical attributes of the polymer 
174  coating system that contains the drug substance are important for stent deployment, drug release, 
175  biocompatibility, and stability.  For some combination products, the constituents may have 
176  synergistic effects that should be evaluated.  In the context of these studies, it is appropriate to 
177  discuss approaches to avoid duplication/redundancy and to develop strategies to streamline the 
178  overlapping aspects of development.  
179   
180  Innovative new technology may also challenge existing approaches for product development.  
181  For example, a new device used to deliver a drug/biologic to a new area of the body that was 
                                                                                                                                                             
guidance document Submission and Resolution of Formal Disputes Regarding the Timeliness of Premarket Review 
of a Combination Product, available at http://www.fda.gov/oc/combination/dispute.pdf.   
8 See OCPs website at http://www.fda.gov/oc/combination.  
  5 Contains Nonbinding Recommendations 
182  previously inaccessible might make it necessary to develop new methods to determine the effect 
183  of such localized/targeted delivery, particularly when it results in higher exposure to that target 
184  than when the drug is systemically administered.  Likewise, innovative technologies such as 
185  nanotechnology or live cellular products may lead to the development of new manufacturing 
186  methodologies or unique safety issues not associated with products manufactured in other ways.   
187   
188  The following sections describe general principles to consider when developing information to 
189  demonstrate the safety and effectiveness of a combination product and its constituent parts.  We 
190  recommend that combination product developers particularly consider the preclinical and non-
191  clinical testing that should be conducted for their product, and how such testing may be 
192  influenced by the interaction of the constituent parts, and any prior approval/clearance of a 
193  constituent part.  FDA believes that the general principles described in this guidance document 
194  would assist developers in providing the appropriate data to help establish the safety and 
195  effectiveness of innovative combination products.  Consideration of these issues in the context of 
196  existing guidance documents may lead to a more targeted and efficient development pathway for 
197  the combination product.   
198   
199   
200  IV.  CURRENTLY MARKETED PRODUCT CONSIDERATIONS  
201   
202  Prior FDA approval and/or clearance of a particular constituent part of a combination product is 
203  often an excellent starting point for considering the appropriate data to establish safety and 
204  effectiveness for its use in a combination product.  FDA recommends that developers fully 
205  consider what is already established about a constituent part; i.e., what existing information and 
206  data are available, to avoid duplication and ensure a more timely and efficient development 
207  process.  Throughout the development process, however, it is critical to recognize that it is the 
208  combination product that is being developed for approval/clearance, not just the constituent part.  
209  While this prior information is often very helpful, developers should recognize that additional 
210  data and information may be necessary to address the scientific and technical issues raised by the 
211  new use of the constituent in the combination product.  These issues may be raised by combining 
212  the constituent parts or by new uses for the constituent in the combination product, such as a new 
213  indication for use, a different target population, a new route of administration, or by different 
214  local or systemic exposure profiles once the products are combined.  For example, developers 
215  should consider:  
216   
217  (cid:131)  Are the constituent parts already approved for an indication? 
218  (cid:131)  Is the indication for a given constituent part similar to that proposed for the combination 
219  product? 
220  (cid:131)  Does the combination product broaden the indication or intended target population 
221  beyond that of the approved constituent part?   
222  (cid:131)  Does the combination product expose the patient to a new route of administration or a 
223  new local or systemic exposure profile for an existing indication?   
224  (cid:131)  Is the drug formulation different than that used in the already approved drug?  
225  (cid:131)  Does the device design need to be modified for the new use? 
226  (cid:131)  Is the device constituent used in an area of the body that is different than its existing 
227  approval? 
  6 Contains Nonbinding Recommendations 
228  (cid:131)  Are the device and drug constituents chemically, physically, or otherwise combined into 
229  a single entity? 
230  (cid:131)  Does the device function as a delivery system, a method to prepare a final dosage form, 
231  and/or does it provide active therapeutic benefit? 
232  (cid:131)  Is there any other change in design or formulation that may affect the safety/effectiveness 
233  of any existing constituent part or the combination product as a whole?   
234  (cid:131)  Is a marketed device being proposed for use with a drug constituent that is a new 
235  molecular entity?   
236  (cid:131)  Is a marketed drug being proposed for use with a complex new device? 
237   
238  As illustrated in the following sections, FDA recommends that the developmental studies should 
239  take into account these questions as appropriate for the constituent parts alone and for the 
240  finished combination product.  FDA furthermore recommends that these issues be considered in 
241  the context of the proposed indication. 
242   
243   
244  V.  PERSPECTIVES BY CONSTITUENT PART 
245   
246  A.  Device constituent considerations 
247   
248  For new device constituent parts, some safety and/or effectiveness testing of the device alone 
249  may be necessary before or along with the studies to establish the safety and effectiveness of the 
250  combination product as a whole.  For device constituent parts that are already approved/cleared 
251  for another purpose, the extent of preclinical testing largely would focus on the new use of the 
252  device constituent as part of the combination product.  For example, if a combination product 
253  incorporates an indwelling, intravenous drug delivery catheter for a new use for long-term, drug 
254  delivery in the brain, new biocompatibility studies may be necessary to establish the safety of the 
255  device materials for placement in neural tissues.  New engineering or functional testing may also 
256  be necessary to establish the suitability of the device design to the new environment in which it 
257  will be used. 
258   
259  Consideration should also be given to the potential interaction (desired or undesired) between the 
260  device and the drug/biological constituents.  For example, it may be appropriate to conduct 
261  studies to evaluate the potential for the following: 
262   
263  Leachables/extractables of the device materials into the drug/biologic substance or final 
 
264  combination product;  
265  Changes in stability of the drug constituent when delivered by the device or when used as a 
 
266  coating on the device;  
267  Drug adhesion/absorption to the device materials that could change the delivered dose;  
 
268  Presence of inactive breakdown products or manufacturing residues from device manufacture 
 
269  that may affect safety, or device actions that could change the drug performance 
270  characteristics at the time of use; or 
271  Changes in the stability or activity of a drug constituent when used together with an energy 
 
272  emitting device. 
  7 Contains Nonbinding Recommendations 
273  Likewise, similar consideration should be given to the effects a drug or biological product may 
274  have on the device constituent.  For example, the material properties of a delivery catheter may 
275  be adversely affected by some drug/biologic products but not others. 
276   
277  CDRH has an active program of evaluating and recognizing consensus standards.9  For many 
278  combination products, it may be appropriate to use these existing consensus standards for the 
279  device constituents of a combination product, including the standard test methods.  For others, 
280  particularly those that are innovative, it may be appropriate to adapt these standards, or it may be 
281  necessary to develop new methodologies.  Because of the range of combination products and 
282  developmental strategies, developers are encouraged to seek early discussions with FDA when 
283  exploring the application of standards to candidate constituent parts and when alternative 
284  methodologies or approaches are being developed.   
285   
286   
287  B.  Drug and biological product constituent considerations10 
288   
289  When a new molecular entity (NME) is a constituent part of a combination product, it is critical 
290  to consider what information is necessary to characterize the safety and effectiveness of the 
291  NME when used in the combination product.  Generally this begins with a consideration of the 
292  NME alone; e.g., the preclinical information necessary to begin the initial studies in human 
293  subjects of the NME and the information needed for combination of the NME and the device 
294  constituent.  For example, certain conventional pharmacology and toxicology studies may be 
295  necessary to establish the safety profile of the NME alone (e.g., genotoxicity, mutagenicity, 
296  immunotoxicity, and local tolerance) before beginning clinical investigation of the combination 
297  product.11  It is also important to consider the timing to initiate any necessary reproductive and 
298  carcinogenicity studies; these types of studies are generally conducted after beginning the 
299  clinical investigation, and they are generally submitted in the marketing application for the 
300  product. 
301   
302  When the combination product contains a drug/biologic constituent that is already approved for 
303  another use, we recommend that the developer address the potential for change in the established 
304  or understood safety, effectiveness, and/or dosing requirements posed by the new combination.  
305  The following are examples of when additional preclinical or clinical safety information or new 
306  clinical studies may be appropriate for the drug/biologic constituent and/or the combination 
307  product: 
308   
309  1.  Approved drug or biological product with a change in formulation, strength,  route of 
310  administration, or delivery method;  
311  2.  New dosage (e.g., absolute dose, dosing duration, dosing regimen, or total exposure); 
                                                 
9 See consensus standards recognized by FDA 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm.   
10 For purposes of this discussion, the term drug applies to drug and most biological product constituent parts. 
11See Guidance to Industry: Format and Content of Non-clinical Pharmacology/Toxicology Section of an 
Application at http://www.fda.gov/cder/guidance/index.htm.  General pharmacology-toxicology guidances may also 
be found at this location. 
  8 Contains Nonbinding Recommendations 
312  3.  New patient population, (e.g., pediatric, geriatric, pregnant or nursing women, or change 
313  in disease or disease status); or 
314  4.  Change in approved indication. 
315   
316  Regardless of the approval status of the drug/biologic constituent, the marketing application 
317  should contain appropriate data to establish the overall safety and effectiveness of the proposed 
318  new dosing regimen or indication as proposed in the combination product.  For a combination 
319  product with a drug or biological product constituent that is already approved, it may be possible 
320  to tailor the pre-clinical development program to address safety questions posed by the new route 
321  or method of delivery, or the change in indication or population.  The goal of these studies would 
322  be to evaluate changes that may result in a different extent or distribution of drug constituent 
323  exposure.12  To the extent that the combination product permits local or systemic drug exposure 
324  that is greater than that occurring with approved dosing regimens, additional safety studies may 
325  also be needed to address the higher doses.  New studies may be appropriate to evaluate the 
326  local/regional toxicity of a drug/device combination product administered directly to targeted 
327  tissue.   
328   
329  Other possible considerations when devising a development plan for a product incorporating a 
330  drug/biologic constituent include: 
331   
332  In vivo pharmacokinetic (PK) studies may be necessary to assess changes in formulation, 
 
333  strength, route of administration, dosing, population or other factors that may alter the 
334  extent or time course of systemic exposure.  These studies might be used to determine 
335  drug release kinetics such as release rate, local peak concentrations of the drug, local 
336  distribution and systemic bioavailability (C , T , etc.).  
max max
337  Dose ranging or dose finding studies13 in humans may be appropriate to determine dose 
 
338  adjustments for safety/effectiveness when therapy is targeted to a local site. 
339  Acute and repeat dose toxicity studies using the new route of administration or method of 
 
340  delivery may be appropriate to determine the NOAEL (no observed adverse effect level) 
341  and toxicity profile of the combination product.  Typically, these studies would evaluate 
342  the intended clinical formulation and dosing regimen/frequency that will closely 
343  approximate its use in clinical settings.  
344    Special safety studies may be appropriate for certain patient populations or risk profiles; 
345  e.g., hepatotoxicity, QT prolongation, special populations.  
346    Specific safety monitoring in the clinical study may be appropriate to obtain data on the 
347  novel aspects presented by the combination product; e.g., local toxicity for a new route of 
348  administration.14   
349   
                                                 
12 See Guidance to Industry: Exposure-Response Relationships - Study Design, Data Analysis, and Regulatory 
Applications at http://www.fda.gov/cder/guidance/5341fnl.doc.
13 See ICH E4 Dose-Response Information to Support Drug Registration at 
http://www.fda.gov/cder/guidance/iche4.pdf.
14 See ICH E1A: The Extent of Population Exposure to Assess Clinical Safety: For Drugs Intended for Long-term 
Treatment of Non-Life-Threatening Conditions at http://www.fda.gov/cder/guidance/iche1a.pdf.
  9 Contains Nonbinding Recommendations 
350  In some instances, developers may be able to provide relevant information from the literature or 
351  may rely on prior agency findings to address these issues.  When this is not possible, then 
352  additional studies may be necessary. 
353   
354   
355   
356  VI.  ADDITIONAL PERSPECTIVES 
357   
358  A.  Clinical Investigation 
359   
360  For most combination products, one investigational application (Investigational New Drug (IND) 
361  or Investigational Device Exemption (IDE) application) is submitted for the clinical investigation 
362  of the combination product as a whole.  Generally, the regulatory guidance for INDs and IDEs 
363  provides substantial flexibility in considering how to address the issues posed by a particular 
364  product.  Two such guidance documents that may be of interest to combination product 
365  developers are: (1) Exploratory IND Studies, which provides an alternative for exploring 
366  candidate products during research and development prior to selecting the composition for 
367  further development,15 and (2) guidance on changes that may occur during investigational 
368  development of a device.16   
369  Clinical development questions frequently arise about trial design, sample size, statistical 
370  methods, clinical endpoints, appropriate number of clinical studies, and appropriate 
371  indications/claims.  We recommend that you consider the science and technology of the 
372  combination product when determining sample size, use of statistical approaches, surrogate 
373  endpoints, techniques to measure drug levels in areas not typically accessible, or techniques to 
374  evaluate drug-device interactions.  Although these issues are beyond the scope of this guidance, 
375  FDA encourages developers to seek early discussion with the Agency around these concerns.   
376  For certain combination products that include a device constituent part, it may be necessary to 
377  evaluate the human factors of device use on the safety and effectiveness of the combination 
378  product.  Such studies would evaluate how users operate the system in realistic, stressful 
379  conditions.  In many cases, these studies include an assessment of all components and 
380  accessories necessary to operate and properly maintain the device; e.g., controls, displays, 
381  software, logic of operation, labels, instructions, analysis of critical tasks, use error hazard and 
382  risk analysis.  We recommend that human factors evaluations take place early in the combination 
383  product development process to identify design features that may need modification before 
384  conducting the key studies to establish the safety and effectiveness of the combination product.     
385   
386   
                                                 
15See Guidance to Industry and Reviewers: Exploratory IND Studies at 
http://www.fda.gov/cder/guidance/7086fnl.pdf. 
16 See Guidance to Industry: Changes or Modifications During the Conduct of a Clinical Investigation at 
http://www.fda.gov/cdrh/ode/guidance/1337.pdf
  10 Contains Nonbinding Recommendations 
387  B.  Manufacturing considerations 
388   
389  Manufacturing, scale-up, and quality management17 are important considerations during the 
390  development of a combination product.  Manufacturing methodologies affect both premarket 
391  development and postmarket regulation.  FDA encourages consideration of the manufacturing 
392  issues posed by the scientific and technical aspects of the drug, biological product, and device 
393  constituent parts, and of the combination product as a whole.  FDA also encourages developers 
394  to carefully consider the effect of the manufacturing methods on the interaction of the constituent 
395  parts.  For example, the stability of a combination product as a whole may be different than that 
396  of the separate constituent parts.  Certain drug or biological product constituent parts may be 
397  altered or destroyed by terminal sterilization techniques.  For constituent parts that use aseptic 
398  manufacturing techniques, developers are encouraged to implement manufacturing techniques to 
399  ensure aseptic control for the combination product.   
400   
401  During premarket investigation, once the preclinical and clinical studies begin, any potential 
402  change in the manufacturing process for the drug, biologic, or device constituents or for the 
403  combination product may affect the safety or effectiveness of the combination product as a 
404  whole.  For example, changes in concentration, inactive ingredients, software, or in the methods 
405  to combine two constituent parts, could affect the performance characteristics of the combination 
406  product.  When applying cellular constituent parts to a device, the performance characteristics 
407  may vary with the time and methods used for cellular incubation before application to the device 
408  constituent.  Additionally, the applicable device constituent design controls would consider 
409  anticipated manufacturing changes during investigational development.  In order to address such 
410  manufacturing considerations, it may be necessary to develop new manufacturing techniques, in-
411  process testing, testing specifications, and other characterization methods to assess changes in 
412  the constituent parts and for the combination product as a whole.  For certain developmental 
413  changes, additional bridging studies (in vitro, preclinical, or clinical) may be appropriate.    
414   
415  In addition to considering manufacturing changes that may occur during premarket development, 
416  FDA also recommends early consideration of anticipated postmarket manufacturing changes for 
417  the combination product or its constituent parts.  FDA encourages manufacturers to establish 
418  arrangements with the manufacturers of constituent parts to maintain sufficient awareness of 
419  manufacturing changes in constituent parts that may occur during the premarket or postmarket 
420  period.  Such awareness could help to ensure continued safety and effectiveness of the 
421  combination product by ensuring that the potential impact of a manufacturing change is 
422  evaluated in a manner appropriate for the stage of combination product development.  As 
423  appropriate, these postmarket manufacturing changes may require careful review, validation and 
424  prior approval before marketing.  For some products, it may be helpful to develop post-approval 
425  change protocols for further discussion with the Agency.  
426   
                                                 
17 FDAs current thinking about good manufacturing practices for combination products is described in Draft 
Guidance for Industry and FDA Staff:  Current Good Manufacturing Practice for Combination Products, available 
at http://www.fda.gov/oc/combination/OCLove1dft.html.  FDA intends to propose current good manufacturing 
practice regulations for combination products; see the April 24, 2006 Federal Register (71 FR 22565). 
 
  11 Contains Nonbinding Recommendations 
427  C.  Reliance on information not developed by the applicant 
428   
429  Investigational or marketing applications often contain trade secret or confidential commercial 
430  information.  In some instances, developers may wish to provide all necessary information in one 
431  marketing application.  However, for combination products being developed by more than one 
432  manufacturer, there may be a desire to provide necessary information to FDA while maintaining 
433  the confidentiality of each manufacturers intellectual property.  This can be accomplished by the 
434  application holder submitting to FDA a letter of authorized cross reference from the owner of the 
435  referenced material.  This letter would grant FDA permission to consider the referenced material 
436  in its review of the current application.  In general, the referenced information may be available 
437  from two sources:   
438   
439  1.  Existing application:  An existing investigational application (IND or IDE) or an 
440  existing marketing application (NDA, BLA, PMA or 510(k)) may provide 
441  information relevant to a new developers application.  In some instances, the 
442  application being cross referenced may be under co-review for use in the combination 
443  product.  In other instances, the cross-referenced application may be approved for 
444  other purposes, but may have information relevant to the new use.  
445   
446  2.  Master file:  Master files provide an administrative method to submit confidential 
447  information to FDA when an appropriate investigational or marketing application for 
448  the constituent is not available.  A master file is not a substitute for an investigational 
449  or marketing application.  FDA neither approves nor disapproves master files; rather, 
450  information in a master file is considered in the context of a particular investigational 
451  or marketing application.  It should be recognized that the information in a master file 
452  may be sufficient to support a marketing application for one product, while additional 
453  information may be necessary to support its use in another product.  For example, this 
454  may occur when specific issues raised by the new use of a constituent are not 
455  addressed in the master file.  Such information could be provided by supplementing 
456  the existing master file, or by providing the necessary information in the application 
457  under review.  More information on drug master files may be found in 21 CFR 
458  314.420 or at http://www.fda.gov/cder/dmf/index.htm.  More information on device 
459  master files is available at 
460  http://www.fda.gov/cdrh/dsma/pmaman/appdxc.html#P7_2. 
461   
462   
463   
464  VII.  EARLY INTERACTION AND COMMUNICATION WITH FDA 
465   
466  FDA strongly encourages early communication and discussion between developers, FDA review 
467  components and, as appropriate, OCP.  Early dialogue allows developers to obtain initial 
468  feedback on the kinds of preclinical and clinical testing that may be necessary.  Such 
469  communication may identify critical issues for product development and help to ensure an 
470  efficient development and approval process.  Further, early and frequent communication 
471  provides the opportunity for FDA to establish its intercenter review team and to develop the 
  12 Contains Nonbinding Recommendations 
472  appropriate scientific expertise to facilitate timely and efficient reviews of any future 
473  submissions.   
474   
475  CBER, CDER and CDRH provide guidance on milestone/collaboration meetings throughout the 
476  development process and submission of investigational and marketing applications.  Pre-
477  investigational (pre-IND and pre-IDE) meetings are particularly useful for discussing innovative 
478  combination products.  Pre-marketing application meetings are also helpful to discuss application 
479  content, as well as the sequence and timing of modular applications or when more than one 
480  marketing application will be submitted for the combination product.  Guidance on how to 
481  arrange developmental meetings can be obtained on the CDER,18 CBER19 and CDRH20 
482  websites.    
483   
484  The lead center should be contacted to schedule meetings in accordance with the procedures and 
485  milestones applicable to the lead center.  We encourage developers to request participation from 
486  relevant review components from both the lead and consulting Centers, where appropriate.  In 
487  addition, OCP is available formally or informally to address jurisdictional, developmental, 
488  premarket review, and postmarket concerns.   
489   
490   
491  A.  Where may I obtain additional information? 
492   
493  OCP is available as a resource to developers and review staff throughout the lifecycle 
494  (assignment, development, premarket review and postmarket regulation) of a combination 
495  product.  The Office can be reached at (301) 427-1934 or by email at combination@fda.gov.  In 
496  addition, the Office maintains an updated list of FDA guidance documents that developers may 
497  find helpful in the development of their products.  The guidance is available at the Offices 
498  Internet Website at http://www.fda.gov/oc/combination. 
499   
500  In addition each center maintains a guidance webpage that provides comprehensive information 
501  on the types of constituents regulated in the center.  The CDER Guidance webpage is accessible 
502  at http://www.fda.gov/cder/guidance/index.htm.  The CDRH Guidance web page is accessible at 
503  http://www.fda.gov/cdrh/guidance.html and the device advice webpage is assessable at 
504  http://www.fda.gov/cdrh/devadvice/.  The CBER Guidance web page is accessible at 
505  http://www.fda.gov/cber/guidelines.htm. 
506   
507   
                                                 
18 See http://www.fda.gov/cder/guidance/3683fnl.pdf.    
19 See http://www.fda.gov/cber/gdlns/ind052501.htm. 
20 See http://www.fda.gov/cdrh/devadvice/ide/print/approval.html , and, Early Collaboration Meetings Under the FDA 
Modernization Act, Final Guidance for Industry and CDRH Staff; http://www.fda.gov/cdrh/ode/guidance/310.html
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