Bridging for Drug-Device 
and Biologic-Device 
Combination Products 
Guidance for Industry 
 
 
 
DRAFT GUIDANCE 
 
This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit electronic comments to https://www.regulations.gov.  Submit written 
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, Rm. 1061, Rockville, MD 20852.  All comments should be identified with the 
docket number listed in the notice of availability that publishes in the Federal Register.  
 
For questions regarding this draft document, contact (CDER) Irene Chan at 301-796-3962 or 
Robert Berlin at 301-796-8828, (CBER) Office of Communication, Outreach, and Development 
at 240-402-8010, (CDRH) CDRH product jurisdiction officer at 
CDRHProductJurisdiction@fda.hhs.gov, or (OCP) Patricia Love at patricia.love@fda.hhs.gov. 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
Center for Devices and Radiological Health (CDRH) 
 
December 2019 
Combination Products
27383982dft.docx 
5/28/2019   
Bridging for Drug-Device 
and Biologic-Device 
Combination Products 
Guidance for Industry 
 
Additional copies are available from: 
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Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
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https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
or 
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Food and Drug Administration 
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https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances 
or 
Office of Policy 
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Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 66, Room 5431 
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Email: CDRH-Guidance@fda.hhs.gov 
https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-assistance/guidance-documents-medical-devices-
and-radiation-emitting-products 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
Center for Devices and Radiological Health (CDRH) 
 
December 2019 
Combination Products 
  Contains Nonbinding Recommendations 
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TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 3 
III.  DEVELOPING AN ANALYTICAL FRAMEWORK FOR IDENTIFYING 
INFORMATION GAPS TO INFORM A BRIDGING AND LEVERAGING 
APPROACH ...................................................................................................................... 4 
IV.  BRIDGING AND LEVERAGING EXAMPLES ........................................................... 6 
A.  Bridging Within an IND from a Drug Developed in a Prefilled Syringe to a Drug Developed 
in an Autoinjector .......................................................................................................................... 7 
B.  Bridging From One Autoinjector (Prototype 1) to Another Autoinjector (Prototype 2) for 
the Same Drug; After Phase 3 Studies Have Been Completed but Before NDA  
  Submission .................................................................................................................................... 11 
C.  Bridging of Data From Combination Product That Employs the Same Device Combined 
With a Different Drug ................................................................................................................. 13 
 
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1  Bridging for Drug-Device and  
2  Biologic-Device Combination Products 
3  Guidance for Industry1 
4   
5   
6   
7   
8  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
9  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
10  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
11  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
12  for this guidance as listed on the title page. 
13   
14   
15   
16   
17  I.  INTRODUCTION 
18   
19  This guidance provides recommendations to industry and FDA staff on how to approach 
20  bridging in new drug applications (NDAs) or biologics license applications (BLAs) for drug-
21  device and biologic-device single entity or copackaged combination products including the 
22  following:2  
23   
24    Bridging of information related to a combination product that employs a different device 
25  constituent part or parts3 with the same drug constituent part or parts4 as the proposed 
26  combination product 
27   
                                                 
1 This guidance has been prepared by the Office of Surveillance and Epidemiology and the Office of New Drugs in 
the Center for Drug Evaluation and Research, in cooperation with the Center for Biologics Evaluation and Research, 
the Center for Devices and Radiological Health, and the Office of Combination Products at the Food and Drug 
Administration.  This guidance is one of several documents FDA is issuing to fulfill the performance goals under the 
sixth authorization of the Prescription Drug User Fee Act (PDUFA VI). 
 
2 See section 503(g) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and the definition of combination 
products in 21 CFR 3.2. 
 
3 See constituent part definition in 21 CFR 4.2. 
 
4 For purposes of this guidance, except where specifically indicated, references to drug or drug constituent part or 
parts include a drug or biological product constituent part submitted as part of a combination product for approval or 
approved under section 505(c) of the FD&C Act (21 U.S.C. 355(c)) or licensed under section 351(a) of the Public 
Health Service Act (PHS Act).  Some of the principles applicable to products submitted for approval under section 
505(b) of the FD&C Act or licensure under section 351(a) of the PHS Act may also be applicable to products 
submitted for approval under section 505(j) of the FD&C Act or licensure under section 351(k) of the PHS Act.  In 
addition, the scientific principles discussed in this guidance may be applicable to combination product submissions 
under sections 515, 513(f)(2), or 510(k) of the FD&C Act. 
 
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28    Bridging of information related to a combination product that employs a different drug 
29  constituent part or parts with the same device constituent part or parts as the proposed 
30  combination product   
31   
32  For the purposes of this guidance, the term bridging refers to the process of establishing the 
33  scientific relevance of information developed in an earlier phase of the development program or 
34  another development program to support the combination product for which an applicant is 
35  seeking approval.  Once the applicant has established the relevance of such information to (i.e., 
36  bridged to) its product, the applicant can leverage that information to streamline its development 
37  program.5  From a scientific perspective, an applicant must bridge its current application to 
38  information developed in an earlier phase of the development program or another development 
39  program if the applicant wishes to leverage that information in its current application.  For 
40  certain types of applications, the use of information from another development program may 
41  require that the applicant own the information or have a right of reference.6  
42   
43  With respect to the recommendations and examples in this guidance, it is assumed that the 
44  applicant owns or has a right of reference or use that allows the applicant to use information 
45  from another development program.   
46   
47  This guidance seeks to clarify how to bridge to information gathered from another development 
48  program to leverage that information in support of an application.  To facilitate that process, this 
49  guidance describes an approach for an applicant to identify and address information gaps for an 
50  application.   
51   
52  This guidance applies to the following: 
53   
54    Human prescription combination products that are the subject of an investigational new 
55  drug application (IND) under 21 CFR part 312, an NDA under 21 CFR part 314, or a 
56  BLA under 21 CFR part 601 
57   
58    Human nonprescription combination products that are the subject of an IND, NDA, or 
59  BLA (as opposed to those covered in a final or tentative over-the-counter drug 
60  monograph) 
61   
                                                 
5 There are certain regulatory considerations that apply to reliance on certain types of information in certain 
applications (e.g., reliance on a previous finding of safety and effectiveness for a drug the applicant does not own or 
to which it has no right of reference in a 505(b)(2) application) but discussion of those considerations is beyond the 
scope of this guidance. See the draft guidance for industry Applications Covered by Section 505(b)(2) (October 
1999).  When final, this guidance will represent the FDAs current thinking on this topic.  For the most recent 
version of a guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-
guidance-documents.  
 
6 See, for example, 21 CFR 314.3, Right of reference or use is the authority to rely upon, and otherwise use, an 
investigation for the purpose of obtaining approval of an NDA [new drug application], including the ability to make 
available the underlying raw data from the investigation for FDA audit, if necessary. 
 
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62  All such products in this guidance are referred to as combination products.  Except where it is 
63  specifically indicated that this is not the case, the terms drug and drug constituent part are used 
64  interchangeably and also refer to biological products and biological product constituent parts; the 
65  terms device and device constituent part are used interchangeably, and persons responsible for 
66  product development are referred to as applicants. 
67   
68  Although this guidance is intended to help applicants consider the type and scope of information 
69  that may be leveraged for a combination product development program, this guidance does not 
70  address all of the issues applicable to any particular combination product.  The Agency 
71  encourages applicants to contact FDA to discuss specific information needed to support their 
72  individual applications.7 
73   
74  This guidance does not discuss the appropriate regulatory pathway an applicant should use to 
75  bring a particular combination product to market.8   
76   
77  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
78  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
79  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
80  the word should in Agency guidances means that something is suggested or recommended, but 
81  not required. 
82   
83   
84  II.  BACKGROUND 
85   
86  While drugs, devices, and biological products retain their discrete regulatory identities when they 
87  are constituent parts of a combination product, combination products comprise a distinct 
88  category of medical products that can be subject to specialized regulatory requirements.9  
89  Accordingly, the regulatory requirements for combination products arise from the statutory and 
90  regulatory requirements applicable to drugs, devices, and biological products.10  Consistent with 
91  section 503(g) of the Federal Food, Drug, and Cosmetic Act, FDA is committed to applying a 
92  consistent, risk-based approach to address similar regulatory questions, including scientific 
93  questions, using relevant expertise from the lead and consulted centers within FDA. 
94   
                                                 
7 See the draft guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA 
Products (December 2017).  When final, this guidance will represent FDAs current thinking on this topic.   
 
8 See the draft guidance for industry and FDA staff Principles of Premarket Pathways for Combination Products 
(February 2019).  When final, this guidance will represent FDAs current thinking on this topic.   
 
9 See the final rule, Current Good Manufacturing Practice Requirements for Combination Products, published 
January 22, 2013 (21 CFR Part 4, Subpart A; 78 FR 4307-22) and the final rule, Postmarketing Safety Reporting 
for Combination Products, published December 20, 2016 (21 CFR Part 4, Subpart B; 81 FR 92603-26). 
 
10 Ibid.  
 
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95  Depending on an applicants development program, there may be circumstances in which an 
96  applicant has its own existing information (or rights of reference to information) about another 
97  combination product or a proposed constituent part that may be leveraged to support approval of 
98  the proposed combination product if an appropriate bridge can be established.  In general, FDA 
99  would require additional data and information only if the information were needed to address 
100  additional questions of safety or effectiveness raised by the proposed use or function of a 
101  constituent part in the combination product.11  For example, in general, if a stand-alone device 
102  proposed to be used as a device constituent part of a combination product has been previously 
103  approved or cleared, the applicant may be able to leverage relevant existing device-related data, 
104  provided that the data has been bridged (i.e., shown to be scientifically relevant), for the 
105  development of a new combination product.   
106   
107  In some cases, the amount of information that can be leveraged for such proposed combination 
108  products may be minimal, or leveraging may not be possible.  For example, a change in route of 
109  administration for a complex biological product may raise additional safety and/or efficacy 
110  considerations, and such considerations may make it difficult to bridge to the proposed 
111  combination product.  Discussions with the Agency about planned leveraging are appropriate to 
112  identify questions early in drug development. 
113   
114   
115  III.  DEVELOPING AN ANALYTICAL FRAMEWORK FOR IDENTIFYING 
116  INFORMATION GAPS TO INFORM A BRIDGING AND LEVERAGING 
117  APPROACH 
118   
119  Developing a framework that identifies where information gaps may exist in a combination 
120  product development program is an important task for applicants.  The following information 
121  assumes that applicants are familiar with existing FDA regulations, guidance documents, and 
122  resources on drug and device development available from the Center for Drug Evaluation and 
123  Research (CDER), the Center for Biologics Evaluation and Research, the Center for Devices and 
124  Radiological Health, and the Office of Combination Products to assess the information that 
125  should be included in an IND, NDA, or BLA, as appropriate.  Under this premise, the example of 
126  a framework below supposes that an applicant seeks to bridge from the FDA-approved, drug-
127  device (delivery system) Combination Product A to proposed Combination Product B.  The 
128  Agency recommends that an applicant use the stepwise approach presented below to conduct a 
129  gap analysis for the proposed Combination Product B: 
130   
131  Step 1. Identify all differences between Combination Products A and B, and consider the 
132  potential effect of the individual and aggregate differences on the safety and effectiveness 
133  profile for Combination Product B.   
134   
                                                 
11 See section 503(g)(3) of the FD&C Act: The [FDA]may require that the sponsor of such combination product 
submit to the [FDA] only data or information that the [FDA] determines is necessary to meet the standard for 
clearance or approval, as applicable, under this Act or th e Public Health Service Act, including any incremental risks 
and benefits posed by such combination product, using a risk-based approach and taking into account any prior 
finding of safety and effectiveness or substantial equivalence for the approved constituent part relied upon by the 
applicant. 
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135  Specifically, for Combination Product B in comparison with Combination Product A, the 
136  safety and effectiveness profile should include a clear, comprehensive listing of the 
137  differences in the device constituent part, the drug constituent part, and the combination 
138  product as a whole.  Some examples of the potential effect of a change in drug or device 
139  constituent part for Combination Product B compared to the existing safety and/or 
140  effectiveness profile for Combination Product A include the following: 
141   
142    Changes to the local injection adverse reaction profile including those related to an 
143  increase in drug concentration, a change in drug viscosity or formulation, or a change 
144  in injection rate 
145   
146    Change in the dose accuracy of the same device constituent part when the drug 
147  formulation is changed 
148   
149    Changes in the manufacturing process and/or device constituent part that may affect 
150  drug quality 
151   
152    Change in whether the intended users can use Combination Product B safely and 
153  effectively when the user interface of the device constituent part changes 
154   
155    Changes in the bioavailability of the drug and/or its metabolic profile that can occur 
156  because of changes in the device, formulation, or route of administration, such as the 
157  following:  
158   
159    Changes in the needle depth, tissue plane, or rate of infusion  
160   
161    Change in drug formulation that results in differential lung depositions even when 
162  the drug is administered with the same device  
163   
164    Changes in drug formulation that can affect the leachable and extractable profiles of 
165  the combination product 
166   
167  Step 2. Identify existing information for Combination Product B (i.e., information that has 
168  been gathered or generated through studies and assessments of the proposed combination 
169  product itself) and compare it to the safety and effectiveness submission requirements 
170  necessary for approval.  
171   
172  Step 3. Identify and explain how and why existing information on Combination Product A 
173  can be bridged and leveraged to support approval of Combination Product B, taking into 
174  account the considerations in Step 1 and the information already gathered in Step 2. 
175   
176  Step 4. Focus on any information gaps remaining from Steps 2 and 3, and consider whether 
177  other existing information, outside of that directly gathered for Combination Product A or B, 
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178  can be reviewed and used to address these gaps under the proposed regulatory pathway as 
179  described in Step 5 below.12 
180   
181  Step 5. Compare findings from Step 2 through 4 and identify the remaining gaps in 
182  information that need to be addressed in the product application. 
183   
184  After completing a gap analysis, FDA recommends that applicants meet with FDAs lead center 
185  review division along with consulting reviewers to discuss what new information or studies may 
186  be needed to support the application for Combination Product B. 
187   
188  Special considerations:  The stepwise framework and associated analyses described above 
189  represent general considerations regarding how the applicant should prepare an application.  
190  However, leveraging may be challenging or not possible with some combination products 
191  because they contain complex constituent parts and/or are likely to be affected by seemingly 
192  minor changes.  For example, combination products that include certain biological products or 
193  complex delivery systems may not allow the same degree of leveraging as would be possible for 
194  a combination product that includes a well-characterized drug or a well-understood device.  
195  Nonetheless, the framework and associated analyses in this guidance are at least potentially 
196  applicable to such combination products. 
197   
198   
199  IV.  BRIDGING AND LEVERAGING EXAMPLES 
200   
201  In this section, we present three case examples to illustrate how an applicant might appropriately 
202  apply the above stepwise framework and associated analyses to determine the bridging strategy 
203  and informational needs in a development program, which it would then present to FDA.  It is 
204  important to note that the cases represent hypothetical examples.  The approach taken provides 
205  one acceptable way to break down the thought process around preparing applications from an 
206  applicants viewpoint.  We recognize that many applicants would likely be considering multiple 
207  steps from the framework simultaneously.  Most importantly, these considerations and 
208  recommendations are not intended to apply to any particular development program.  Product-
209  specific considerations will lead to differing informational requirements by FDA.  We encourage 
210  applicants to discuss their particular development program and bridging strategy with FDA.  
211   
212  If the applicant determines early in a drug development program that the intent will be to market 
213  multiple presentations or a presentation that is different from that studied in early development,13 
214  FDA encourages the applicant to conduct clinical studies using the device constituent parts with 
215  which it intends to market the combination product (i.e., the final finished combination product).  
216  By doing so, bridging to clinical data likely would not be needed because the data would have 
217  been developed with the final finished combination product.   
218   
                                                 
12 Note that use of certain sources of information may not be permitted under certain regulatory pathways, but that 
discussion is beyond the scope of this guidance.  
 
13 For the purposes of this guidance, the term presentation refers to the device constituent part of the combination 
product. 
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219  A.  Bridging Within an IND from a Drug Developed in a Prefilled Syringe to a 
220  Drug Developed in an Autoinjector 
221   
222  In this hypothetical case example, the applicant is developing a combination product containing a 
223  new molecular entity (NME) drug constituent part with the initial plan to market it in a prefilled 
224  syringe (PFS) presentation, intended for home use by laypersons, including patients.  During the 
225  course of development, the applicant decided that it would also like to market the NME in an 
226  autoinjector presentation.  The final finished combination product for the newly proposed 
227  presentation will be an autoinjector assembled around the original PFS.  The primary container 
228  closure in direct contact with the drug (i.e., barrel, plunger, and needle) remains the same and the 
229  drug formulation remains the same.  The route of administration (subcutaneous) is the same.  
230  The applicant intends to market both the PFS and autoinjector presentations commercially. 
231   
232  Using the stepwise framework, the applicants gap analysis identifies the following: 
233   
234  Step 1. The applicant identifies the differences between the first and second presentations.  
235  The principal difference is the change of the device constituent part made by adding an 
236  autoinjector to the PFS combination product.  In this case, the autoinjector results in three 
237  key changes: 1) it adds a new secondary container closure, 2) it changes the method of 
238  injecting the drug constituent part, and 3) it has a different user interface.   
239   
240  In considering the potential effect of the individual and aggregate differences on the safety 
241  and effectiveness of the autoinjector combination product as a whole, the applicant identifies 
242  the following gap-analysis considerations: 
243   
244    The difference in the user interface leaves an unanswered question regarding whether 
245  the user interface design supports safe and effective use, which may change its safety 
246  and effectiveness profile as compared to the PFS.  
247   
248    Changes in assembly of the prefilled syringe into the autoinjector could change 
249  quality considerations for the drug constituent part if the manufacturing process for 
250  the autoinjector adversely affects the drug, including, but not limited to, degradation 
251  associated with assembly and the effect of the process on sterility.  Likewise, 
252  chemistry, manufacturing, and controls (CMC) considerations in this context include 
253  impacts on syringe resistance to breakage, functionality throughout shelf life, and 
254  expiration dating.   
255   
256    Changes in the method of injecting the drug constituent part may affect the local 
257  adverse reaction profile because of a change in the rate at which the drug is delivered 
258  to the target tissue.  For example, it is expected that the PFS is associated with more 
259  variability in injection time with real world use, whereas the autoinjector is designed 
260  to meet a specific injection time specification.   
261   
262    Changes in the method of injecting the drug constituent part may affect the 
263  pharmacokinetic (PK) profile of the drug.  For example, changing the delivery 
264  method may lead to differences including consistency or variability of injection angle, 
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265  tissue depth (potentially associated with the rate of drug delivery as determined by the 
266  injection time), and completeness of the injection.   
267   
268    Assembling the autoinjector around the PFS will require, among other things, 
269  assessment of design features of the additional autoinjector combination product.14 
270   
271  Step 2. The applicant has not yet developed information specifically for the drug combined 
272  with the autoinjector presentation and, therefore, will have to either leverage existing 
273  information or develop new supporting data.   
274   
275  Step 3. The applicant conducted phase 3 studies with the PFS presentation.  These studies 
276  provided data on PK, nonclinical data, toxicity, safety and effectiveness, and leachable and 
277  extractable profiles.  The applicant identifies the following information that could be applied 
278  to the new autoinjector combination product and the associated rationale: 
279   
280    Because the proposed drug, indication, dosage, formulation, and route of 
281  administration are the same, the applicant believes that if the PK profile is shown to 
282  be the same through testing, then nonclinical, toxicity, and safety and effectiveness 
                                                 
14 Combination products are subject to 21 CFR part 4, which sets forth current good manufacturing practice 
(CGMP) requirements for combination products.  The constituent parts of a combination product retain their 
regulatory status (as a drug or device, for example) after they are combined.  The CGMP requirements that apply to 
each of the constituent parts apply to the combination product they constitute. 
For single-entity and co-packaged combination products that include both a drug and a device, such as 
those covered in this guidance, manufacturers may implement a streamlined approach for these combination 
products (21 CFR 4.4(b)).  Under this approach, combination product manufacturers may meet the requirements of 
both the drug CGMPs and device quality system QS regulation by designing and implementing a CGMP operating 
system that demonstrates compliance with the drug CGMPs and the following provisions from the device QS 
regulation: 21 CFR 820.20 (management responsibility); 21 CFR 820.30 (design controls); 21 CFR 820.50 
(purchasing controls); 21 CFR 820.100 (corrective and preventive action); 21 CFR 820.170 (installation); and 21 
CFR 820.200 (servicing).  See 21 CFR 4.4(b)(1).  One of the specified QS regulation provisions codifies the 
obligation to comply with 21 CFR 820.30 design controls requirements for these drug-device combination products, 
including design verification and validation.  See 21 CFR 4.4(b)(1)(ii).  Design control activities confirm that there 
are no negative interactions between constituent parts and ensure that their combined use results in a combination 
product that is safe and effective and performs as expected.  The focus of design control discussion in this guidance 
is the information required to demonstrate that the final combination product achieves its identified performance 
targets under the identified conditions of use, as opposed to the procedural requirements of 21 CFR 820.30 for 
developing and managing such information (e.g., requirements concerning design and development planning and 
design history file).  Data needed to make such design verification and validation demonstrations vary depending on 
the combination product and its intended use but typically include, among other things, bench data, 
preclinical/clinical testing data,  and human factors (HF) studies.  For further information on design control 
requirements for combination products, see the guidance for industry and FDA staff Current Good Manufacturing 
Practice Requirements for Combination Products (January 2017) (2017 CGMP Guidance for Combination 
Products). 
Moreover, a biological product regulated under section 351 of the Public Health Service Act is also, by 
definition, a drug or a device.  Accordingly, for combination products that include a biological product, in addition 
to complying with the drug CGMP and device QS regulation requirements as applicable in accordance with 21 CFR 
part 4, manufacturers of such products must comply with the CGMP requirements in 21 CFR parts 600 through 680 
that would apply to the biological product if it were not part of a combination product (21 CFR 4.4(b)(3)). 
 
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283  data gathered in the existing clinical program for the PFS presentation could also 
284  apply for the autoinjector presentation. 
285   
286    Because the primary container closure (the PFS) is the same for both presentations 
287  (drug will be in contact with the glass of the PFS, elastomeric plunger, and needle 
288  with use), and because the applicant expects that the secondary container closure 
289  autoinjector materials, during manufacture and storage of the combination product, 
290  will not come in direct contact with the drug or change its characteristics, the 
291  applicant believes that the leachable and extractable profile gathered for the PFS 
292  presentation should also apply for the autoinjector presentation.   
293   
294  Step 4. The applicant considers whether other existing information may be leveraged to 
295  support the items in Step 4.  In the course of examining other available information, the 
296  applicant identifies the following: 
297   
298  An autoinjector with the same user interface was previously approved as part of a 
299  combination product with another drug in the applicants portfolio.  The approved 
300  combination product was developed for a different disease state and indication and for use in 
301  a different patient population with differing injection sites.  The approved combination 
302  product has been marketed for two years and there are currently no adverse compliance 
303  actions or postmarketing safety issues under investigation by the applicant.  The applicant 
304  considers whether it is appropriate to establish a bridge between the previously approved 
305  combination product and the proposed autoinjector in order to leverage human factors 
306  validation data.  The applicant recognizes, however, that since the product was developed for 
307  another population and indication, it will be challenging to bridge the applications and 
308  intends to conduct a HF validation study and prepare a HF validation study report  to be 
309  submitted as part of the marketing application.15   
310   
311  The applicant also believes that it should be able to bridge the autoinjectors with regard to 
312  device performance that is unrelated to the drug since this would be unchanged between the 
313  products. In particular, because the previously approved autoinjector design used the same 
314  syringe with the same prestaked needle for its prefilled drug, the applicant believes it can 
315  leverage design verification data unrelated to the drug being injected (e.g., extended needle 
316  length, autoinjector activation force, and cap removal force).  The applicant, however, 
317  intends to generate additional verification data on factors affected by the drug (e.g., dose 
318  accuracy, injection time, etc.).  Additionally, the applicant considers the possibility that the 
319  change in indication, injection site or user population could impact the acceptability, from a 
320  validation perspective, of dose accuracy, extended needle length, injection time, autoinjector 
321  activation force, cap removal force and other autoinjector performance specifications.  
322  Therefore, the applicant plans to provide design validation confirming that the autoinjector 
323  performance specifications are adequate for the new drug.   
                                                 
15 Regardless of whether HF studies are submitted for the marketing application, such studies and/or analysis of 
whether the studies are needed may still need to be included as part of design control documentation for the 
combination product.  See, for example, 21 CFR 820.30(g) & (j). 
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324   
325  Step 5. The applicant determines that the following information may still be needed: 
326   
327    Human factors (HF) validation data for the autoinjector presentation to support the 
328  new user interface. 
329   
330    Local adverse event data to assess how the new interface may affect pain on delivery.  
331  This may include any potential change to injection time, which may change the rate at 
332  which the drug is delivered to the target tissue. 
333   
334    CMC and engineering data: syringe resistance to breakage, functionality, 
335  maintenance of sterility over shelf life, degradation of the drug from the assembly 
336  process, and expiration dating.  Note that the companys testing related to sterility and 
337  degradation would primarily be intended to verify that the new process did not create 
338  issues. 
339   
340    Design verification and validation data for the autoinjector presentation,16 including 
341  dose accuracy and injection time.17  The applicant also intends to provide a copy of 
342  design control documentation for the delivery system and combination product as a 
343  whole, including documentation of design requirements and specifications, design 
344  verification, design validation, and risk analysis for use of the applicants previously 
345  approved autoinjector with a new drug.   
346   
347     The applicant intends to assess how any changes in drug delivery affect the PK 
348  profile of the combination product.  Changes in delivery include changes in the tissue 
349  plane in which the drug is delivered, changes to the rate of delivery (because of 
350  change in injection time between the PFS and autoinjector), and changes in the 
351  consistency of the injection angle.  The extent to which existing safety data or 
352  effectiveness data can be bridged and leveraged will depend on PK comparisons that 
353  will allow assessment of any differences in bioavailability between the products.  If 
354  no differences are observed in the PK profile the applicant will leverage nonclinical, 
355  toxicity, and safety and effectiveness data gathered in the existing clinical program 
356  for the PFS presentation.  If differences are observed in the PK profile between the 
357  two presentations (e.g., in maximum concentration, in area under the curve, in shape 
                                                 
16 See, for example, 21 CFR 820.30(f)-(g).  Design verification confirms that the combination product meets the 
applicants design requirements/specifications (21 CFR 820.30(f)); see also 2017 CGMP Guidance for Combination 
Products, at 23.  Design verification activities may include, for example, performance tests, safety tests, or visual 
inspections (2017 CGMP Guidance for Combination Products, at 23).  Design validation ensures that the 
combination product is designed correctly to achieve its intended purpose(s) (21 CFR 820.30(g)).  Design validation 
may include simulated use testing or clinical/nonclinical evaluation, including HF and software validation (2017 
CGMP Guidance for Combination Products, at 24). 
 
17 See the guidance for industry and FDA staff Technical Considerations for Pen, Jet, and Related Injectors 
Intended for Use with Drugs and Biological Products (June 2013). 
 
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358  of the concentration-time profile), the applicant intends to gather additional 
359  information to evaluate clinical effect of these differences.18 
360   
361   
362  B.  Bridging From One Autoinjector (Prototype 1) to Another Autoinjector 
363  (Prototype 2) for the Same Drug; After Phase 3 Studies Have Been Completed 
364  but Before NDA Submission 
365   
366  In this hypothetical case example, the applicant developed an autoinjector for Drug Product X, 
367  which was used through completion of its phase 3 clinical studies.  During the course of 
368  development for submission, the applicant decided to make modifications to the TBM 
369  autoinjector (Prototype 2) to improve its functionality; however, the applicant does not intend to 
370  modify the device performance specifications (e.g., dose accuracy, injection time).  In this case, 
371  the primary container closure in direct contact with the drug (i.e., barrel, plunger, and needle) 
372  remains the same.  The assembly process used during manufacture to form the autoinjector 
373  remains the same.  The drug formulation remains the same.  The route of administration is the 
374  same (subcutaneous).  The user interface is the same.   
375   
376  Using the stepwise framework, the applicants gap analysis identifies the following:  
377   
378  Step 1. The applicant identifies the differences between the clinically studied autoinjector 
379  (Prototype 1) presentation and the TBM autoinjector (Prototype 2) presentation.  The 
380  dimensions and materials of the internal components of the rear and front shell subassemblies 
381  of the combination product were modified to improve the functionality for the combination 
382  product without changing the user interface.   
383   
384  In considering the potential effect of the individual and aggregate differences on safety and 
385  effectiveness introduced by the device modifications, the applicant identifies the following 
386  considerations: 
387   
388    The revision of the autoinjector would not be expected to change the quality 
389  considerations for the drug constituent part if the container closure in direct contact 
390  with the drug and the formulation remains the same.  The manufacturing process for 
391  Prototype 2 is comparable to that for Prototype 1, so the manufacturing process for 
392  the revision of the autoinjector would not be expected to affect the quality of the drug 
393  constituent part.  However, differences in functional performance of the device 
394  constituent part, if any, may affect the drug constituent part. 
395   
396    Device changes may affect the PK profile of the drug.  For example, changing the 
397  dimensions and materials of the rear and front shell subassemblies internal 
398  components may lead to differences including consistency or variability of injection 
399  angle, tissue depth (potentially associated with the rate of drug delivery as 
400  determined by the injection time), and completeness of the injection.  
                                                 
18 For further information, see the draft guidance for industry Bioavailability Studies Submitted in NDAs or INDs  
General Considerations (February 2019).  When final, this guidance will represent the FDAs current thinking on 
this topic.   
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401   
402  Step 2. The applicant did not gather new clinical data for the TBM product, but as reflected 
403  in Step 3 conducted verification testing on the TBM autoinjector (Prototype 2) to confirm 
404  that device performance remains unchanged between the clinically studied (Prototype 1) and 
405  TBM (Prototype 2) versions of the device.  This included testing in accordance with relevant 
406  standards as well as an assessment of certain performance requirements that the applicant has 
407  identified as potentially affected by the modifications to the components and that, if affected, 
408  could adversely affect the devices operations.  In this case, the following performance 
409  requirements were included in the verification testing of the TBM device (Prototype 2): 
410   
411    Dose accuracy  
412    Injection depth (needle extension) 
413    Injection time  
414    Activation force 
415   
416  The applicant is aware that the above are examples of factors that could affect the drug 
417  delivery and should be assessed over combination product shelf life.  The applicant has 
418  compared the identified performance requirements for both autoinjector prototypes (1 and 2) 
419  and determined that the performance requirements remain unchanged between the clinically 
420  studied (Prototype 1) and TBM (Prototype 2) versions of the device.   
421   
422  Step 3. The applicant previously conducted phase 3 studies with Prototype 1 of the 
423  autoinjector presentation.  The applicant has also performed design verification testing and 
424  completed HF validation testing on the clinically studied autoinjector (Prototype 1).  The 
425  applicant identifies the following information that can be applied to the modified TBM 
426  autoinjector (Prototype 2) presentation:  
427   
428    As noted above, testing confirmed that the dose accuracy, delivery time, injection 
429  depth, injection angle and site of injection are the same for Prototype 1 and TBM 
430  Prototype 2 bridging that information for these presentations; therefore, the applicant 
431  has determined that the PK studies conducted using Prototype 1 of the autoinjector 
432  can be leveraged. 
433   
434    The user interface is not changing.  Additionally, the activation force and injection 
435  time remain the same; therefore, the applicant has determined that the HF data 
436  between Prototype 1 and 2 can be bridged.  Accordingly, the HF data collected for the 
437  combination product using the Prototype 1 autoinjector can be leveraged for the 
438  combination product using the Prototype 2 autoinjector presentation.  
439   
440    The proposed indication, dosage, and administration are the same and, as noted 
441  previously, there is no change to the delivery of the drug (e.g., dose accuracy, 
442  injection time, injection depth).  Therefore, the applicant has determined that the 
443  nonclinical, toxicity, and safety and effectiveness data gathered in the existing clinical 
444  program using the Prototype 1 autoinjector presentation can be bridged to the 
445  Prototype 2 autoinjector presentation and leveraged. 
446   
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447    The primary container closure is the same for both Prototype 1 and Prototype 2 
448  autoinjectors, and the applicant can demonstrate that the autoinjector components and 
449  materials used during manufacture and storage of the combination product do not 
450  come in direct contact with the drug.  Therefore, the applicant has determined that the 
451  CMC information for the drug constituent part and leachable profile gathered using 
452  the Prototype 1 autoinjector presentation can be bridged to the Prototype 2 
453  autoinjector presentation and leveraged. 
454   
455    The primary container closure remains the same and the injection time remains 
456  unchanged from the clinically studied Prototype 1 autoinjector to the TBM Prototype 
457  2 autoinjector.  Therefore, the applicant has determined that it is possible to bridge 
458  information regarding the products and leverage the drug-device compatibility study 
459  from Prototype 1. 
460   
461  Step 4.  The applicant determines that there is no other existing information that may be 
462  leveraged.   
463   
464  Step 5. The applicant believes no new information needs to be generated beyond that 
465  described above.  The applicant intends to support the assessment through submission of data 
466  demonstrating comparability between the designs, including through submission of  full 
467  design verification data for the TBM Prototype 2 to demonstrate that device performance is 
468  comparable to Prototype 1.  In addition, the applicant intends to include a side-by-side 
469  comparison of the user interface for the combination product using Prototype 1, which was 
470  evaluated in the HF validation study, and the combination product using Prototype 2 as part 
471  of the NDA submission to facilitate review to demonstrate that there are no differences in the 
472  user interface. 
473   
474   
475  C.  Bridging of Data From Combination Product That Employs the Same Device 
476  Combined With a Different Drug 
477   
478  In this hypothetical case example, the applicant previously developed Combination Product A, 
479  which was approved by FDA in an NDA and includes a prefilled drug cartridge attached to a 
480  metered-dose inhaler.  Combination Product A is indicated for the prevention and relief of 
481  bronchospasm in patients 18 years of age and older with reversible obstructive airway disease.  
482  The applicant is now early in the development of Combination Product B, which combines an 
483  NME drug constituent part with the same metered-dose inhaler as in Combination Product A.  
484  For Combination Product B, the applicant is seeking an indication of prevention and relief of 
485  bronchospasm in patients 4 years of age and older with reversible obstructive airway disease. 
486   
487  The same route of administration applies to Combination Products A and B.  Both combination 
488  products require the same actuation force to administer an inhalation.  Both combination 
489  products are intended for use in an emergency-use scenario to rapidly reverse bronchospasm. 
490   
491  Using the stepwise framework, the applicants gap analysis identifies the following: 
492   
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493  Step 1. The applicant identifies the differences between Combination Products A and B.  The 
494  key differences are the change in the drug constituent part and the inclusion of a pediatric age 
495  group. 
496   
497  In considering the potential effect of the individual and aggregate differences in the safety 
498  and effectiveness profile of the two different drugs and the combination product as a whole, 
499  the applicant determines that full characterization of the NME will be required to establish 
500  safety and effectiveness of the drug constituent part.  Additionally, the inclusion of the 
501  pediatric age group leaves an unanswered question of whether this user population can use 
502  the product safely and effectively. 
503   
504  Step 2. The applicant has not yet developed any information for Combination Product B and, 
505  therefore, will have to either leverage existing information on the device constituent part or 
506  develop new data.  
507   
508  Step 3. The applicant determines that the user interface is the same between Combination 
509  Products A and B, and the uses, and environments of use of the products is unchanged.19  For 
510  the adult population the results of their use-related risk analysis did not identify any new or 
511  differing use-related risks between Combination Products A and B, thereby creating a bridge 
512  for adult user interface information between the products.  The applicant believes, however, 
513  that an assessment will be needed in the pediatric population to assess HF since that group 
514  was not studied for Combination Product A.  In addition, the applicant determines that the 
515  design control system developed for Combination Product A may be usable, subject to the 
516  assessment discussed in Step 5, for design verification and validation of Combination 
517  Product B. 
518   
519  The applicant also determines that it could rely on previously conducted biocompatibility 
520  studies with Combination Product A (assessing contact of the mouth and lips with the plastic 
521  of the inhaler) because the materials remain the same. 
522   
523  Step 4. The applicant determines that there is no other existing information that may be 
524  leveraged.   
525   
526  Step 5. The applicant determines that it will need to conduct studies to fully characterize the 
527  NME in Combination Product B and reassess the applicability of the design inputs and 
528  outputs (design specs) for Combination Product A because of the change in drug and 
529  intended patient population.  Also, because of these differences between Combination 
530  Products A and B that could affect device design and performance, the applicant determined 
531  that phase 3 clinical studies of Combination Product B, including the TBM device, are 
532  needed as well as other design verification testing for Combination Product B.  In addition, 
533  the applicant intends to produce a HF validation study report for the pediatric population. 
534   
                                                 
19 See the guidance for industry Safety Considerations for Product Design to Minimize Medication Errors (April 
2016) for more information. 
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