Updating ANDA Labeling 
After the Marketing Application 
for the Reference Listed Drug 
Has Been Withdrawn 
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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 http://www.regulations.gov.  Submit written 
comments to the Division of Dockets Management (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) Emily Helms Williams, 301-796-
3600.  
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
July 2016 
Generics 
 
   
Updating ANDA Labeling 
After the Marketing Application 
for the Reference Listed Drug 
Has Been Withdrawn  
Guidance for Industry 
 
 
 
 
 
 
 
 
Additional copies are available from: 
Office of Communications, Division of Drug Information  
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD 20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
July 2016 
Generics 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
TABLE OF CONTENTS 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  SCOPE OF GUIDANCE .................................................................................................. 4 
IV.  UPDATING LABELING OF ANDAs THAT RELY ON WITHDRAWN RLDs ...... 4 
A.  Examples of Labeling Updates for ANDAs That Rely on Withdrawn RLDs........................... 5 
B.  Process for Labeling Updates ....................................................................................................... 7 
C.  Relationship of this Guidance to Existing Authorities and Processes ....................................... 7 
1. Safety Labeling Changes Under Section 505(o)(4) of the FD&C Act ............................................. 7 
2. Section 409I of the Public Health Services Act ................................................................................ 8 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
1  Updating ANDA Labeling After the Marketing Application for the 
2  Reference Listed Drug Has Been Withdrawn  
1
3  Guidance for Industry  
4   
5   
6  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
7  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
8  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
9  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
10  for this guidance as listed on the title page.   
11   
12   
13   
14   
15  I.  INTRODUCTION  
16   
17  This guidance describes a process for updating labeling for abbreviated new drug applications 
18  (ANDAs) in cases where FDA has withdrawn approval of the new drug application (NDA)2 for 
19  the ANDAs reference listed drug (RLD)3 for reasons other than safety or effectiveness.  Where 
20  approval of the NDA for the RLD has been withdrawn by FDA under these circumstances 
21  (referred to in this guidance as a withdrawn RLD), and ANDAs are pending or generic drugs 
22  continue to be marketed under one or more ANDAs that rely on the withdrawn RLD, the 
23  labeling of those pending or marketed ANDA products may need to be updated to reflect 
24  changes that would have been necessary had the NDA for the RLD not been withdrawn.   
25   
26  This guidance sets forth ways in which FDA may seek to facilitate the revision of labeling to 
27  reflect updated information for ANDAs that rely on withdrawn RLDs.  This guidance will be of 
28  interest to the holders of pending or approved ANDAs that rely upon a withdrawn RLD, as well 
29  as to applicants seeking to submit ANDAs relying on withdrawn RLDs.  We anticipate that this 
30  guidance will help facilitate labeling updates for approved ANDAs as well as the approval of 
31  certain pending ANDAs where the NDA for the RLD has been withdrawn.   
32   
33  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
34  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
35  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
                                                 
1 This guidance has been prepared by the Office of Regulatory Policy, the Office of Generic Drugs, the Office of 
New Drugs, and the Office of Surveillance and Epidemiology in the Center for Drug Evaluation and Research at the 
Food and Drug Administration.  
2 For purposes of this guidance, we use the phrase new drug application or NDA to refer to an application 
approved under section 505(c) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355(c)), 
including applications based on a finding of effectiveness under the Drug Efficacy Study Implementation (DESI) 
review process. 
3 See 21 CFR 314.3 (defining reference listed drug and listed drug); see also Abbreviated New Drug Applications 
and 505(b)(2) Applications (Proposed Rule), 80 FR 6802 at 6814 (February 6, 2015).  
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
36  the word should in Agency guidances means that something is suggested or recommended, but 
37  not required.  
38   
39   
40  II.  BACKGROUND 
41   
42  A generic drug is required to have the same labeling as the RLD at the time of approval, except 
43  for changes required because of differences approved under a suitability petition (see section 
44  505(j)(2)(C) of the FD&C Act and 21 CFR 314.93) or because the generic drug and the RLD are 
45  produced or distributed by different manufacturers (see section 505(j)(2)(A)(v) of the FD&C 
46  Act).  FDA regulations provide examples of permissible differences in labeling that may result 
47  where a proposed generic drug and the RLD are produced or distributed by different 
48  manufacturers, including the omission of an indication or other aspect of labeling protected by 
49  patent or exclusivity and labeling revisions made to comply with current FDA labeling 
50  guidelines or other guidance.  21 CFR 314.94(a)(8)(iv).  
51   
52  As a general matter, all holders of marketing applications for drug products (both NDAs and 
53  ANDAs) have an ongoing obligation to ensure their product labeling is accurate, and not false or 
54  misleading.  When new information becomes available that causes the labeling to become 
55  inaccurate, false or misleading, the application holder must take steps to update its labeling (see, 
56  e.g., 21 CFR 201.56(a)(2)).  Any drug is misbranded if its labeling is false or misleading, or does 
57  not provide adequate directions for use and adequate warnings (sections 301(a) and (b), and 
58  502(a), (f), and (j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 331(a) 
59  and (b), and 352(a), (f), and (j))). 
60   
61  Where the NDA for the RLD has not been withdrawn, RLD holders often propose changes to the 
62  labeling by submitting them to the NDA.  ANDA holders are expected to update their labeling 
63  after FDA has approved relevant changes to the labeling for the corresponding NDA RLD.  FDA 
64  may withdraw approval of an ANDA if it finds that the labeling for the drug product that is the 
65  subject of the ANDA is no longer consistent with that for the RLD (section 505(e) of the FD&C 
66  Act and 21 CFR 314.150(b)(10)).   
67      
68  FDA believes ANDA applicants are familiar with the mechanisms for updating labeling for 
69  pending and marketed ANDAs where the NDAs for the RLDs have not been withdrawn.  
70  However, there has been confusion regarding the process for updating labeling for ANDAs 
71  referencing RLDs where the NDAs have been withdrawn.   
72   
73  NDAs for RLDs may be withdrawn voluntarily, at the NDA holders request, for reasons other 
74  than safety and effectiveness.  Specifically, FDA will withdraw approval of an NDA at the 
75  applicants request where the drug that is the subject of the application is no longer being 
76  marketed, and if certain other conditions are satisfied, including the absence of any FDA finding 
77  that the drug is unsafe or ineffective for its approved conditions of use (see, e.g.,  314.150(c) 
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
78  (21 CFR 314.150(c))).4  As noted above, withdrawal of an NDA RLD under these circumstances 
79  is referred to in this guidance as a withdrawn RLD.5   
80   
81  Where an RLD has been withdrawn, ANDA products that were approved in reliance on the 
82  withdrawn RLD may continue to be marketed, and new ANDAs must refer to the withdrawn 
83  RLD as the basis for ANDA submission (provided that there has been a determination that the 
84  NDA RLD was not withdrawn for reasons of safety or effectiveness) (see  314.122(c) (21 CFR 
85  314.122(c))). 
86       
87  Under these circumstances, where approval of the NDA for an RLD has been withdrawn, the 
88  NDA holder can no longer update labeling for the withdrawn RLD.6  Yet as a drug is used over 
89  time, the scientific communitys understanding of the drug may evolve based on data from 
90  various sources, including published literature and postmarketing data.  Therefore, the labeling 
91  of ANDAs that rely on the withdrawn RLD might eventually become inaccurate and outdated, 
92  resulting in labeling that is false and/or misleading, for example.  Likewise, new original 
93  ANDAs that rely on the withdrawn RLD might include proposed labeling based on the last 
94  approved RLD labeling that includes outdated information that is false and/or misleading.   
95    
96  If an NDA for a certain drug has been withdrawn, there may be other drugs that contain the same 
97  active ingredient (or an active ingredient in the same pharmacologic or therapeutic class) for 
98  which approval of the NDA has not been withdrawn.  The labeling of those other drugs, as well 
99  as the labeling of any corresponding ANDAs, may have been updated to reflect any new 
100  scientific information that is needed for the safe and effective use of the drug. This creates a 
101  situation in which certain NDAs and ANDAs for a given active ingredient have up-to-date 
102  labeling, while other ANDAs do not, simply because those other ANDAs rely on an RLD for 
103  which approval of the NDA has been withdrawn.  In such cases the labeling of pending ANDAs 
104  or marketed ANDAs products may need to be updated to reflect changes that would have been 
105  necessary had the NDA for the RLD not been withdrawn. 
106   
                                                 
4 If the NDA for the RLD has been withdrawn for reasons other than safety or effectiveness, a therapeutically 
equivalent drug product approved under an ANDA may be designated as the reference standard for use in 
conducting an in vivo study to demonstrate bioequivalence.   
5 Withdrawal of approval of an NDA is considered effective upon the date specified in the notice of withdrawal 
published in the Federal Register.  Until that date, an NDA holder that has submitted a request under 21 CFR 
314.150 to withdraw the approval of an NDA will continue to be responsible for ensuring that the labeling of the 
drug product approved under the NDA remains accurate and up to date.  
6 In cases where marketing of the RLD product has been discontinued but approval of the NDA has not been 
withdrawn under  314.150 or section 505(e) of the FD&C Act (referred to in this guidance as a discontinued 
RLD), the NDA holder must still comply with applicable statutory and regulatory requirements.  These 
requirements include, for example, proposing any necessary revisions to update product labeling for the 
discontinued RLD (see, e.g.,  201.56(a)(2)).  ANDA products approved in reliance on a discontinued RLD may 
continue to be marketed, and new ANDAs must refer to the discontinued RLD as the basis for ANDA submission 
(see  314.122(c)).  The Agency will continue to list discontinued RLD drug products on the Discontinued Drug 
Product List in FDAs Approved Drug Products With Therapeutic Equivalence Evaluations (the Orange 
Book), unless FDA determines that the drug product was withdrawn from sale for reasons of safety or 
effectiveness, in which case the drug product will be removed from the Orange Book.     
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
107  In this guidance, FDA clarifies that consistent with the statute, where the RLD is withdrawn, 
108  certain labeling changes may continue to be made for pending ANDAs and marketed ANDAs.7   
109   
110   
111  III.  SCOPE OF GUIDANCE    
112   
113  This guidance is limited to labeling updates for generic drugs that are the subject of new original, 
114  pending ANDAs or approved ANDAs that rely on an RLD for which approval of the NDA has 
115  been withdrawn for reasons other than safety or effectiveness.   
116    
117  Consistent with this guidance, FDA may seek to facilitate certain updates to the labeling for a 
118  new original, pending ANDA or an already-approved ANDA that relies on a withdrawn RLD 
119  when the previously approved labeling for the withdrawn RLD has become outdated and such 
120  changes would have been necessary had the RLD not been withdrawn.   
121        
122  The process described in this guidance is intended to complement existing Agency authorities 
123  and processes, including FDAs authority under the Food and Drug Administration Amendments 
124  Act of 2007 (FDAAA) to require certain safety labeling changes (SLCs) to the labeling of certain 
125  prescription drug products.  The relationship of this guidance to certain existing FDA authorities 
126  and processes is further discussed in section IV.C below.   
127   
128   
129  IV.  UPDATING LABELING OF ANDAs THAT RELY ON WITHDRAWN RLDs 
130   
131  ANDA holders are responsible for reviewing postmarketing data and published literature as 
132  appropriate to satisfy applicable reporting requirements (e.g., 21 CFR 314.81, 314.98).  
133  However, FDA (as well as ANDA holders and applicants) may be aware of data relevant to 
134  labeling updates in a variety of situations.  For example, relevant data may already be reflected in 
135  the updated labeling of other drugs in the same pharmacologic or therapeutic class (e.g., class 
136  labeling); in non-product specific literature; or in postmarketing information.  The updates 
137  contemplated by this guidance generally would not involve reliance on product-specific, 
138  proprietary information about another drug.  Any changes proposed under this guidance must be 
139  consistent with the requirement that an ANDA include sufficient information to show that the 
140  conditions of use have been previously approved for the RLD (section 505(j)(2)(A)(i)).       
141    
                                                 
7 The approach proposed in this guidance is consistent with FDA statements made in the context of determinations 
that certain drug products that have been withdrawn from sale were not withdrawn for reasons of safety or 
effectiveness, including statements to the effect that [i]f FDA determines that labeling for these drug products 
should be revised to meet current standards, the Agency will advise ANDA applicants to submit such labeling.  
See, e.g., 80 FR 27320 at 27321 (May 13, 2015) (determining that SODIUM SULAMYD (sulfacetamide sodium) 
Ophthalmic Solution and Ophthalmic Ointment were not withdrawn from sale for reasons of safety or 
effectiveness).   
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
142  A.  Examples of Labeling Updates for ANDAs That Rely on Withdrawn RLDs 
143   
144  In general, the labeling changes contemplated under this guidance include changes necessary to 
145  ensure that labeling adequately describes information essential for safe and effective use; that 
146  labeling is accurate and meets current standards; and that labeling is not false or misleading 
147  under section 502 of the FD&C Act.  Revisions described by this guidance may include changes 
148  based on data that have become available since the RLD was withdrawn, including published 
149  literature and other data that emerge after products have entered the market. 
150   
151  More specifically, the labeling changes contemplated under this guidance may be needed: 
152   
153    To achieve consistency with the labeling of other products that have the same active 
154  ingredient or an active ingredient in the same pharmacologic or therapeutic class, or with 
155  the labeling of other products approved for the same indication, where appropriate;  
156    To correct outdated information related to a previously approved indication; and/or 
157    To achieve consistency with applicable regulations and current FDA labeling guidelines 
158  or other guidance (as already contemplated under  314.94(a)(8)(iv)). 
159   
160  Examples of the updates contemplated by this guidance might include the following (this list is 
161  not intended to be exhaustive):8 
162   
163    Updating the indication statement in the INDICATIONS AND USAGE section to reflect 
164  current disease terminology (e.g., changing Juvenile Rheumatoid Arthritis to Juvenile 
165  Idiopathic Arthritis) or to modify the description of an outdated restriction on the use of 
166  the drug in specific situations.  
167   
168    For systemic antibacterial drug products, including the required statement about 
169  antimicrobial resistance in the INDICATIONS AND USAGE section (see 21 CFR 
170  201.24(b)). 
171   
172    For parenteral products, including the following required statement or appropriate 
173  modification in the DOSAGE AND ADMINISTRATION section:  Parenteral drug 
174  products should be inspected visually for particulate matter and discoloration prior to 
175  administration, whenever solution and container permit (see 21 CFR 201.57(c)(3)(iv)). 
176   
177    Removing a risk from the CONTRAINDICATIONS section if the benefit outweighs the 
178  risk of use in the situation or subpopulation (e.g., the risk is theoretical) (see 21 CFR 
179  201.57(c)(5)). 
180   
                                                 
8 FDA intends to use the process outlined in section IV.B to address these types of labeling changes, unless, in 
particular circumstances, such changes fall within FDAs authority to require SLCs pursuant to section 505(o)(4) of 
the FD&C Act.  As noted above in section III, the process described in this guidance is intended to complement 
existing Agency authorities and processes, including FDAs authority to require SLCs.   
  5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
181    Revising the WARNINGS AND PRECAUTIONS section to include current steps to 
182  prevent, mitigate, monitor for, or manage a clinically significant adverse reaction or risk.   
183   
184    Revising the ADVERSE REACTIONS section to include a new adverse reaction based 
185  on postmarketing experience.   
186   
187    Revising the ADVERSE REACTIONS section to include the following recommended 
188  statement or appropriate modification before the presentation of adverse reactions from 
189  spontaneous reports:   
190   
191  The following adverse reactions have been identified during postapproval 
192  use of drug X. Because these reactions are reported voluntarily from a 
193  population of uncertain size, it is not always possible to reliably estimate 
194  their frequency or establish a causal relationship to drug exposure.   
195   
196  See FDA guidance for industry, Adverse Reactions Section of Labeling for Human 
197  Prescription Drug and Biological Products  Content and Format. 9     
198   
199    Adding a new clinically significant drug interaction in the DRUG INTERACTIONS 
200  section based on postmarketing data showing that a newly approved product interacts 
201  with the active ingredient in the ANDA product or with products in the ANDA products 
202  class. 
203   
204    Revising the OVERDOSAGE section to include overdose management strategies that are 
205  consistent with current Poison Control recommendations.  
206   
207    For systemic antibacterial drug products, updating susceptibility test interpretive criteria, 
208  susceptibility test methods, and quality control parameters in the Microbiology subsection 
209  of the CLINICAL PHARMACOLOGY section.  See FDA guidance for industry, 
210  Updating Labeling for Susceptibility Test Information in Systemic Antibacterial Drug 
211  Products and Antimicrobial Susceptibility Testing Devices;10 see also section 1111 of 
212  FDAAA.   
213   
214    Making changes to keep up to date with class Medication Guides (e.g., if there is a class 
215  Medication Guide for nonsteroidal anti-inflammatory drugs (NSAIDs), all ANDA 
216  NSAID products -- including those with withdrawn NDA RLDs -- should have the 
217  current version of the class NSAID Medication Guide).   
218   
219    Making changes requested by FDA prior to withdrawal of an NDA RLD that are 
220  determined to be necessary for safe and effective use.   
                                                 
9 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA 
Drugs guidance Web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.   
10 Available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
  6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
221   
222    Making changes or updates described in Agency regulations, guidance, or Federal 
223  Register notices even if they do not specifically address the labeling of ANDAs where the 
224  NDA RLD is withdrawn.     
225   
226  B.  Process for Labeling Updates 
227   
228  ANDA holders have the ability to submit any of the labeling updates contemplated by this 
229  guidance, i.e. those changes needed to ensure that labeling is accurate and meets current 
230  standards for an ANDA whose RLD is withdrawn, through the submission of a prior approval 
231  supplement (PAS).  If FDA determines that a change proposed in this manner is appropriate and 
232  approves the supplement, the Agency may request that other ANDA holders and any ANDA 
233  applicants relying on the same withdrawn RLD make the same updates, where appropriate.  This 
234  latter step is intended to ensure that labeling remains uniform across generic drugs that rely on 
235  the same RLD.   
236   
237  FDA may also request a changes being effected (CBE-0) supplement from ANDA holders (see 
238  21 CFR 314.70(c)(6)(iii)(E)) if FDA becomes aware of labeling updates that are needed to 
239  ensure that labeling is accurate and meets current standards for an ANDA or ANDAs whose 
240  RLD is withdrawn.11  Under these circumstances, the Agency would also solicit an amendment 
241  reflecting the needed updates from any ANDA applicants seeking initial approval that rely on the 
242  same RLD.  Such an amendment would be necessary prior to ANDA approval.   
243   
244  C.  Relationship of This Guidance to Existing Authorities and Processes  
245   
246  The process described in this guidance is intended to complement existing Agency authorities 
247  and processes.  Two of these are described below.   
248   
249  1.  Safety Labeling Changes Under Section 505(o)(4) of the FD&C Act 
250   
251  The Food and Drug Administration Amendments Act of 2007 (FDAAA) gave FDA explicit 
252  authority to require certain safety labeling changes (SLCs) to the labeling of prescription drug 
253  products marketed under NDAs and under ANDAs whose RLD is not currently marketed (i.e., 
254  ANDAs with a withdrawn RLD or discontinued RLD as described in the Background 
255  section of this guidance).  If FDA becomes aware of new safety information12 that it believes 
                                                 
11 FDA has issued a proposed rule that would allow ANDA holders to independently submit CBE-0 supplements 
making certain safety-related updates to their labeling, based on newly acquired information.  See 78 FR 67985 
(November 13, 2013).  That proposed rule, along with comments received, remains under review.  If the proposed 
rule is finalized, the final rule will govern the process for carrying out labeling updates that are within the scope of 
the rule.  The process described in this guidance would not alter ANDA holders obligation to maintain up-to-date 
labeling, whether under the current regulatory framework or a future scenario at such time as the proposed rule is 
finalized. 
12 See 21 U.S.C. 355-1(b)(3).  The term new safety information includes certain information about a serious risk 
or an unexpected serious risk associated with the use of a drug that FDA has become aware of since the drug was 
approved, since a risk evaluation and mitigation strategy (REMS) was required, or since the last assessment of the 
approved REMS for the drug. 
  7  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
256  should be included in labeling, FDA issues a safety labeling change notification letter, which 
257  may include proposed labeling changes, to the affected application holder(s) (see section 
258  505(o)(4) of the FD&C Act).  Application holders must then submit either a supplement with the 
259  proposed labeling changes, or a rebuttal statement explaining why the proposed changes are not 
260  warranted, within 30 days.  FDA reviews and acts on these supplements and rebuttal statement 
261  within defined time frames (see FDA guidance for industry, Safety Labeling Changes  
262  Implementation of Section 505(o)(4) of the FD&C Act.13 
263  The FDAAA SLC process is separate and distinct from the process described in this guidance.  
264  FDA will continue to use its FDAAA SLC authorities where appropriate in situations where 
265  FDA becomes aware of new safety information about a serious risk or an unexpected serious 
266  risk that the Agency believes should be included in product labeling.   
267  This guidance addresses certain situations in which needed updates to the labeling of ANDAs 
268  that rely on withdrawn RLDs may not be captured by the FDAAA SLC process.  For example:   
269    The FDAAA SLC authorities apply only to approved NDAs and ANDAs.  When new 
270  original ANDAs are submitted that rely on a withdrawn RLD, the FDAAA SLC 
271  authorities do not extend to the draft labeling submitted as part of those pending 
272  applications.  Under this guidance, FDA will consider the FDAAA SLC notification that 
273  is sent to the holders of approved applications to be FDA labeling guidelines or other 
274  guidance within the meaning of  314.94(a)(8)(iv).  Applicants with pending ANDAs 
275  will be able to submit amendments to their applications with labeling that reflects the 
276  safety labeling change made by the holders of approved ANDAs relying on the same 
277  RLD, and this will be considered a change made to comply with current FDA labeling 
278  guidelines or other guidance within the meaning of the regulation. 
279   
280    Before FDAAA came into effect on March 25, 2008, certain labeling updates had been 
281  accomplished through other regulatory procedures, including class labeling changes.  
282  Those updates were typically carried out in the first instance by updates to NDA RLD 
283  labeling that would then have been reflected in the labeling of ANDAs relying on that 
284  RLD.  Where an RLD affected by the update was withdrawn, however, the corresponding 
285  ANDAs may have never adopted these updates.  Where appropriate under the process 
286  described in this guidance (for example where labeling changes are not implemented 
287  through the FDAAA SLC process), FDA will ask ANDA holders that rely on withdrawn 
288  RLDs to make these updates to their labeling consistent with this guidance.   
289   
290  2.  Section 409I of the Public Health Service Act 
291   
292  Under section 409I of the Public Health Service Act (42 U.S.C.  284m), the National Institutes 
293  of Health (NIH) and FDA implement a program for pediatric studies of drugs.  NIH may under 
294  certain circumstances award funds to an entity with appropriate expertise for the conduct of 
295  studies needed to provide safety and efficacy information for pediatric labeling.  Upon 
                                                 
13 Available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
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296  completion of these pediatric studies, a study report that includes all data generated in connection 
297  with the studies is placed in a public docket assigned by FDA.  FDA will review the data 
298  generated, and if labeling changes are determined to be appropriate, FDA may request CBE-0 
299  supplements from the affected application holders to reflect those changes.  Affected application 
300  holders may include holders of ANDAs that rely on withdrawn RLDs.   
301   
302  The section 409I process will not be affected by this guidance.   
303   
304   
  9