Submissions for Postapproval Modifications to a Combination Product Approved Under a BLA, NDA, or PMA: Draft Guidance for Industry and FDA Staff

Administrative draft guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Guidance for Industry and FDA Staff:
Submissions for Postapproval Modifications
to a Combination Product Approved Under a
BLA, NDA, or PMA
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 90 days of
publication in the Federal Register of the notice announcing the availability of the draft
guidance. Submit written comments to the Division of Dockets Management (HFA-305), Food
and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, MD 20852. Submit
electronic comments to http://www.regulations.gov. All comments should be identified with the
docket number listed in the notice of availability that publishes in the Federal Register.
Additional copies are available from:
Office of Combination Products
Food and Drug Administration
WO32, Hub/Mail Room #5129
10903 New Hampshire Avenue
Silver Spring, MD 20993
(Tel) 301-796-8930
(Fax) 301-847-8619
http://www.fda.gov/CombinationProducts/default.htm.
For questions regarding this draft document contact the Office of Combination Products, Office
of Special Medical Programs in the Office of the Commissioner, Dr. Patricia Love, 301-796-
8933 or combination@fda.gov.
U.S. Department of Health and Human Services
Food and Drug Administration
Office of Combination Products
Office of Special Medical Programs
Office of the Commissioner
January 2013
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Guidance for Industry and FDA Staff:
Submissions for Postapproval Modifications
to a Combination Product Approved Under a
BLA, NDA, or PMA
Additional Copies are available from:
Food and Drug Administration
WO32, Hub/Mail Room #5129
10903 New Hampshire Avenue
Silver Spring, MD 20993
(Tel) 301-796-8930
(Fax) 301-847-8619
http://www.fda.gov/oc/combination
U.S. Department of Health and Human Services
Food and Drug Administration
Office of Combination Products
Office of Special Medical Programs
Office of the Commissioner
January 2013
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TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
III. 	WHAT TYPE OF SUBMISSION TO PROVIDE WHEN MAKING A CHANGE
TO AN APPROVED COMBINATION PRODUCT? ................................................... 3
IV. 	ILLUSTRATIONS BY TYPE OF CHANGE BEING MADE ..................................... 8
V. 	HOW CAN I DISCUSS MY OPTIONS WITH FDA? ................................................ 10
VI. 	WHERE CAN I OBTAIN ADDITIONAL INFORMATION? .................................. 11

Guidance for Industry and FDA Staff:1
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Submissions for Postapproval Modifications to a
Combination Product Approved Under a BLA, NDA, or PMA
(Draft)
This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s)	6
current thinking on this topic. It does not create or confer any rights for or on any person and	7
does not operate to bind FDA or the public. You can use an alternative approach if the approach	8
satisfies the requirements of the applicable statutes and regulations. If you want to discuss an	9
alternative approach, contact the FDA staff responsible for implementing this guidance. If you	10
cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of	11
this guidance.	12
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I. 	INTRODUCTION
This document provides guidance to industry and FDA staff on the underlying principles
to determine the type of marketing submission that may be required for postapproval
changes to a combination product, as defined in 21 CFR 3.2(e), that is approved under
one marketing application, i.e., a biologics license application (BLA), a new drug
application (NDA), or a device premarket approval application (PMA).
This guidance supplements existing guidance documents developed by the Center for
Biologics Evaluation and Research (CBER), the Center for Devices and Radiological
Health (CDRH), the Center for Drug Evaluation and Research (CDER), and the Office of
Combination Products (OCP).
This guidance does not address changes to combination products that are not approved
under a BLA, NDA or PMA (e.g., those cleared solely under a device premarket
notification submission2 or those marketed under an over-the-counter drug monograph3).
Nor does this guidance address changes to combination products that were approved
under more than one marketing application. Further, while this guidance does address
the type of submission to provide when making a change to a constituent part of a
combination product approved under one marketing application, it does not address the
scientific or technical content to provide in any such submission.
FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and
should be viewed only as recommendations, unless specific regulatory or statutory
1 This guidance has been prepared by the Office of Combination Products (OCP) in the Office of Special
Medical Programs, Office of the Commissioner, in cooperation with the Center for Biologics Evaluation
and Research (CBER), the Center for Drug Evaluation and Research (CDER), and the Center for Devices
and Radiological Health (CDRH) at the Food and Drug Administration.
2 Device premarket notification submissions are also referred to as 510(k) submissions.
3 See 21 CFR Part 330.
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requirements are cited. The use of the word should in Agency guidances means that
something is suggested or recommended, but not required.
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II. 	BACKGROUND
As defined in 21 CFR 3.2(e), a combination product is a product comprised of any
combination of a drug and a device; a biological product and a device; a drug and a
biological product; or a drug, device, and a biological product.4 Under Section 503(g)(1)
of the Federal Food, Drug, and Cosmetic Act (FD&C Act), a combination product is
assigned to a center (CBER, CDER, or CDRH) with primary jurisdiction (the lead center)
for premarket review and postmarket regulation. The lead center assignment is based on
a determination of the primary mode of action (PMOA) of the combination product or
other defined regulatory criteria when the PMOA cannot be determined with reasonable
certainty.5 Regardless of center assignment, in most instances FDA may regulate the
entire combination product under one type of marketing application (e.g., one BLA,
NDA, or PMA).6 This one application would include all necessary information to
support the approval of the combination product as a whole, including each of its
constituent parts (drug, device, and/or biological product).7
For a combination product that is approved under one application, there may be
uncertainty on the part of the application holder in determining the appropriate regulatory
pathway for submitting a postmarket submission for a change to a constituent part or to
the combination product as a whole.8 The FD&C Act,9 the Public Health Service Act
(PHS Act),10 and FDA’s associated regulations11 contain provisions describing when a
4 Combination product includes: (1) A product comprised of two or more regulated components, i.e.,
drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or
otherwise combined or mixed and produced as a single entity; (2) Two or more separate products packaged
together in a single package or as a unit and comprised of drug and device products, device and biological
products, or biological and drug products; (3) A drug, device, or biological product packaged separately
that according to its investigational plan or proposed labeling is intended for use only with an approved
individually specified drug, device, or biological product where both are required to achieve the intended
use, indication, or effect and where upon approval of the proposed product the labeling of the approved
product would need to be changed; e.g., to reflect a change in intended use, dosage form, strength, route of
administration, or significant change in dose; or (4) Any investigational drug, device, or biological product
packaged separately that according to its proposed labeling is for use only with another individually
specified investigational drug, device, or biological product where both are required to achieve the intended
use, indication, or effect. 21 CFR 3.2(e).
5 21 CFR 3.2(m) and 3.4(a), (b). See also Final Rule for Definition of Primary Mode of Action of a
Combination Product, published August 25, 2005, 70 Fed. Reg. 49848, accessible at
http://www.fda.gov/OHRMS/DOCKETS/98fr/05-16527.pdf.
6 In some instances FDA may require two or more marketing applications for a combination product. 21
CFR 3.4(c). Further, as appropriate, FDA may accept two marketing applications upon request by the
applicant(s).
7 See Section 503(g)(2) of the FD&C Act.
8 For purposes of this document, changes to the combination product are assumed to not affect the primary
mode of action, the lead center assignment or the underlying type of marketing application for the
combination product.
9 Sections 505, 506A, and 515(d) of the FD&C Act.
10 Section 351 of the PHS Act.
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postmarket submission is required for a change to an approved, stand-alone12 drug,
device, or biological product or its manufacturing process.
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13 As a general matter, these
provisions set forth similar criteria for determining when a postapproval submission is
required; e.g., a prior approval submission is generally required for a product change that
could affect safety or effectiveness.14 These provisions do not, however, expressly
address the criteria for when, how, and what type of submission to submit for a change to
a constituent part of an approved combination product. The intent of this guidance
document is to provide clarity in the postapproval change requirements and consistency
in the type of postmarket submission to provide for a change to a combination product
approved under one application (BLA, NDA, or PMA), regardless of which agency
center has lead jurisdiction for the combination product.
III. 	WHAT TYPE OF SUBMISSION TO PROVIDE WHEN MAKING A
CHANGE TO AN APPROVED COMBINATION PRODUCT?
As stated above, a combination product is comprised of different constituent parts. These
constituent parts retain their regulatory identity as a drug, device or biological product.
Therefore, if a change is made to any constituent part of the combination product that
would have required a postmarket submission to FDA if the constituent part were a stand-
alone product, then a postmarket submission is required for the combination product. In
addition, a postmarket submission would also be required for the combination product if
a change to any of the constituent parts would otherwise trigger the requirements
associated with the application type used for approval of the combination product. In
cases where the regulatory identity of the constituent part differs from the approved
application type for the combination product, and a change is made that would require a
postmarket submission to FDA, the requirement for submitting information about the
change to the agency is generally satisfied with one postmarket submission to the original
application. The type of submission to provide for the change will depend on the type of
application used to obtain approval of the combination product. For example, a change to
the device constituent part of a combination product approved under an NDA should be
reflected in the appropriate postmarket NDA submission and be submitted to that NDA.
In some cases, it may be easier to first identify the type of submission typically associated
with the constituent part before determining what type of submission is required to the
original application that was used for approval of the combination product. To aid in this
determination, tables are provided in this document to generally align the corresponding
postmarket submissions for changes to a constituent part of a combination product
approved under a BLA, NDA, or PMA.
11 21 CFR 314.70, 601.12, and 814.39.
12 For purposes of this document, the term “stand-alone” refers to an individual drug, device, or biological
product that is not part of a combination product.
13 The types of submissions describing a change to an approved product include, but are not limited to, a
new original application, a prior approval supplement, a changes being effected supplement, and an annual
or periodic report.
14 For purposes of this document, the term change or modification is used interchangeably to apply to a
postapproval or postmarket change to an approved application or approved product.
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The following steps outline the process for determining which type of submission to
provide for a postmarket change to a constituent part of a combination product approved
under a BLA, NDA, or PMA.
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1. 	Identify the type of premarket application used to obtain approval of the
combination product (NDA, BLA, or PMA).
2. 	Identify the type of postapproval submission that ordinarily would have been
submitted for the modification(s), if the constituent part(s) were marketed as a
stand-alone product. For a device constituent part, apply the appropriate device
criteria in determining what type of submission to FDA would ordinarily have
been submitted because of a change to the device constituent part.15 For a
biological product or drug constituent part, apply the appropriate biological
product and drug criteria, respectively.
3. 	If the original application type used for approval of the combination product (step
1 above) is the same as that customarily used for the constituent part being
changed, then submit the postapproval submission identified in step 2. If not,
then proceed to step 4.
4. 	Use the tables below as guidance in determining the appropriate postapproval
change submission type for the combination product. The tables correlate the
submission type typically used for the changed constituent part as identified in
step 2 with the appropriate submission type for the combination product based on
the original application under which the combination product was approved.
Table 1, page 6 identifies the types of NDA or BLA submissions to submit when making
a change to a device constituent part of a combination product approved under an NDA
or BLA. Column 1 identifies the type of PMA submission that would customarily be
submitted for a change in the device constituent part if it were a stand-alone device
approved under a PMA.16 Column 2 identifies the types of NDA or BLA submissions to
submit for the change in the device constituent part of the combination product.17
Table 2, page 7 identifies the types of PMA submissions to submit when making a
change to a biological product/drug constituent part of a combination product approved
under a PMA. Column 1 provides information on both BLA and NDA submissions.
Specifically, it identifies the types of NDA submissions that would customarily be
15 For example, if the stent material of a PMA-approved drug eluting stent is changed, determine whether
such a change would require a real-time PMA supplement, a 180-day PMA supplement, a panel-track PMA
supplement, or an original PMA.
16 See sections 515 and 737 of the FD&C Act, 21 CFR 814.39, and FDA Guidance for Modifications to
Devices Subject to Premarket Approval (PMA) - The PMA Supplement Decision-Making Process (2008), at
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UC
M089360.pdf).
17 This document does not address combination products approved with an ANDA under Section 505(j) of
the FD&C Act. For such products, applicants should consider whether a postmarket change to a device
constituent part would be permissible under the ANDA.
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submitted for a change if the drug constituent part were a stand-alone drug approved
under an NDA.
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18 It also identifies the types of BLA submissions that would customarily
be submitted for a change to the biological product constituent part if it were a stand-
alone biological product licensed under a BLA.19 Column 2 identifies the types of PMA
submissions to submit when the change is in the biological product/drug constituent part
of a combination product approved under a PMA.
To use these tables, first refer to relevant provisions in the FD&C Act, FDA regulations,
and FDA guidance on the type of postmarket change being made to the constituent part to
help you determine the type of submission ordinarily required for such a change. For a
list of potentially applicable guidance documents, see Section VI of this document. You
can then use the tables to identify the type of corresponding submission to provide for the
combination product.
(Continue to next page)
18 See FD&C Act Section 505, 21 CFR 314.70, and FDA Guidance for Changes to an Approved NDA or
ANDA (2004), at http://www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatoryInformation/Guidances/ucm077097.pdf). Also, see FDA Guidance for
Contents of a Complete Submission for the Evaluation of Proprietary Names (2010), at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM07506
8.pdf.
19 See 21 CFR 601.12 and FDA Guidance for Changes to an Approved Application: Biological Products
(1997), at http://www.fda.gov/downloads/BiologicsBloodVaccines/
GuidanceComplianceRegulatoryInformation/Guidances/Blood/UCM170166.pdf.
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Table 1: Type of NDA/BLA Submission for a Change in a Device Constituent Part of a
Combination Product Approved under an NDA/BLA
If the Device Constituent Part Were a
Stand-Alone Device Approved under a PMA
and the Change Would Have Required the
Following Submission
Then Submit Information on the Device
Change Using This Type of NDA/BLA*
Submission for the Combination
Product
PMA Original 	NDA/BLA Original
PMA Panel-Track Supplement
(New indication/population, without any other
change to the constituent parts, supported by new
clinical data and the original preclinical data)
Prior Approval Supplement (Efficacy)
Design change and labeling
change supported by new
preclinical and/or limited
confirmatory clinical data
Prior Approval Supplement (Efficacy)
Changes supported by limited
confirmatory data (i.e., clinical
bioequivalence or
bioavailability data)
Manufacturing site change not
requiring any clinical data
Prior Approval Supplement
(Manufacturing)
(With or without labeling changes)
PMA 180-day
Supplement
 Design
 Manufacturing
site change
 Labeling
change
including
nomenclature
(And with a
change from the
next column)
Significant labeling change
that does not qualify for a
Special PMA Supplement -
Changes Being Effected, does
not change the indication, and
does not include a design
change
Prior Approval Supplement (Labeling)
PMA Real-Time Supplement
(Design or labeling change that does not require
clinical data and for which the data provided fall
within only one scientific discipline, e.g., electrical
engineering, microbiology, or sterilization)
Prior Approval Supplement
(Manufacturing or Labeling)
30-day Notice (Manufacturing process or method
change only)
30-day Changes Being Effected
Special PMA Supplement - Changes Being
Effected
Changes Being Effected
PMA Periodic Report 	Annual Report
*Time lines and FDA-industry interactive procedures will be those of the NDA/BLA
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Table 2: Type of PMA Submission for a Change in a Biological Product/Drug
Constituent Part of a Combination Product Approved under a PMA
If the Biological Product/Drug Constituent Part
Were a Stand-Alone Biological Product/Drug
Approved under a BLA/NDA and the Change
Would Have Required the Following Submission
Then Submit Information on the
Biological Product/Drug Change
Using This Type of PMA*
Submission for the Combination
Product
BLA Original; NDA Original (Section 505(b)(1) or
(b)(2)) (New biological product, new drug, or new
formulation with new clinical data and new
preclinical data)
PMA Original
New indication/population, without
any other change to the constituent
parts, supported by new clinical data
and the original preclinical data
Panel-Track Supplement
Prior Approval
	Supplement –
Efficacy	
Same indication with manufacturing
change in drug/biological product
requiring clinical data
180-day Supplement
Drug/biological product
manufacturing change requiring only
bioequivalence or bioavailability
clinical data
180-day Supplement
Prior Approval
	Supplement –
	Manufacturing
Drug/biological product
manufacturing and related labeling
change that does not require any type
of clinical or preclinical (animal) data
180-day Supplement or Real-Time
Supplement
(depending on amount and
complexity of data)
Prior Approval Supplement – Labeling
(When the labeling change does not rely on a
clinical trial and is not related to a manufacturing
change)
180-day Supplement or Real-Time
Supplement
(depending on amount and
complexity of data)
30-day Changes Being Effected (Manufacturing
process or method change only)
PMA 30-day Notice
Changes Being Effected (Manufacturing or
Labeling)
Special PMA Supplement - Changes
Being Effected
Annual Report 	PMA Periodic Report
*Time lines and FDA-industry interactive procedures will be those of the PMA
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IV. 	ILLUSTRATIONS BY TYPE OF CHANGE BEING MADE	158
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This section provides examples of some of the more significant changes that may be
made to constituent parts of a combination product (i.e., changes that may require prior
approval from FDA). The types of submissions that such changes may require,
depending upon the submission type used to obtain approval of the combination product,
are identified. These recommendations are based on relevant statutory and regulatory
provisions as well as relevant CDER, CDRH, and CBER guidance documents (see
Section VI of this document).
1. 	Certain changes in the combination product device constituent part (e.g.,
those that result in a combination product new indication for use, new
clinical effects, or in a modified analyte and indication/patient population
for an in vitro diagnostic) customarily require new preclinical and clinical
data to provide support for safety and effectiveness.20 Generally, for any
such changes that do not affect the primary mode of action, select the
submission type to match the application type used to obtain approval of
the combination product:
a. 	PMA Original21
b. 	NDA Original22
c. 	BLA Original
2. 	Changes in the drug constituent part substance, drug constituent part
production process, quality controls, equipment, or facilities that affect
controlled release or drug particle size or have a substantial potential to
have an adverse effect on the identity, strength, quality, purity, or potency
of the drug constituent part.23 Such changes include those that may affect
the sterility assurance of the drug constituent part, such as process changes
for sterile drug substances and sterile packaging components.24 Generally,
for any such change, select the submission type to match the application
type used to obtain approval of the combination product:
a. 	NDA Prior Approval Supplement
20 In some instances the change in the device constituent part may result in a new combination product.
21 Ordinarily, changes to a device that require new preclinical and clinical data are submitted in an original
PMA as explained in FDA guidance. FDA Guidance, Modifications to Devices Subject to Premarket
Approval (PMA) - The PMA Supplement Decision-Making Process (2008) (see Section IV.A), at
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UC
M089360.pdf.
22 For more information on the type of original NDA submissions, you may wish to refer to the FDA Draft
Guidance, Applications Covered by Section 505(b)(2), at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079345.
pdf.
23 21 CFR 314.70(b).
24 FDA Guidance, Changes to an Approved NDA or ANDA (2004) (see Section VII.B), at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm077097.
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b. 	BLA Prior Approval Supplement	192
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c. 	PMA 180-day Supplement
3. 	Modified chemical formulation of the device constituent part (not a
chemical that would be considered a drug constituent part of the
combination product), hardware or software modification of the device
constituent part, or other design modification to the device constituent part
(without also changing the indication or patient population) for which only
new preclinical testing and/or limited confirmatory clinical data are
necessary to demonstrate reasonable assurance of safety and effectiveness
of the modified device constituent part.25 Generally, for any such change,
select the submission type to match the application type used to obtain
approval for the combination product:
a. 	PMA 180-day Supplement
b. 	BLA Prior Approval Supplement
c. 	NDA Prior Approval Supplement
4. 	Changes in the biological product constituent part, production process,
quality controls, equipment, facilities, or responsible personnel that have a
substantial potential to have an adverse effect on the identity, strength,
quality, purity, or potency of the product.26 Generally, for any such
change, select the submission type to match the application type used to
obtain approval for the combination product:
a. 	BLA Prior Approval Supplement
b. 	NDA Prior Approval Supplement
c. 	PMA 180-day Supplement
5. 	Changes in indication or in patient population (without any other change
to the combination product itself or to any constituent part, except for
relevant changes to the labeling) that require substantial clinical data to
provide reasonable assurance of safety and effectiveness for the change
but either no or very limited new preclinical testing. Generally, for any
such change, select the submission type to match the application type used
to obtain approval for the combination product:
a. 	PMA Panel-Track27
25 See Section 737(4)(C) of the FD&C Act and 21 CFR 814.39(a)(6); see also FDA Guidance,
Modifications to Devices Subject to Premarket Approval (PMA) - The PMA Supplement Decision-Making
Process (2008) (see Section IV.C), at
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UC
M089360.pdf.
26 21 CFR 601.12(b).
27 See Section 737(4)(B) of the FD&C Act and 21 CFR 814.39(a)(1); see also FDA Guidance,
Modifications to Devices Subject to Premarket Approval (PMA) - The PMA Supplement Decision-Making
Process (2008) (see Section IV.B), at
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b. 	NDA Prior Approval Supplement	230
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c. 	BLA Prior Approval Supplement
The preceding tables and illustrations provide correlations between NDA, BLA, and
PMA submissions for a change to a single constituent part of a combination product
approved under a single application. When changes are made to multiple constituent
parts, the recommendations in Section III, above, still apply for each change. If the
applicable submission requirements for each change do not match (e.g., one change
requires a prior approval supplement and another requires a changes being effected
supplement), then the type of submission should be that associated with the most
significant change being submitted. For example, a manufacturer of a drug eluting stent
approved under a PMA would like to modify the design of the stent and delete a test for
the drug to comply with an official compendium that is consistent with FDA statutory
and regulatory requirements. In isolation, the change in the design of the stent would
generally require the submission of a PMA 180-day supplement, whereas the change in
the test to comply with an official compendium for the drug would generally be
submitted in an NDA Changes Being Effected-30 day supplement. In this case, when
submitted together, the manufacturer should submit the PMA 180-day supplement for
both changes.
FDA cautions that this document provides information only on the type of submission
that should be made by the application holder when making a change to a constituent part
of a combination product approved under a BLA, NDA, or PMA. It does not address the
type and amount of information to include in each submission. Finally, FDA reminds
industry that the recommendations in this guidance document do not affect other
requirements that may apply to the application type used to obtain approval of a
particular combination product.
V. 	HOW CAN I DISCUSS MY OPTIONS WITH FDA?
FDA recognizes that this guidance provides general recommendations and that the tables
provided above are intended as useful tools, but may not provide the applicable
correlation in all cases. There may be added complexity based on certain types of
combination products. Further, FDA recognizes that it may not be possible to isolate the
change of one constituent part from another constituent part (e.g., those meeting the
definition in 21 CFR 3.2(e)(1) or if one constituent part activates or changes the other
constituent part). FDA encourages applicants to anticipate the type of postapproval
changes that they wish to make and to develop protocols to help establish comparability
of the modifications in methodology or products to the original approved combination
product. Further, FDA encourages industry to discuss with FDA the type of information
that may be necessary to address the change to the constituent part, including whether
and how this change may affect the other constituent part(s) and the combination product
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UC
M089360.pdf.
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Contains Nonbinding Recommendations
Draft — Not for Implementation
as a whole; and any alternative approaches for submission types the applicant may
propose.
273
274
275
276
277
278
279
280
281
282
283
284
285
286
287
288
289
To discuss possible postmarket changes to combination products, as well as the type of
information and type of submission to provide to FDA, applicants should request a
meeting with the intercenter review team. The meeting request should be sent to the lead
center that approved the original application, with a cover letter requesting inclusion of
representatives from the consulting center(s). OCP may attend such a meeting as well.
The meeting request should include background material to support any proposed
approach.
VI. 	WHERE CAN I OBTAIN ADDITIONAL INFORMATION?
OCP is available as a resource to industry and FDA review staff throughout the lifecycle
(assignment, development, premarket review and postmarket regulation) of a
combination product. OCP can be reached at (301) 427-1934 or by email at
combination@fda.gov. In addition, OCP maintains an updated list of FDA guidance
documents that industry may find helpful in the development of their products. The list is
available at OCP’s Internet Website at
290
291
292
http://www.fda.gov/CombinationProducts/default.htm. Each center also maintains a
webpage for guidance documents and information on the types of submissions addressed
in this guidance document.
293
294
295
296
297
298
299
300
301
In considering possible changes to constituent parts and their potential to affect the safety
and effectiveness of the approved combination product, the following FDA webpages
may be useful. These webpages include information on requesting meetings with FDA:
 	BLA Therapeutic Biologic Applications;
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelope	302
303 	dandApproved/ApprovalApplications/TherapeuticBiologicApplications/default.ht
304
305
306
m
 	NDA webpage;
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelope	307
308
309
310
dandApproved/ApprovalApplications/NewDrugApplicationNDA/default.htm
 	PMA webpage;
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarke	311
312
313
314
tYourDevice/PremarketSubmissions/PremarketApprovalPMA/default.htm
 	BLA webpage;
http://www.fda.gov/BiologicsBloodVaccines/DevelopmentApprovalProcess/Biol	315
316
317
ogicsLicenseApplicationsBLAProcess/default.htm
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 	Drug and Therapeutic Biologic Labeling website;	318
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/LawsActs	319
320
321
322
323
andRules/ucm084159.htm
 	PDUFA reauthorization performance Goals and Procedures Fiscal Years 2012
through 2017;
http://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/U	324
325
326
327
328
CM270412.pdf
 	FDA and Industry Actions on Premarket Approval Applications (PMAs): Effect
on FDA Review Clock and Goals, October 15, 2012;
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDo	329
330
331
332
333
334
335
336
337
cuments/ucm089733.htm
In addition, the following FDA guidance documents, which focus on postmarket
modifications to regulated articles, may help applicants in assessing which type of
postapproval submission is typically required for various types of changes and may be
helpful when applying Tables 1 and 2 of this document:
 	Changes to an Approved Application: Biological Products;
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRe	338
339
340
341
342
gulatoryInformation/Guidances/Blood/UCM170166.pdf
 	Modifications to Devices Subject to Premarket Approval (PMA) - The PMA
Supplement Decision-Making Process (2008);
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/G	343
344
345
346
uidanceDocuments/UCM089360.pdf
 	Real-Time Premarket Approval Application (PMA) Supplements (2006);
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/G	347
348
349
350
351
352
uidanceDocuments/ucm089612.pdf
 	30-day Notices, 135-Day Premarket Approval (PMA) Supplements and 75-Day
Humanitarian Device Exemption (HDE) Supplements for Manufacturing Method
or Process Changes (2011);
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/G	353
354
355
356
uidanceDocuments/UCM080194.pdf
 	Changes to an Approved NDA or ANDA (2004);
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio	357
358
359
360
361
n/Guidances/ucm077097.pdf
 	Changes to an Approved Application: Biological Products: Human Blood and
Blood Components Intended for Transfusion or for Further Manufacture (2001);
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInf	362
ormation/Guidances/Blood/ucm076729.htm	363
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Contains Nonbinding Recommendations
Draft — Not for Implementation
13
364
365
366
 	Demonstration of Comparability of Human Biological Products, Including
Therapeutic Biotechnology-derived Products (1996);
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidance	367
s/ucm122879.htm	368
369
370
371
 	Changes to an Approved Application for Specified Biotechnology and Specified
Synthetic Biological Products (1997);
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio	372
n/Guidances/UCM124805.pdf	373
374
375 	 	Q10 Pharmaceutical Quality System (2009);
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio	376
n/Guidances/ucm073517.pdf	377
378
379 	 	Q8, Q9, and Q10 Questions and Answers(R4) (2010);
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio	380
n/Guidances/UCM210822.pdf	381
382
383 	 	Cooperative Manufacturing Arrangements for Licensed Biologics (2008);
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRe	384
gulatoryInformation/Guidances/General/UCM069908.pdf	385
386
387
388
389
390
391
Finally, applicants may refer to the following FDA draft guidance documents for
additional information. When finalized, these will provide FDA policy on these subjects.
 	CMC Postapproval Manufacturing Changes Reportable in Annual Reports;
(Draft 2010);
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio	392
n/Guidances/UCM217043.pdf	393
394
395
396
 	Annual Reports for Approved Premarket Approval Applications (PMA) (Draft
2006);
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/G	397
uidanceDocuments/ucm089398.pdf	398
399
400
401
 	Public Availability of Labeling Changes in “Changes Being Effected”
Supplements (Draft 2006);
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio	402
n/Guidances/ucm075091.pdf	403