Guidance for Industry
 
Postmarketing Safety Reporting
 
for Human Drug and Biological
 
Products Including Vaccines
 
DRAFT GUIDANCE 
This guidance document is being distributed for comment purposes only.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draft guidance.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 comments to Dockets Management Branch (HFA-305), Food and 
Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20857. All comments 
should be identified with the docket number listed in the notice of availability that publishes 
in the Federal Register. 
For questions on the content of the draft document contact (CDER) Min Chen, 301-827
3169 (phone); 301-827-5190 (fax), or (CBER) Miles Braun, 301-827-3974 (phone); 301
827-3529 (fax). 
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)
 
March 2001
  Guidance for Industry
 
Postmarketing Safety Reporting
 
for Human Drug and Biological
 
Products Including Vaccines
 
Additional copies are available from: 

Drug Information Branch (HFD-210) 

Center for Drug Evaluation and Research (CDER) 

5600 Fishers Lane, Rockville, MD 20857 

(Tel) 301-827-4570 

Internet at http://www.fda.gov/cder/guidance/index.htm 

or 

Office of Communication, Training and Manufacturers Assistance (HFM-40) 

Center for Biologics Evaluation and Research (CBER) 

1401 Rockville Pike, Rockville, MD 20852-1448
 
(Fax) 1-888-CBERFAX or 301-827-3844 

(Voice Information) 1-800-835-4709 or 301-827-1800 

Internet at http://www.fda.gov/cber/guidelines.htm 

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)
 
March 2001
  TABLE OF CONTENTS 
I.  INTRODUCTION..................................................................................................................................................................1
 
A.  WHAT DOES THIS GUIDANCE DISCUSS?..........................................................................................................................1
 
B.  WHAT DOES THIS GUIDANCE NOT   DISCUSS?................................................................................................................. 2
 
C.  GOOD GUIDANCE PRACTICES.............................................................................................................................................2
 
II.  BACKGROUND....................................................................................................................................................................3
 
A.  FINAL RULES.......................................................................................................................................................................3
 
B.  GUIDANCES ......................................................................................................................................................................... 3
 
C.  PROPOSED RULES ............................................................................................................................................................... 4
 
III.  WHO MUST REPORT.........................................................................................................................................................4
 
IV.  WHAT DO I REPORT?.......................................................................................................................................................5
 
A.  TYPE OF ADVERSE EXPERIENCES .....................................................................................................................................6
 
B.  DATA ELEMENTS TO INCLUDE IN A POSTMARKETING INDIVIDUAL CASE SAFETY REPORT ......................................... 8
 
V.  TYPE OF REPORTS ............................................................................................................................................................9
 
A.  15-DAY REPORTS OF SERIOUS, UNEXPECTED ADVERSE EXPERIENCES........................................................................9
 
B.  PERIODIC REPORTS .......................................................................................................................................................... 11 

C.  FOLLOWUP REPORTS ....................................................................................................................................................... 15 

D.  DISTRIBUTION REPORTS FOR BIOLOGICAL PRODUCTS INCLUDING VACCINES ............................................................ 18 

VI.  SPECIAL REPORTING SITUATIONS .....................................................................................................................18
 
A.  SCIENTIFIC LITERATURE REPORTS.................................................................................................................................18 

B.  POSTMARKETING, CLINICAL TRIAL, OR SURVEILLANCE STUDIES ................................................................................ 19 

C.  FOREIGN REPORTS ........................................................................................................................................................... 20 

D.  DEATH REPORTS..............................................................................................................................................................20 

E.  OVERDOSE REPORTS........................................................................................................................................................ 20 

F.  LACK OF EFFECT REPORTS ............................................................................................................................................. 21 

G.  INFORMATION ON THE INTERNET.................................................................................................................................... 21 

H.  PEDIATRIC PATIENTS.......................................................................................................................................................21 

I.  PRESCRIPTION DRUGS MARKETED FOR HUMAN USE WITHOUT AN APPROVED APPLICATION................................22 

J.  ANOTHER APPLICANT=S PRODUCT.................................................................................................................................22 

K.  MULTIPLE SUSPECT PRODUCTS ..................................................................................................................................... 22 

L.  SUSPECT DRUGS WITH MULTIPLE NDAS OR ANDAS BY THE SAME APPLICANT...................................................23 

M.  TWO OR MORE MARKETERS OF A PRODUCT ................................................................................................................ 23 

N.  UNAPPROVED INDICATIONS ............................................................................................................................................. 23 

O.  PRODUCT INTERACTIONS ................................................................................................................................................ 23 

P.  REPORTS FROM THE FDA ............................................................................................................................................... 23 

Q.  PRODUCT DEFECTS.......................................................................................................................................................... 24 

R.  REPORTING AMBIGUITIES................................................................................................................................................24 

VII.  CODING OF ADVERSE EXPERIENCES IN INDIVIDUAL CASE SAFETY REPORTS ..................................24
 
VIII.  REPORTING FORMATS.............................................................................................................................................25
 
A.  FDA FORM 3500A........................................................................................................................................................... 25 

B.  VAERS FORM FOR VACCINES......................................................................................................................................... 28 

C.  CIOMS I FORM FOR FOREIGN ADVERSE EXPERIENCES................................................................................................29 

D.  DISTRIBUTION REPORTS FOR BIOLOGICAL PRODUCTS INCLUDING VACCINES ............................................................ 29 
 E.  ELECTRONIC SUBMISSIONS..............................................................................................................................................30 

IX.  HOW AND WHERE TO SUBMIT POSTMARKETING SAFETY REPORTS.........................................................30
 
A.  HUMAN DRUG PRODUCTS ............................................................................................................................................... 30 

B.  HUMAN BIOLOGICAL PRODUCTS AND VACCINES ........................................................................................................... 31 

X.  WRITTEN PROCEDURES FOR POSTMARKETING SAFETY REPORTING.......................................................31
 
XI.  REQUESTS FOR WAIVERS TO POSTMARKETING SAFETY REPORTING REQUIREMENTS ....................32
 
A.  SUBMISSION OF FDA FORM 3500A FOR NONSERIOUS, EXPECTED ADVERSE EXPERIENCES.....................................32 

B.  SUBMISSION OF PSUR FORMAT FOR THE PERIODIC REPORT ....................................................................................... 32 

C.  SUBMISSION DATE AND FREQUENCY FOR PSUR REPORTS .......................................................................................... 33 

D.  HOW AND WHERE TO SUBMIT WAIVER REQUESTS......................................................................................................34 

XII.  VALIDATION OF ADVERSE EXPERIENCE COMPUTER SYSTEMS ..............................................................34
 
APPENDIX A: GLOSSARY.......................................................................................................................................................35
 
APPENDIX B: REPORT CHECKLIST.....................................................................................................................................38
 
APPENDIX C: FDA FORM 500A.......................................................................................................41 

APPENDIX D: FORM VAERS-1......................................................................................................43 

APPENDIX E: CIOMS 1 FORM........................................................................................................45 

APPENDIX F: ONE-PAGE FDA FORM 3500A.....................................................................................46 
 Draft  Not for Implementation 
1
 
1  Guidance for Industry
2
 
3  Postmarketing Safety Reporting for Human Drug and
 
4  Biological Products  Including Vaccines 

5
 
6
 
7
 
8
 
9  This draft guidance, when finalized, represents the Food and Drug Administration's (FDAs) 

10  current thinking on this topic.  It does not create or confer any rights for or on any person and
does not operate to bind FDA or the public.  An alternative approach may be used if such
11 
approach satisfies the requirements of the applicable statutes and regulations.
12 
13 
14 
15 
16 
17  I.  INTRODUCTION 
18 
19  This guidance is intended to assist applicants and other responsible parties in fulfilling the 
20  FDA=s existing postmarketing safety reporting requirements for human marketed drug and 
21  biological products at 21 CFR 310.305, 314.80, 314.98, 600.80, and 600.81.2  Under 
22  these regulations, postmarketing safety reports must be submitted to the Agency for the 
23  following: 
24 
25  1.   Serious and unexpected adverse experiences from all sources (domestic and 
26  foreign) 
27 
28  2.   Spontaneously reported adverse experiences that occur domestically and that are: 
29 
30     Serious and expected 
31     Nonserious and unexpected 
32     Nonserious and expected 
33 
34  A.  What Does This Guidance Discuss? 
35 
36  This guidance discusses the following postmarketing reports: 
                                                
1  This guidance has been prepared by FDA=s Safety Reporting Regulations Working Group, which includes 
representatives from the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation 
and Research (CBER). 
2 The FDA is planning to propose revisions to these regulations (see section II.C in this guidance). As these 
proposals are finalized the Agency will revise this guidance to provide industry with assistance in fulfilling the 
new regulatory requirements. 
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37 
38     15-Day Reports of Serious, Unexpected Adverse Experiences 
39     Periodic Reports 
40     Followup Reports 
41     Distribution Reports for Biological Products Including Vaccines 
42 
43  This guidance addresses the following regulations for the following products.3 
44 
Regulation  Product 
21 CFR 310.305  Prescription drugs marketed for human use without an 
an approved application 
21 CFR 314.80  Human drugs with approved NDAs 
21 CFR 314.98  Human drugs with approved ANDAs 
21 CFR 600.80  Human biological products with approved BLAs 
21 CFR 600.81  Human biological products with approved BLAs 
45 
46  If you believe the procedures described in this guidance are inapplicable to a particular 
47  product or that other procedures are appropriate, you should discuss the matter with the 
48  Agency to ensure that your procedures comply with applicable statutes and regulations. 
49 
50  B.  What Does This Guidance Not Discuss? 
51 
52  This guidance does not discuss the following: 
53 
54     IND Safety Reports (21 CFR 312.32)4 
55     Safety Update Reports for Drugs (21 CFR 314.50(d)(5)(vi)(b)) 
56     Approved NDA Annual Reports (21 CFR 314.81(b)(2)) 
57     Approved BLA Annual Reports (21 CFR 601.28) 
58 
59  This guidance does not apply to the following products: 
60 
61     In vitro diagnostic products 
62     Whole blood or its components 
63     Product manufacturing defects (unless the defect is associated with an 
64  adverse experience in humans) 
65 
66  C.   Good Guidance Practices 
67 
68  The Agency's good guidance practices (GGPs) regulation5 does not allow the use of 
69  mandatory language in guidances unless it is used to describe regulatory requirements. In 
                                                
3 NDA means new drug application, ANDA means abbreviated new drug application, and BLA means 
biologics license application 
4 IND means investigational new drug application 
2
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70  most guidances, we provide the related cite whenever mandatory language is used to 
71  indicate the basis for the use of such language. This guidance discusses regulatory 
72  requirements in great detail. To avoid including the same regulatory cites repeatedly and 
73  to make the guidance user friendly, we will indicate at the beginning of those sections that 
74  include extensive discussions of regulatory requirements which cites are particularly 
75  relevant. The use of mandatory language (e.g., must, have to, required) will signify a 
76  regulatory requirement while the use of words such as should and recommend will indicate 
77  Agency policy. 
78 
79 
80  II.  BACKGROUND 
81 
82  The FDA has undertaken a major effort to clarify and revise its regulations regarding pre
83  and postmarketing safety reporting requirements for human drug and biological products. 
84  To date, the Agency has issued a number of final rules and guidances for industry on this 
85  topic; several proposed rules are under development. 
86 
87  A.  Final Rules 
88 
89     Expedited Safety Reports for Human Drug and Biological Products 
90   
91  In the Federal Register of October 7, 1997 (62 FR 52237), the FDA published a 
92  final rule amending its regulations for expedited safety reporting to implement 
93  certain definitions, reporting periods, and formats recommended by the International 
94  Conference on Harmonisation of Technical Requirements for Registration of 
95  Pharmaceuticals for Human Use (ICH). These recommendations are discussed in 
96  the ICH guidance E2A Clinical Safety Data Management: Definitions and 
97  Standards for Expedited Reporting; March 1, 1995. 
98 
99     Postmarketing Expedited Increased Frequency Reports for Human Drug and 
100  Biological Products 
101 
102  In the Federal Register of June 25, 1997 (62 FR 34166), the FDA published a final 
103  rule revoking requirements to submit postmarketing increased frequency reports to 
104  the Agency in an expedited manner for human drug and biological products. 
105 
106  B.  Guidances 
107 
108  With regard to postmarketing safety reporting for human drug and biological products, the 
109  FDA has made three final guidances available: 
110 
111     Postmarketing Reporting of Adverse Drug Experiences (March 1992) 
                                                                                                                                                            
5 The Agency's regulation on good guidance practices published on September 19, 2000 (21 CFR 10.115; 65 
FR 56468). 
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112 
113     Guideline for Adverse Experience Reporting for Licensed Biological 
114  Products (October 1993) 
115 
116     Postmarketing Adverse Experience Reporting for Human Drug and 
117  Licensed Biological Products: Clarification of What to Report (August 27, 
118  1997). 
119 
120  When finalized, this guidance will replace the three guidances listed above and will reflect 
121  the new regulatory requirements in the final rules of June 25, 1997, and October 7, 1997. 
122 
123  C.  Proposed Rules 
124 
125  The Agency currently is in the process of developing proposed rules to further amend its 
126  safety reporting requirements for human drug and biological products. Many of the 
127  provisions in these proposed rules will be based on recommendations developed by ICH. 
128  For instance, the Agency is planning to propose additional amendments to its expedited 
129  safety reporting regulations based on the ICH E2A guidance. 
130 
131  In addition, the FDA is planning, as indicated in the final rule of October 7, 1997, to 
132  repropose amendments to its postmarketing periodic safety reporting requirements that 
133  were initially proposed in the Federal Register of October 27, 1994 (59 FR 54046).  The 
134  new postmarketing periodic safety reporting proposals will be based on recommendations 
135  in the ICH guidance E2C Clinical Safety Data Management: Periodic Safety Update 
136  Reports for Marketed Drugs (May 19, 1997). 
137 
138  The Agency also is planning to issue a proposal requiring the electronic submission of 
139  postmarketing safety reports consistent with recommendations developed by ICH.6 
140 
141  As these proposed rules are finalized, this postmarketing safety reporting guidance for 
142  human drug and biological products will be revised to provide industry with assistance in 
143  fulfilling the new regulatory requirements. 
144 
145 
146  III.  WHO MUST REPORT 
147 
148  According to the regulations, the following persons have postmarketing safety reporting 
149  responsibilities: 
150 
151     Manufacturers are required to submit postmarketing expedited safety reports to the 
152  FDA for prescription drug products marketed for human use without an approved 
153  application ( 310.305). 
                                                
6 See advance notice of proposed rulemaking on electronic reporting of postmarketing adverse drug 
reactions; request for comments, 63 FR 59746, November 5, 1998. 
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154 
155     Applicants (individual or corporate entity that holds an NDA or ANDA) are required 
156  to submit postmarketing safety reports to the FDA for human drug products with 
157  approved NDAs ( 314.80) and ANDAs ( 314.98). 
158 
159     Licensed manufacturers (individual or corporate entity that holds a BLA) are 
160  required to submit postmarketing safety reports to the FDA for human licensed 
161  biological products with approved BLAs ( 600.80 and 600.81). 
162 
163     Any person whose name appears on the label of a marketed drug as its packer or 
164  distributor ( 310.305(c)(1)(i)) or manufacturer, packer, or distributor 
165  ( 314.80(c)(1)(iii)) has postmarketing safety reporting responsibilities. 
166 
167     Any person whose name appears on the label of a licensed biological product as its 
168  manufacturer, packer, distributor, shared manufacturer, joint manufacturer, or any 
169  other participant involved in divided manufacturing has postmarketing safety 
170  reporting responsibilities ( 600.80(c)(1)(iii)). 
171 
172  For the purposes of this guidance, the term applicant includes all persons with 
173  postmarketing safety reporting responsibilities under  310.305, 314.80, 314.98, 600.80, 
174  and 600.81. 
175 
176  According to the regulations at  310.305(d), 314.80(f), and 600.80(f), if an applicant 
177  becomes aware of a reportable adverse experience, the applicant is responsible for 
178  preparing a postmarketing safety report and submitting it to the FDA. Applicants should 
179  not assume that their responsibilities are fulfilled if they ask the person who pointed out a 
180  reportable adverse experience to submit a safety report to the FDA. 
181 
182 
183  IV.  WHAT DO I REPORT? 
184 
185  The following paragraphs discuss the types of adverse experiences that must be reported 
186  to the FDA under  310.305, 314.80, 314.98, and 600.80. This section also describes 
187  the minimum data elements that should be included in an individual case safety report. 
188 
189  An adverse experience is any undesirable event that is associated with the use of a drug 
190  or biological product in humans whether or not considered product-related by the 
191  applicant.7  An individual case safety report describes an adverse experience(s) for a 
192  patient or subject. Individual case safety reports of domestic adverse experiences for 
193  marketed human drug and biological products, except vaccines, must be submitted to the 
194  FDA on FDA Form 3500A; a Vaccine Adverse Event Reporting System (VAERS) form 
195  must be used for adverse experiences associated with the use of vaccines. Individual 
196  case safety reports of foreign adverse experiences can be submitted on FDA Form 3500A 
                                                
7 See Appendix A for definition of adverse experience. (See also  310.305(b), 314.80(a) and 600.80(a).) 
5
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197  (VAERS form for vaccines) or, if preferred, on a Council for International Organizations for 
198  Medical Sciences (CIOMS) I form. See section VIII in this guidance for discussion of 
199  reporting formats for individual case safety reports. 
200 
201  A.  Type of Adverse Experiences 
202 
203  1.  Adverse Experiences that are Serious and Unexpected from All Sources 
204  (Domestic and Foreign)8 
205 
206  Serious and unexpected adverse experiences from all sources, whether domestic 
207  or foreign, must be submitted to the FDA. Possible sources include, for example, 
208  scientific literature, postmarketing studies, or commercial marketing experience. 
209 
210  Scientific literature reports include published and unpublished scientific papers that 
211  are known to the applicant (see section VI.A in this guidance for reporting of 
212  adverse experiences from the scientific literature). 
213 
214  Postmarketing studies include in vitro, animal, clinical, and epidemiological or 
215  surveillance investigations (see section VI.B in this guidance for reporting of 
216  adverse experiences from studies). Adverse experiences from studies must only 
217  be submitted to the FDA if the applicant believes that there is a reasonable 
218  possibility that the drug or biological product caused the adverse experience (see 
219   310.305(c)(1)(ii), 314.80(e)(1) and 600.80(e)(1)). 
220 
221  2.  Other Spontaneously Reported Adverse Experiences (Domestic Only)9 
222 
223  Adverse experiences occurring in the United States from commercial marketing 
224  experience must be submitted to the FDA if they are spontaneously reported to 
225  applicants and are: 
226 
227     serious and expected 
228     nonserious and unexpected, or 
229     nonserious and expected 
230 
231  Applicants can request a waiver of the requirement to submit individual case safety 
232  reports of nonserious, expected adverse experiences for drugs and certain 
233  biological products (see section XI.A in this guidance on waiver requests). 
234 
235  3.  Serious Adverse Experiences10 
                                                
8 The requirements for reports of serious, unexpected adverse experiences can be found in  310.305(c), 
314.80(c)(1) and 600.80(c)(1). 
9 The requirements for reports describing these adverse experiences can be found in  314.80(c)(2) and 
600.80(c)(2). 
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236 
237  The outcome of an adverse experience must be determined before a report can be 
238  identified as serious. A serious report must have one or more of the following 
239  outcomes: 
240 
241     Death 
242     Life-threatening adverse experience 
243     Initial inpatient hospitalization or prolongation of hospitalization 
244     Significant or persistent disability/incapacity 
245     Congenital anomaly/birth defect (including that occurring in a fetus) 
246     Important medical event based upon appropriate medical judgment that may 
247  jeopardize the patient or subject and may require medical or surgical 
248  intervention to prevent one of the other outcomes listed in the definition of 
249  serious. 
250 
251  A patient admitted to a hospital for 1 or more days as a result of an adverse 
252  experience, even if released on the same day, would qualify for the initial  inpatient 
253  hospitalization outcome. An emergency room visit that results in admission to the 
254  hospital would also qualify for the initial inpatient hospitalization outcome. 
255  However, emergency room visits that do not result in admission to the hospital 
256  would not qualify for this outcome and, instead, should be evaluated for one of the 
257  other outcomes in the definition of serious (e.g., life-threatening adverse 
258  experience, important medical event). 
259 
260  Persons incarcerated because of actions allegedly caused by a drug (e.g., 
261  psychotropic drugs and rage reactions) have sustained a substantial disruption in 
262  their ability to conduct normal life functions. Thus, these adverse experiences would 
263  qualify for the significant or persistent disability/incapacity outcome. 
264 
265  Important medical events would include allergic bronchospasm requiring intensive 
266  treatment in an emergency room or at home, blood dyscrasias or convulsions that 
267  do not result in inpatient hospitalization, or the development of drug dependency or 
268  drug abuse. Applicants should mark the "other" box in item B2 of FDA Form 3500A 
269  for adverse experiences identified as important medical events. 
270 
271  Applicants should actively seek the outcome for a suspected serious adverse 
272  experience reported to them. If unable to initially determine the outcome for an 
273  adverse experience, an applicant should continue to actively seek information in an 
274  attempt to determine an outcome. For a serious adverse experience that was not 
275  initially reported to the applicant by a health care professional (e.g., report from a 
276  consumer), the applicant should actively pursue contacting the health care 
                                                                                                                                                            
10 See Appendix A for definition of serious adverse experience. (See also  310.305(b), 314.80(a) and 
600.80(a).) 
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277  professional associated with the care of the patient to gather further medical 
278  perspective on the case. 
279 
280  4.  Unexpected and Expected Adverse Experiences11 
281 
282  The current FDA-approved labeling for the human drug or biological product should 
283  be used as the reference document to determine whether an adverse experience is 
284  unexpected or expected.  An adverse experience would be considered unexpected 
285  if it is not included in the products current FDA-approved labeling and expected if it 
286  is included in this document. 
287 
288  5.   Spontaneous Report12 
289 
290  Spontaneous reports are unsolicited communications from individuals (e.g., health 
291  care professional, consumer) to applicants that concern adverse experiences. 
292  Spontaneous reports should not include adverse experiences identified from 
293  information solicited by applicants such as individual cases or findings derived from 
294  a study (e.g., any organized data collection scheme). 
295 
296  B.  Data Elements to Include in a Postmarketing Individual Case Safety Report 
297 
298  Before considering any clinical incident for submission to the FDA in an individual case 
299  safety report, applicants should, at a minimum, have knowledge of the following four data 
300  elements: 
301 
302  1.  An identifiable patient 
303  2.  An identifiable reporter 
304  3.  A suspect drug or biological product 
305  4.  An adverse experience or fatal outcome suspected to be due to the suspect 
306  drug or biological product 
307 
308  If any one of these basic elements remains unknown after being actively sought by the 
309  applicant, a report on the incident should not be submitted to the FDA because reports 
310  without such information make interpretation of their significance difficult, at best, and 
311  impossible, in most instances. Instead, the applicant should maintain records of its efforts 
312  to obtain the basic elements for an individual case in its corporate drug or biological 
313  product safety files. If an applicant submits a report to the FDA that lacks any of the four 
314  basic elements, it will be returned to the applicant marked insufficient data for a report. 
315 
                                                
11 See Appendix A for definitions of unexpected and expected adverse experiences. (See also  
310.305(b), 314.80(a) and 600.80(a).) 
12 See Appendix A for definition of spontaneous report. 
8
  316  An applicant that is actively seeking information on an adverse experience should use 
317  direct verbal contact with the initial reporter of the adverse experience (e.g., in person, by 
318  telephone or other interactive means such as a videoconference). The applicant should not 
319  merely send the initial reporter a letter requesting information concerning the adverse 
320  experience. Applicants should use a health care professional (e.g., physician, physician 
321  assistant, dentist, pharmacist, nurse) for contacts with initial reporters because such 
322  persons should be able to understand the medical consequences of the case and ask 
323  appropriate questions to acquire relevant information rapidly to determine the significance 
324  of the case. 
325 
326  With regard to an identifiable patient, reports of the type Asome patients got anaphylaxis@ 
327  should be excluded until further information about the patients is obtained. A report stating 
328  that Aan elderly woman had anaphylaxis@ or a Ayoung man experienced anaphylaxis@ should 
329  be included because there is enough information to suspect that specific patients were 
330  involved. Patients should not be identified by name or address. Instead, the applicant 
331  should assign a unique code (e.g., patient initials) to each report. 
332  For spontaneous reports, the applicant should assume that an adverse experience or fatal 
333  outcome was suspected to be due to the suspect drug or biological product (implied 
334  causality). For clinical studies, an adverse experience or fatal outcome need not be 
335  submitted to the FDA unless the applicant concludes that there is a reasonable possibility 
336  that the product caused the adverse experience or fatal outcome (see  310.305(c)(1)(ii), 
337  314.80(e)(1) and 600.80(e)(1)). An adverse experience should, at a minimum, consist of 
338  signs (including abnormal laboratory findings, if appropriate), symptoms, or disease 
339  diagnosis (including any colloquial descriptions obtained) for purposes of reporting. Thus, 
340  a report stating that a patient Aexperienced unspecified injury,@ or a patient Asuffered 
341  irreparable damages@ should not be included until more specific information about the 
342  adverse experience can be determined. 
343 
344 
345  V.  TYPE OF REPORTS 
346 
347  The following paragraphs discuss the types of postmarketing safety reports that must be 
348  submitted to the FDA based on the regulations as listed. 
349 
350  A.  15-Day Reports of Serious, Unexpected Adverse Experiences13 
351 
352  Individual case safety reports of serious, unexpected adverse experiences from all sources 
353  (domestic and foreign) must be reported to the FDA as soon as possible, but in no case 
354  later than 15 calendar days of initial receipt of the information by the applicant. See section 
355  VIII in this guidance for discussion of reporting formats for individual case safety reports. 
356 
                                                
13 The requirements for 15-Day Reports can be found in  310.305(a), (c)(1)(i) and (d)(1),  314.80(c)(1)(i) and 
(f)(1), and 600.80(c)(1)(i) and (f)(1). 
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357  An applicant should not wait for the initial reporter of a serious, unexpected adverse 
358  experience to send them written information about the experience before submitting a 15
359  day report to the FDA. An applicant can and should submit a 15-day report to the FDA 
360  based only on verbal information. 
361 
362  1.  Determination of 15-Day Reporting Period 
363 
364  Serious, unexpected adverse experiences must be submitted to the FDA no later 
365  than 15 calendar days of initial receipt of the information by the applicant. For 
366  reporting purposes, this information should include, at a minimum, the four basic 
367  elements (i.e., an identifiable patient, an identifiable reporter, a suspect drug or 
368  biological product, and a serious, unexpected adverse experience). The date the 
369  company has knowledge of these four basic elements should be entered into item 
370  G4 of FDA Form 3500A or Box 25 of the VAERS form (i.e., this date represents 
371  Day 0 of the 15-day time clock). 
372 
373  If the 15th calendar day occurs on a weekend or U.S. Federal holiday, the 15-day 
374  report should be submitted the first working day after the weekend or U.S. Federal 
375  holiday. 
376 
377  The applicant should exercise due diligence to acquire all the information for an 
378  individual case safety report immediately upon receipt of a suspected serious, 
379  unexpected adverse experience (e.g., completion of all the applicable elements on 
380  FDA Form 3500A). The applicant should maintain records of its efforts to obtain 
381  this information and should include in the narrative section of FDA Form 3500A (i.e., 
382  item B5), a chronological description of these efforts if there is a delay in obtaining 
383  such information. 
384 
385  When an applicant receives a report of a serious, unexpected adverse experience 
386  but it is not possible to complete all the applicable elements for an individual case 
387  safety report within 15 calendar days, a preliminary report that contains at least the 
388  four basic elements should be submitted. Additional followup information should be 
389  actively sought and submitted within 15 calendar days after obtaining the new 
390  information (see section V.C in this guidance for discussion of followup reports). 
391 
392  For foreign reports, the 15-day time clock begins when the applicant or its foreign 
393  affiliate has received the four basic elements for a 15-day report. Applicants should 
394  therefore establish effective mechanisms to ensure rapid information transfer from 
395  their foreign affiliates. 
396 
397  2.  Supporting Documentation 
398 
399  For individual case safety reports of serious, unexpected adverse experiences, the 
400  FDA encourages applicants to include relevant hospital discharge summaries and 
401  autopsy reports/death certificates. Applicants should also include in their report a 
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402  list of other relevant documents (e.g., medical records, relevant laboratory data, 
403  electrocardiograms, and other concise critical clinical data) maintained in their 
404  corporate drug or biological product safety files. The FDA can request that copies 
405  of one or more of these documents be provided to the Agency. Applicants should 
406  submit copies of these documents to the Agency within 5 calendar days after 
407  receipt of the request. 
408 
409  3.  Report Identification 
410 
411  Fifteen-day reports must be submitted in duplicate under separate cover 
412  prominently identified as "15-Day Alert Report."  For this purpose, the 15-Day Alert 
413  Report identification should be included on the outside envelope. 
414 
415  For prescription drugs marketed for human use without an approved application, a 
416  single copy of the 15-day report and a copy of the U.S. labeling must be submitted. 
417  These reports should be marked on the outside envelope with "15-Day Alert Report 
418  - 310.305." 
419 
420  Multiple 15-day reports and 15-day followup reports can be submitted in the same 
421  envelope, but they should not be stapled together (see section V.C for discussion of 
422  followup reports). 
423 
424  B.  Periodic Reports14 
425 
426  The following paragraphs discuss the reporting frequency for submission of periodic 
427  reports and the content of these reports. See section XI in this guidance for requests for 
428  waivers of the requirement to submit postmarketing periodic safety reports (e.g., waiver to 
429  use periodic safety update report (PSUR) format recommended by ICH for periodic report 
430  instead of format described in the regulations, waiver to submit individual cases of 
431  nonserious, expected adverse experiences in periodic report). 
432 
433  1.  Timing of Postmarketing Periodic Reports 
434 
435  Postmarketing periodic reports are required to be submitted to the FDA for each 
436  approved NDA, ANDA, and BLA and are due quarterly for the first 3 years after U.S. 
437  approval of the application and annually thereafter. If marketing is delayed, these 
438  reports should still be submitted quarterly for the first 3 years of marketing. Upon 
439  written notice, the FDA may extend or reestablish the requirement that an applicant 
440  submit quarterly reports or require that the applicant submit periodic reports at 
441  different time intervals. 
442 
443  Periodic reports due quarterly must be submitted within 30 calendar days of the last 
444  day of the reporting quarter. Reports due annually must be submitted each year 
                                                
14 The requirements for periodic reports can be found in  314.80(c)(2) and 600.80(c)(2). 
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445  within 60 calendar days of the anniversary date of U.S. approval of the application 
446  for the drug or biological product (i.e., NDA, ANDA, BLA). 
447 
448  Periodic submissions should be clearly marked "Periodic Adverse Experience 
449  Submission" on the front cover of each volume. Each page of the periodic report 
450  should be numbered and include the name and NDA or ANDA number if the 
451  periodic report is for a drug product; the name and submission tracking number 
452  (STN) should be used if the periodic report is for a biological product (a STN for a 
453  biological product can be found on the Internet at www.fda.gov/cber/stn/stn.htm). 
454 
455  2.  Content of a Postmarketing Periodic Report 
456 
457  The regulations require a postmarketing periodic report to contain: 
458 
459     a narrative summary and analysis of the information in the report and an analysis 
460  of the 15-day Alert reports submitted during the reporting interval 
461     an FDA Form 3500A for each spontaneously reported adverse experience 
462  occurring in the United States that was not reported in a 15-day Alert report 
463     a history of actions taken since the last report because of adverse experiences. 
464 
465  The information contained within a postmarketing periodic report should be divided 
466  into four sections in the order described below and should be clearly separated by 
467  an identifying tab. If information for one of these sections is not included, the 
468  applicant should simply explain why the information is not provided. 
469 
470  a.   Section 1: Narrative summary and analysis 
471 
472  A narrative summary and analysis of the information in the postmarketing 
473  periodic report and an analysis of the 15-day reports (i.e., serious, 
474  unexpected adverse experiences) submitted during the reporting period 
475  must be provided and should include: 
476 
477     The number of non-15-day15 initial adverse experience reports and 
478  the number of non-15-day followup reports contained in this periodic 
479  report and the time period covered by the periodic report. 
480 
481     A line listing of the 15-day reports submitted during the reporting 
482  period. This line listing should include the manufacturer report 
483  number, adverse experience term(s), and the date the 15-day report 
484  was sent to the FDA. 
485 
                                                
15 These include serious and expected adverse experiences, nonserious and unexpected adverse 
experiences, and nonserious and expected adverse experiences. 
12
  486     A summary tabulation by body system (e.g., cardiovascular, central 
487  nervous system, endocrine, renal) of all adverse experience terms 
488  and counts of occurrences submitted during the reporting period. The 
489  information should be taken from : 
490 
491  -  15-day reports submitted to the FDA; 
492  -  non-15-day reports submitted in the periodic report; 
493  -  reports forwarded to the applicant by the FDA; and 
494  -  any nonserious, expected adverse experiences not submitted to 
495  the FDA but maintained on file by the applicant. 
496 
497  For the adverse experience term product interaction, the interacting 
498  products should be identified in the tabulation. 
499 
500     A summary listing of the adverse experience reports in which the drug 
501  or biological product was listed as one of the suspect products, but 
502  the report was filed to another NDA, ANDA, or BLA held by the 
503  applicant. 
504 
505     A narrative discussion of the clinical significance of the 15-day reports 
506  submitted during the reporting period and of any increased reporting 
507  frequency of serious, expected adverse experiences when, in the 
508  judgment of the applicant, it is believed the data reflect a clinically 
509  meaningful change in adverse experience occurrence. This narrative 
510  should assess clinical significance by type of adverse experience, 
511  body system, and overall product safety relating the new information 
512  received during this reporting period to what was already known 
513  about the product. The narrative should also state what further 
514  actions, if any, the applicant plans to undertake based on the 
515  information gained during the reporting period and include the time 
516  period for completing the actions (i.e., when the applicant plans to 
517  start and finish the action and submit the information to the Agency). 
518 
519     The narrative discussion should indicate, based on the information 
520  learned during the reporting period, whether the applicant believes 
521  either that (1) no change in the products current approved labeling is 
522  warranted or (2) there are safety-related issues that need to be 
523  addressed in the approved product labeling. If changes in the 
524  approved product labeling are under consideration by the FDA, the 
525  applicant should state in the narrative the date and number of the 
526  supplemental application submitted to address the labeling changes. 
527 
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528  b.   Section 2: Narrative discussion of actions taken 
529 
530  A narrative discussion of actions taken must be provided, including any 
531  labeling changes and studies initiated since the last periodic report. This 
532  section should include: 
533 
534     A copy of current U.S. product labeling 
535 
536     A list of any labeling changes made during the reporting period 
537 
538     A list of studies initiated 
539 
540     A summary of important foreign regulatory actions (e.g., new 
541  warnings, limitations in the indications and use of the product) 
542 
543     Any communication of new safety information (e.g., a Dear Doctor 
544  letter) 
545 
546  c.  Section 3: Index line listing 
547 
548  An index line listing of FDA Form 3500As or VAERS forms included in 
549  section 4 of the periodic report must be provided. The line listing for each 
550  FDA Form 3500A or VAERS form submitted should include: 
551 
552     Manufacturer report number 
553 
554     Adverse experience term(s) 
555 
556     Page number of FDA Form 3500A or VAERS form as located in the 
557  periodic report 
558 
559     Identification of interacting products for any product interaction listed 
560  as an adverse experience. 
561 
562  d.   Section 4: FDA Form 3500As or VAERS forms 
563 
564  FDA Form 3500As or VAERS forms must be provided for the following 
565  spontaneously reported adverse experiences that occurred in the United 
566  States during the reporting period: 
567 
568     Serious and expected 
569 
570     Nonserious and unexpected 
571 
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572     Nonserious and expected 
573 
574  Applicants are encouraged to request a waiver of the requirement to submit 
575  individual case safety reports of nonserious, expected adverse experiences 
576  for drugs and certain biological products as described below (see section 
577  XI.A in this guidance). 
578 
579  Adverse experiences due to a failure to produce the expected 
580  pharmacologic action (i.e., lack of effect) should be included in this section 
581  (see section VI.F in this guidance). 
582 
583  For individual case safety reports of serious, expected adverse experiences, 
584  the FDA encourages applicants to include relevant hospital discharge 
585  summaries and autopsy reports/death certificates, as well as lists of other 
586  relevant documents as described for 15-day reports of serious, unexpected 
587  adverse experiences (see section V.A.2 in this guidance). 
588 
589  Initial non-15 day reports should be included in the periodic report in a 
590  separate section from non-15 day followup reports (see the following section 
591  V.C for discussion of non-15 day followup reports). All initial and followup 
592  information obtained for an adverse experience with a given periodic 
593  reporting period should be combined and submitted in the periodic report as 
594  one initial non-15 day report (i.e., an initial non-15 day report and a non-15 
595  day followup report describing the same adverse experience should not be 
596  submitted in the same periodic report). 
597 
598  An FDA Form 3500A or VAERS form for a serious, unexpected adverse 
599  experience should not be included in a periodic report because this adverse 
600  experience should have been previously submitted to the FDA as a 15-day 
601  report. 
602 
603  If no adverse experiences were identified for the human drug or biological product 
604  for the time period involved and no regulatory actions concerning safety were taken 
605  anywhere in the world where the product is marketed, the periodic report should 
606  simply state this and be submitted to the FDA along with a copy of the current U.S. 
607  labeling. 
608 
609  C.  Followup Reports16 
610 
611  The following paragraphs discuss the content of and reporting considerations for 15-day 
612  followup reports that are submitted in an expedited manner and non-15 day followup 
613  reports that are submitted as part of a postmarketing periodic report. A followup report 
614  provides information about an adverse experience that has been previously reported as an 
                                                
16 The requirements for followup reports can be found in  310.305(c)(2), 314.80(c) and 600.80(c). 
15
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615  initial report with a unique manufacturer report number. The followup report should be 
616  identified with the same unique manufacturer report number as the initial report. 
617 
618  A 15-day followup report must be submitted within 15 calendar days of receipt of new 
619  information on a 15-day report. Followup information to adverse experiences submitted 
620  initially in a periodic report can be submitted in the next periodic report. 
621 
622  1.  Content of Followup Reports 
623 
624  A followup report should provide a complete picture of the current understanding of 
625  the adverse experience. Relevant information from the initial report should be 
626  combined with the followup information to present an accurate and comprehensive 
627  description of the adverse experience as it is understood at the time of the followup. 
628  Information from the initial report later found to be inaccurate should not be repeated 
629  in the followup report. All new information including correction of previously 
630  submitted inaccurate information that is included in a followup report should be 
631  highlighted (e.g., with an asterisk, underlined). 
632 
633  The narrative section of the followup report should be concise (i.e., item B5 of FDA 
634  Form 3500A) because the FDAs adverse event reporting database (AERS) is 
635  limited for this section of the form. 
636 
637  For serious adverse experiences, applicants should exercise due diligence in 
638  obtaining followup information for the purposes of completing all the applicable 
639  elements for an individual case safety report (e.g., FDA Form 3500A). For adverse 
640  experiences that are determined to be nonserious and for which the four basic 
641  elements are known (see section IV.B), additional followup is not necessary. 
642 
643  Any attachments submitted with an initial report (e.g. scientific journal articles, 
644  hospital discharge summaries) should not be resubmitted with a followup report. 
645 
646  2.  Reporting Considerations 
647 
648  A copy of the initial report or a previous followup report should not be sent with the 
649  latest followup report. Fifteen-day followup reports should not be submitted in the 
650  same envelope with periodic reports. 
651 
652  If the initial report was submitted as a 15-day report, the followup report should be 
653  submitted as a 15-day followup report even if the followup information shows that the 
654  adverse experience was expected or not serious. All subsequent followup reports 
655  for adverse experiences that are expected or not serious should be submitted in 
656  periodic reports. A 15-day followup report should be submitted if the adverse 
657  experience is found to be serious and unexpected, even if the original report was 
658  not submitted as a 15-day report. 
659 
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660  If a new adverse experience occurs that is associated with the initial adverse 
661  experience, a followup report should be submitted. However, if the new adverse 
662  experience is not associated with the initial adverse experience (e.g., occurs after a 
663  subsequent administration of the product), an initial report with a new manufacturer 
664  report number should be submitted for the new adverse experience. In these cases, 
665  the applicant should consider the clinical relevance of the adverse experiences to 
666  each other when determining whether an initial report or followup report should be 
667  submitted. 
668 
669  Followup reports should not be submitted if additional relevant information is not 
670  obtained for the adverse experience. However, as described in the regulations, 
671  applicants should maintain records of their efforts to obtain additional information, 
672  particularly for serious adverse experiences. FDA may request this documentation. 
673 
674  3.  Reporting Forms 
675 
676  For followup reports, particular attention should be paid to completing the following 
677  items on FDA Form 3500A: 
678 
679     Item G3 - Mark health professional if at any time a health professional 
680  provided information for the report. 
681     Item G4 - Use the date the followup information was received by the 
682  applicant. 
683     Item G7- Mark followup, and indicate whether this is the 1st, 2nd, 3rd, 
684  ... followup report. 
685     Item G9 - Use the same unique manufacturer report number assigned 
686  to the initial report. This is essential to prevent duplicate counting of 
687  reports and to ensure that the followup information is coupled with the 
688  correct initial report. 
689 
690  For followup reports, particular attention should be paid to completing the following 
691  items on the VAERS form for vaccines: 
692 
693     Top right - Indicate the name of the person who provided information 
694  for the report. 
695     Box 24 - Use the same manufacturer report number assigned to the 
696  initial report. This is essential to prevent duplicate counting of reports 
697  and to ensure that the followup information is coupled with the correct 
698  initial report. 
699     Box 25 - Use the date the followup information was received by the 
700  applicant. 
701     Box 27 - Mark followup, and indicate whether this is the 1st, 2nd, 3rd, 
702  ... followup report. 
703 
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704  4.  Report Identification 
705 
706  Fifteen-day followup reports must be submitted in duplicate under separate cover 
707  prominently identified as "15-Day Alert Report-Followup."  For this purpose, the 15
708  Day Alert Report-Followup identification should be included on the outside 
709  envelope. 
710 
711  D.  Distribution Reports for Biological Products Including Vaccines 
712 
713  This section is based primarily on regulations in  600.81. These regulations only apply to 
714  human biological products with approved BLAs. Unless otherwise notified by the Director, 
715  Center for Biologics Evaluation and Research, an applicant must submit at periodic 
716  intervals two copies of a report containing information about the quantity of the product 
717  distributed domestically (including distributors) under the BLA. 
718 
719  Distribution reports are due within the first 6 months after approval of a BLA, and, 
720  subsequently, at 6-month intervals. Upon written notice, the FDA can require that the 
721  applicant submit reports under this section at alternate times. 
722 
723  The report must include the bulk lot, fill lot, and label lot numbers for the total number of 
724  dosage units of each strength or potency distributed (e.g., 50,000 per 10-milliliter vials), 
725  labeled date of expiration, and date of distribution of fill lot or label lot. The report must also 
726  include information about any significant amount of a fill lot or label lot that may have been 
727  returned. Disclosure of financial or pricing data is not required. According to the 
728  regulations, the FDA can require submission of more detailed product distribution 
729  information, if needed. 
730 
731  See section VIII.E in this guidance for a suggested reporting format for distribution reports. 
732 
733 
734  VI.  SPECIAL REPORTING SITUATIONS 
735 
736  A.  Scientific Literature Reports17 
737 
738  Serious, unexpected adverse experiences reported in the scientific literature (or in an 
739  unpublished scientific paper) that are known to the applicant must be submitted as 15-day 
740  reports on an FDA Form 3500A or comparable format. Applicants can use literature 
741  search services (e.g., Weekly Reactions) to identify adverse experiences in the scientific 
742  literature. A copy of the article or manuscript must be attached to the completed FDA 
743  Form 3500A; it is not sufficient to submit only abstracts of articles. All reports from the 
744  scientific literature and unpublished scientific papers should be marked Literature in item 
745  G3 of FDA Form 3500A. 
                                                
17 The requirements for scientific literature reports can be found in  314.80(c)(1)(i), 314.80(d), 
600.80(c)(1)(i), and 600.80(d). 
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746 
747  A separate FDA Form 3500A should be completed for each identifiable patient that 
748  experiences a serious, unexpected adverse experience. Thus, if an article describes six 
749  patients that experience a given serious, unexpected adverse experience, six FDA Form 
750  3500As should be completed. In such cases, a copy of the article should be attached only 
751  to one of the FDA Form 3500As. All other FDA Form 3500As submitted for the article 
752  should reference the manufacturer report number of the FDA Form 3500A that has the 
753  copy of the article attached. 
754 
755  If multiple products are mentioned in the article, an FDA Form 3500A should be submitted 
756  only by the applicant whose product is the suspect drug. The suspect product is that 
757  identified by the article=s author and is usually mentioned in the article=s title. If the 
758  applicant believes that the suspect product is different from the one identified by the author 
759  of the article, the applicant should indicate such information in the narrative section of the 
760  FDA Form 3500A. 
761 
762  Reports of serious, unexpected adverse experiences described in the scientific literature 
763  should be submitted for products that have the same active moiety as a product marketed 
764  in the United States. This is true even if the excipient, dosage forms, strengths, routes of 
765  administration, and indications vary. 
766 
767  When a serious, unexpected adverse experience is based on a foreign language article or 
768  manuscript, the applicant should translate the publication into English promptly. The original 
769  article or unpublished scientific paper and translation should be attached to the submitted 
770  FDA Form 3500A. 
771 
772  B.  Postmarketing, Clinical Trial, or Surveillance Studies18 
773 
774  For the purposes of this section, a study refers to the systematic collection of data involving 
775  solicitation of adverse experience information (e.g., derived from a clinical trial, patient 
776  registry). Adverse experiences incidental to other types of studies not involving monitoring 
777  adverse experiences of products should be treated as spontaneous reports (see Appendix 
778  A in this guidance for definition of spontaneous report). For purposes of safety reporting, 
779  reports of suspected adverse experiences obtained from company sponsored patient 
780  support programs and disease management programs should be handled as if they were 
781  study reports and not as spontaneous reports. 
782 
783  Serious, unexpected adverse experiences that occur during a study must be submitted as 
784  15-day reports. These adverse experiences are only required to be reported if there is a 
785  reasonable possibility that the drug or biological product caused the adverse experience. 
786 
                                                
18 The requirements for reporting adverse experiences from studies can be found in  310.305(c)(1), 
314.80(c)(2)(iii), 314.80(e)(1), 600.80(c)(2)(iii), and 600.80(e)(1). 
19
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787  Adverse experiences occurring with marketed drug or biological products during IND trials 
788  must also be submitted, as prescribed under  312.32, to the FDA new drug review 
789  division in the Center for Drug Evaluation and Research or the product review office in the 
790  Center for Biologics Evaluation and Research that has responsibility for oversight of the 
791  IND. 
792 
793  For each adverse experience, a suspect product should be identified. Reports from 
794  blinded studies should be submitted only after the code is broken. The blind should always 
795  be broken for each patient or subject that experiences a serious, unexpected adverse 
796  experience unless arrangements have been made otherwise with the responsible FDA 
797  review division. Exceptions to breaking the blind usually involve situations in which 
798  mortality or certain serious morbidities are indeed the clinical endpoint. This is consistent 
799  with the ICH E2A guidance. 
800 
801  C.  Foreign Reports19 
802 
803  Foreign reports of serious, unexpected adverse experiences must be submitted as 15-day 
804  reports. Other foreign reports, including serious and expected, nonserious and unexpected, 
805  and nonserious and expected adverse experiences are not required to be submitted. 
806 
807  Reports of foreign serious, unexpected adverse experiences should be submitted for 
808  products that have the same active moiety as a product marketed in the United States. 
809  This is true even if the excipient, dosage forms, strengths, routes of administration, and 
810  indications vary. When a foreign report is submitted on a product that is not identical to a 
811  product marketed in the United States, item C1 of FDA Form 3500A should contain the 
812  foreign trade name, the generic name, and the NDA number for the product with the same 
813  active moiety that is marketed in the United States. 
814 
815  D.  Death Reports 
816 
817  Death is always a serious outcome (see definition of serious in Appendix A of this 
818  guidance and at  310.305(b), 314.80(a) and 600.80(a)). Thus, if death is associated 
819  with an unexpected adverse experience, or if death is associated with an expected 
820  adverse experience but the labeling does not specifically state that the adverse experience 
821  may be associated with a fatal outcome, a 15-day report should be submitted. 
822 
823  E.  Overdose Reports 
824 
825  Reports of overdose should be submitted only when the overdose is associated with an 
826  adverse experience. If the adverse experience associated with the overdose is serious 
827  and unexpected, a l5-day report should be completed. If the adverse experience is serious 
828  and expected, nonserious and unexpected, or nonserious and expected, a non-15 day 
                                                
19 The requirements for reporting of foreign adverse experiences can be found in  310.305(c)(1)(i), 
314.80(c)(2)(iii) and 600.80(c)(2)(iii). 
20
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829  report should be submitted in the periodic report for spontaneously reported domestic 
830  cases. 
831 
832  F.  Lack of Effect Reports 
833 
834  The definition of adverse experience includes any failure of expected pharmacological 
835  action that is synonymous with lack of effect (see definition of adverse experience in 
836  Appendix A of this guidance and at  310.305(b), 314.80(a) and 600.80(a)). All 
837  spontaneously reported cases of a lack of effect that occur in the United States should be 
838  reported on FDA Form 3500A and submitted in the periodic report with other adverse 
839  experiences. The lot number of the suspect product should be included in item C6 of FDA 
840  Form 3500A. 
841 
842  If the report of lack of effect is for an unapproved indication, the event should not be 
843  reported to the FDA as an individual case safety report. Instead, this information should be 
844  included in the narrative summary section of the periodic report. 
845 
846  G.  Information on the Internet 
847 
848  Adverse experience information that is submitted to an applicant via the Internet (e.g., e
849  mail) should be reported to the FDA if the applicant has knowledge of the four basic 
850  elements for an individual case safety report (see section IV.B in this guidance). 
851  Applicants should review any Internet sites sponsored by them for adverse experience 
852  information, but are not responsible for reviewing any Internet sites that are not sponsored 
853  by them. However, if an applicant becomes aware of an adverse experience on an Internet 
854  site that it does not sponsor, the applicant should review the adverse experience and 
855  determine if it should be reported to the FDA. 
856 
857  H.  Pediatric Patients 
858 
859  For children under 3 years of age, the child=s date of birth and age in days or months (e.g., 
860  15 months) should be included under item A2 of FDA Form 3500A. The word days or 
861  months should be clearly written. For all pediatric patients, body weight (item A4 of FDA 
862  Form 3500A) and dose (item C2 of FDA Form 3500A) should be included. 
863 
864  For reports of a congenital anomaly, the age and sex of the infant should be included. 
865  Followup reports for the infant should be considered followup to the initial report; followup 
866  for the mother should be submitted as a new initial individual case safety report on a 
867  separate FDA Form 3500A. The date that the congenital anomaly is detected should be 
868  used as the event onset date (e.g., birth date of the infant, date pregnancy is terminated, 
869  date congenital anomaly is detected by ultrasound or other diagnostic technique). This 
870  date should be used in item B3 of FDA Form 3500A. 
871 
21
  872  I.  Prescription Drugs Marketed for Human Use Without an Approved 
873  Application20 
874 
875  For prescription drugs marketed for human use without an approved NDA or ANDA, all 
876  serious, unexpected adverse experiences must be reported to the FDA on an FDA Form 
877  3500A within 15 calendar days.  These reports must be submitted in SINGLE copy under 
878  separate cover. The report should be marked on the outside envelope "15-Day Alert 
879  Report - 310.305." A copy of the U.S. product labeling must accompany each report. 
880 
881  Postmarketing periodic reports should not be submitted for these drugs. 
882 
883  J.  Another Applicant==s Product 
884 
885  Reports of adverse experiences in which the initial reporter identifies the suspect product 
886  as one marketed by another applicant should be promptly forwarded to that applicant. An 
887  applicant who receives a report of an adverse experience regarding one of its products 
888  from another applicant must submit the report to the FDA within the same time constraints 
889  applicable to any report received from a third party (see section VI.K in this guidance). 
890 
891  An applicant should only submit a report of an adverse experience to the FDA for a 
892  suspect product marketed by another applicant if the applicant of the suspect product is 
893  unknown or the report is for a serious, unexpected adverse experience occurring during the 
894  conduct of a study. 
895 
896  K.  Multiple Suspect Products 
897 
898  If a reportable adverse experience involves two or more suspect products from the same 
899  applicant, only one FDA Form 3500A should be completed. The FDA Form 3500A should 
900  reference only one manufacturer report number. The report should be submitted to the 
901  NDA, ANDA, or BLA considered most suspect by the initial reporter. If each product is 
902  equally suspect, the report should be submitted to the product first in alphabetical order. 
903  The adverse experience should also be reported in the narrative summary section of the 
904  periodic report for the other product(s). 
905 
906  However, if one suspect product is a licensed non-vaccine biologic and the other is a 
907  licensed vaccine, separate reporting forms should be submitted. An FDA Form 3500A 
908  should be used for the licensed non-vaccine biologic and a VAERS form should be used 
909  for the licensed vaccine. 
910 
911  If a reportable adverse experience involves two or more suspect products and two or more 
912  applicants, an applicant may choose to submit an FDA Form 3500A to the FDA on the 
913  adverse experience that describes detailed information including the product(s) from the 
                                                
20 The requirements for prescription drugs marketed for human use without an approved application can be 
found in  310.305. 
22
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914  other applicant. In such a case, the other applicant should receive a copy of the FDA Form 
915  3500A including its manufacturer report number so that the other applicant can reference 
916  this report when providing any relevant followup information to the FDA. The other applicant 
917  should not submit to the FDA information originally submitted to the Agency by the first 
918  applicant. 
919 
920  L.  Suspect Drugs with Multiple NDAs or ANDAs by the Same Applicant 
921 
922  A drug substance can be the subject of more than one approved NDA or ANDA. If an 
923  applicant receives a report for a drug and the specific application is identifiable, the report 
924  should be submitted to that application. However, if a drug substance has more than one 
925  application and it cannot be determined which of the approved applications is involved, the 
926  report should be submitted to the application for the drug product that was approved first 
927  and that has the same general route of administration as the suspect drug substance. This 
928  would usually be the application with the lowest number. 
929 
930  M.  Two or More Marketers of a Product 
931 
932  If two or more companies that co-market a specific drug product have an approved NDA 
933  for the product, one of the companies should be identified as having primary responsibility 
934  for reporting adverse experiences for the drug product to the FDA to avoid duplicative 
935  reporting of adverse experiences. This would also be true for two or more companies that 
936  co-market a specific biological product and have an approved BLA for the product. 
937 
938  N.  Unapproved Indications 
939 
940  An adverse experience associated with the use of a product for an unapproved indication 
941  should be reported to the FDA as is required for any other spontaneously reported adverse 
942  experience occurring in the United States (e.g., 15-day report for a serious, unexpected 
943  adverse experience or periodic report for a nonserious, unexpected adverse experience). 
944  However, a lack of effect report for an unapproved indication should not be reported on an 
945  FDA Form 3500A. Instead, such information should be included in the narrative summary 
946  section of a periodic report. 
947 
948  O.  Product Interactions 
949 
950  If an applicant receives a report identified as a product interaction, each of the products 
951  should be identified as a suspect product in item C1 of FDA Form 3500A. 
952 
953  P.  Reports from the FDA21 
954 
                                                
21  The requirements for submitting reports received from the FDA can be found in  310.305(c)(5), 
314.80(b), and 600.80(b). 
23
  Draft  Not for Implementation 
955  Sometimes FDA forwards individual case safety reports (i.e., FDA Form 3500As) to 
956  applicants. For example, applicants can participate in the FDAs MedWatch-to
957  Manufacturer Program. This program is designed to expedite transmission from the FDA 
958  to applicants participating in the program cases of serious adverse experiences reported 
959  directly to the FDA voluntarily by initial reporters (e.g., health care professionals, 
960  consumers). Details of the program can be found on the Internet at 
961  www.fda.gov/medwatch/report/mmp.htm. 
962 
963  Applicants that receive individual case safety reports from FDA are not required to 
964  resubmit them to the Agency. However, followup information to these initial reports must 
965  be submitted to the FDA (see section V.C in this guidance). 
966 
967  Q.  Product Defects 
968 
969  If a product defect results in an adverse experience, the adverse experience should be 
970  reported as any other spontaneously reported adverse experience occurring in the United 
971  States (e.g., 15-day report for a serious, unexpected adverse experience or periodic report 
972  for a nonserious, unexpected adverse experience). 
973 
974  R.  Reporting Ambiguities 
975 
976  In some cases, it may be difficult to interpret specific criteria used for reporting. Examples 
977  include determining whether an adverse experience is expected or unexpected or whether 
978  a patient is identifiable or not. For these and any other ambiguities, the applicant should 
979  use a conservative approach and err on the side of reporting the adverse experience to the 
980  FDA. Thus, if there is doubt, consider an adverse experience to be unexpected, consider 
981  a patient to be identifiable, and so on. 
982 
983 
984  VII.  CODING OF ADVERSE EXPERIENCES IN INDIVIDUAL CASE SAFETY 
985  REPORTS 
986 
987  Companies currently use a variety of medical terminologies to code adverse experiences 
988  in individual case safety reports (e.g., COSTART, WHOART, MedDRA). At this time, the 
989  FDA will accept adverse experiences coded with any of these terminologies. However, as 
990  recommended by ICH, the Agency encourages companies to use MedDRA for this 
991  purpose and as indicated in the FDAs advanced notice of proposed rulemaking on this 
992  topic (63 FR 59746; November 5, 1998), the Agency plans to propose to require use of 
993  MedDRA as the terminology for coding adverse experiences in individual case safety 
994  reports submitted to the FDA. 
995 
996  Companies can license MedDRA from an international maintenance and support services 
997  organization (MSSO) (toll free number 877-258-8280 (703-345-7799 in Washington D.C. 
998  area), fax 703-345-7755, e-mail subscrib@meddramsso.com, Internet at 
999  www.meddramsso.com). 
24
  Draft  Not for Implementation 
1000 
1001 
1002  VIII.   REPORTING FORMATS22 
1003 
1004  Individual case safety reports of adverse experiences that occur domestically for marketed 
1005  human drugs and biological products, except vaccines, must be submitted to the FDA on 
1006  FDA Form 3500A; a VAERS form must be used for vaccines. Foreign adverse 
1007  experiences can be submitted either on FDA Form 3500A or, if preferred, on a CIOMS I 
1008  form. Foreign adverse experiences associated with the use of vaccines can be submitted 
1009  on either a VAERS form or, if preferred, a CIOMS I form. A separate FDA Form 3500A, 
1010  VAERS form, or CIOMS I form must be completed for each individual person experiencing 
1011  an adverse experience. 
1012 
1013  The following paragraphs describe how to acquire or generate the various reporting forms 
1014  for individual case safety reports and how to obtain information on FDAs pilot program for 
1015  electronic submission of these reports. This section also describes a suggested reporting 
1016  format for distribution reports for human biological products with approved BLAs. 
1017 
1018  The following abbreviations should be used when specific information is not available for 
1019  an individual case safety report or distribution report: 
1020 
1021     NA for not applicable 
1022     NI for no information at this time (but may be available later) 
1023     UNK for unknown 
1024 
1025  A.  FDA Form 3500A 
1026 
1027  See Appendix C of this guidance for a copy of the form.23 
1028 
1029  1.  Copies of the FDA Form 3500A can be obtained in the following ways: 
1030 
1031     From the Internet at www.fda.gov/medwatch/report/mfg.htm. Print the 
1032  form or download it as a PDF file. Form software can also be 
1033  downloaded and used to complete the forms using a personal 
1034  computer. Completed forms should be mailed to the FDA because 
1035  this software does not permit electronic submission of reports. The 
1036  software is also available on disk. For a copy of the disk, call 1-800
1037  FDA-1088 or send an electronic request via the MedWatch comment 
1038  page (www.fda.gov/medwatch/report/mfg.htm). Note: this software 
                                                
22 The requirements for reporting formats can be found in  310.305(d), 314.80(f) and 600.80(f).
23  Instructions for completing FDA Form 3500A are available on the Internet at 
www.fda.gov/medwatch/report/instruc.htm. 
25
  Draft  Not for Implementation 
1039  contains both FDA Form 3500 for voluntary reporting and FDA Form 
1040  3500A for mandatory reporting. 
1041 
1042     By Fax - Call 1-800-FDA-1088 and make the following selections: 
1043 
1044  Press 1 (health professional) 
1045  Press 2 (obtain a copy of a form) 
1046  Press 4 (obtain fax of FDA Form 3500A). 
1047 
1048     By Mail - Up to 10 copies of FDA Form 3500A can be obtained from: 
1049 
1050  Office of Post-marketing Drug Risk Assessment 
1051  Center for Drug Evaluation and Research (HFD-400) 
1052  Food and Drug Administration 
1053  5600 Fishers Lane, Room 15B-31 
1054  Rockville, MD 20857 
1055 
1056                                    OR 
1057 
1058  Office of Biostatistics and Epidemiology 
1059  Center for Biologics Evaluation and Research (HFM-210) 
1060  Adverse Experience Reporting 
1061  1401 Rockville Pike 
1062  Rockville, MD 20852-1448 
1063 
1064  Additional copies can be obtained from: 
1065 
1066  Consolidated Forms and Publications Distribution Center 
1067  Washington Commerce Center 
1068  3222 Hubbard Rd. 
1069  Landover, MD 20785 
1070 
1071  2.  Copies can be created by: 
1072 
1073     Photocopying a blank FDA Form 3500A 
1074 
1075     Producing a computer-generated facsimile of FDA Form 3500A 
1076 
1077  In place of using the preprinted forms, a computer-generated facsimile of 
1078  FDA Form 3500A can be used after approval, in writing, by FDA ( 
1079  310.305(d)(3), 314.80(f)(3) and 600.80(f)(3)). This computer-generated 
1080  facsimile of FDA Form 3500A should: 
1081 
1082  a.  Contain all the elements (i.e., 2-column format, sections, blocks, titles, 
1083  descriptors within blocks, text for disclaimer) of FDA Form 3500A in 
26
  Draft  Not for Implementation 
1084  the identical enumerated sequence of the form, except as otherwise 
1085  noted. For reports in which no suspect medical device is involved, the 
1086  box Section D. Suspect Medical Device on the front page of FDA 
1087  Form 3500A can be replaced with the box Section G. All 
1088  Manufacturers located on the back page of the form. This would allow 
1089  reporters of adverse experiences for drug and biological products to 
1090  use a one-page form for reporting. See Appendix F of this guidance 
1091  for a sample of a one-page FDA Form 3500A). 
1092 
1093  b.  Have, at least, a 1/4" margin around the entire form so that 
1094  information is not lost during scanning, copying or faxing of the 
1095  document (the left-hand margin may be increased up to 2" to permit 
1096  binding (e.g., hole-punching) of the form) (all other margins have to 
1097  continue to be at least 1/4"). 
1098 
1099  c.  Include the name of the company centered on the top of the front 
1100  page. 
1101 
1102  d.  Include in the lower left corner of the front page the phrase 3500A 
1103  Facsimile instead of the phrase FDA Form 3500A (date of form [e.g., 
1104  6/93]). 
1105 
1106  e.  Include in the upper right corner of the front page above the FDA Use 
1107  Only box the phrase FDA Facsimile Approval: [include date of 
1108  approval by FDA], instead of the phrase See OMB statement on 
1109  reverse. 
1110 
1111  f.  Have the data and text contained within the boxes on a computer
1112  generated FDA Form 3500A conform to the following specifications: 
1113 
1114     The font size should not be less than 10 point. 
1115 
1116     A font type should be selected that is easy to read (e.g., CG 
1117  Times, Arial) and not condensed. The form may be copied or 
1118  faxed multiple times. For visual contrast, the font type used for 
1119  the data and text should, if possible, be different from the font 
1120  type used to create the FDA Form 3500A. 
1121 
1122     Have all data and text contained within each of the boxes (e.g., 
1123  a box marked with an Ax@ should be centered within the box, 
1124  and narratives should include margins so that letters are not 
1125  obscured or made ambiguous by lines defining a box.). 
1126 
27
  Draft  Not for Implementation 
1127     Have the phrase continued included at the end of each field 
1128  that has additional information continued onto another page. 
1129 
1130  g.  Have continuation pages containing additional information for 
1131  narrative entries conform to the following specifications: 
1132 
1133     Each page should be identified as Page _ of _. 
1134 
1135     Each page should include the manufacturer report number in 
1136  the upper right corner. 
1137 
1138     Each page should include the name of the company in the 
1139  upper right corner. 
1140 
1141     The section and block number (e.g., Block B5) for each 
1142  narrative entry should be included. 
1143 
1144  For approval of computer-generated facsimiles of FDA Form 3500As, companies 
1145  should mail their requests along with two copies of the computer-generated 
1146  facsimile, a blank one and one with all the boxes completed with sample data/text, 
1147  to: 
1148 
1149  Information Technology Staff 
1150  OPDRA/CDER/FDA Room 15B23 
1151  HFD-420 
1152  5600 Fishers Lane 
1153  Rockville, MD 20857 
1154 
1155  Companies can contact the Information Technology Staff at 301-827-3223 to check 
1156  on the status of an approval request. Companies that are using a computer
1157  generated facsimile of FDA Form 3500A from a vendor that has already obtained 
1158  approval, in writing, from the FDA for the form do not have to submit another 
1159  approval request to the Agency (the vendor=s name and approval date should 
1160  appear in the upper right corner of the form). 
1161 
1162  B.   VAERS Form for Vaccines 
1163 
1164  See Appendix D of this guidance for a copy of the form.24 
                                                
24  A guidance for industry entitled How to Complete the Vaccine Adverse Event Reporting System Form 
(VAERS-1) (October 1999) is available on the Internet at www.fda.gov/cber/guidelines.htm or from the Office 
of Communication, Training and Manufacturers Assistance (HFM-40), CBER, 1401 Rockville Pike, Rockville, 
MD 20852-1448, (Fax) 1-888-CBERFAX or 301-827-3844, (Voice Information) 1-800-835-4709 or 301-827
1800. 
28
  Draft  Not for Implementation 
1165 
1166  1.  Copies of the VAERS form can be obtained by calling 1-800-822-7967. 
1167 
1168  2.  In place of using the preprinted forms, a computer-generated facsimile of the 
1169  VAERS form can be used after approval, in writing, by FDA ( 600.80(f)(3)). 
1170  To request approval of a computer-generated facsimile of a VAERS form, a 
1171  printed copy with data to illustrate how each data field will be reported should 
1172  be submitted to: 
1173 
1174  Office of Biostatistics and Epidemiology (HFM-210) 
1175  Center for Biologics Evaluation and Research, FDA 
1176  1401 Rockville Pike 
1177  Rockville, MD 20852-1448 
1178 
1179  C.  CIOMS I Form for Foreign Adverse Experiences 
1180 
1181  CIOMS, working with several member nations and industry, has developed a format for 
1182  international adverse experience reporting (CIOMS I form) (see Appendix E of this 
1183  guidance). Applicants can use an FDA Form 3500A or, if preferred, a CIOMS I form for 
1184  submission of 15-day reports of foreign adverse experiences to the FDA. Applicants 
1185  cannot use a CIOMS I form for submissions of adverse experiences that occur within the 
1186  United States. For these adverse experiences, an FDA Form 3500A must be used. 
1187 
1188  D.  Distribution Reports for Biological Products Including Vaccines 
1189 
1190  This section on distribution reports only applies to human biological products with 
1191  approved BLAs. Under  600.81, distribution reports must include the bulk lot, fill lot, and 
1192  label lot numbers for the total number of dosage units of each strength or potency 
1193  distributed (e.g., 50,000 per 10-milliliter vials), labeled date of expiration, and date of 
1194  distribution of fill lot or label lot. The report must also include information about any 
1195  significant amount of a fill lot or label lot that may have been returned. 
1196 
1197  The regulations do not specify a reporting form or format for distribution reports. One 
1198  suggested report format is shown here: 
1199 
1200
1201                                                        Product name, strength                                 
1202  Biologics License No.                          Product Code                   
1203 
Bulk Lot  Fill Lot  Label Lot  Expiration  Distribution  No. of Doses  No. of Doses 
No.  No.  No.  Date  Date  Distributed  Returned 
1204 
29  Draft  Not for Implementation 
1205 
1206  If there is more than one distribution date for a lot, the report should include each 
1207  distribution date and the number of doses distributed. When reporting returned doses, the 
1208  number of doses distributed should not be repeated. 
1209 
1210  For vaccines, if available, distribution of doses can be reported by public, private, or 
1211  military sectors. 
1212 
1213  E.  Electronic Submissions 
1214 
1215  The FDA is in the process of developing a system for electronic submission of 
1216  postmarketing safety reports. At this time, applicants can submit, under a pilot program, 
1217  certain individual case safety reports electronically. Details of this pilot program are 
1218  available on the Internet at www.fda.gov/cder/aerssub. The Agency also plans to have a 
1219  system for electronic submission of distribution reports for biological products including 
1220  vaccines in the near future.   
1221                                                                  
1222 
1223  IX.  HOW AND WHERE TO SUBMIT POSTMARKETING SAFETY REPORTS 
1224 
1225  All submissions should be legible and typewritten with a minimum acceptable font size of 
1226  10 point. Legible photostatic copies can be submitted. However, visual contrast should be 
1227  adequate to ensure clear readable archival images. The applicant must submit one or two 
1228  copies of each safety report as specified in this section unless a waiver is granted 
1229  permitting a different number of copies (see section XI in this guidance). 
1230 
1231  A.  Human Drug Products 
1232 
1233  1.  For prescription drugs marketed for human use without an approved NDA 
1234  or ANDA, postmarketing 15-day reports (initial and followup) should be sent 
1235  as single  copies to: 
1236 
1237  Office of Post-marketing Drug Risk Assessment (HFD-400) 
1238  Center for Drug Evaluation and Research 
1239  Food and Drug Administration 
1240  5600 Fishers Lane 
1241  Rockville, MD 20857 
1242 
1243  2.  For drugs with approved ANDAs, postmarketing 15-day reports, (initial and 
1244  followup), and periodic reports should be sent as single copies to: 
1245 
1246  Office of Post-marketing Drug Risk Assessment (HFD-400) 
1247    Center for Drug Evaluation and Research 
1248    Food and Drug Administration 
1249    5600 Fishers Lane 
30
  Draft  Not for Implementation 
1250    Rockville, MD 20857 
1251 
1252  3.  For drugs with approved NDAs, postmarketing 15-day reports (initial and 
1253  followup), and periodic reports should be sent in duplicate to: 
1254 
1255  Food and Drug Administration 
1256  Central Document Room 
1257  12229 Wilkins Ave. 
1258  Rockville, MD 20852 
1259 
1260  B.  Human Biological Products and Vaccines 
1261 
1262  1.  For vaccines, postmarketing 15-day reports (initial and followup), and 
1263  periodic reports should be sent in duplicate to: 
1264 
1265  VAERS 
1266  P.O. Box 1100 
1267  Rockville, MD 20849-1100 
1268 
1269  2.  For biological products other than vaccines, postmarketing 15-day reports 
1270  (initial and followup) and periodic reports should be sent in duplicate to: 
1271 
1272  Office of Biostatistics and Epidemiology (HFM-210) 
1273  Center for Biologics Evaluation and Research, FDA 
1274  Adverse Experience Reporting 
1275  1401 Rockville Pike 
1276  Rockville, MD 20852-1448 
1277 
1278  3.  For all biological products and vaccines, distribution reports ( 600.81) 
1279  should be sent in duplicate to: 
1280 
1281  Office of Biostatistics and Epidemiology (HFM-210) 
1282  Center for Biologics Evaluation and Research, FDA 
1283  Distribution Reports 
1284  1401 Rockville Pike 
1285  Rockville, MD 20852-1448 
1286 
1287 
1288  X.  WRITTEN PROCEDURES FOR POSTMARKETING SAFETY REPORTING 
1289 
1290  Each applicant must develop written standard operating procedures for the surveillance, 
1291  receipt, evaluation, and reporting of adverse experiences to the FDA ( 310.305(a), 
1292  314.80(b) and 600.80(b)). The FDA will consider an applicant responsible for information 
1293  known to its employees, affiliates, and contractors. For this purpose, applicants should 
31
  Draft  Not for Implementation 
1294  develop procedures that allow for expedited handling of adverse experience reports. 
1295  Records of due diligence should be maintained. This applies to surveillance and 
1296  processing for both domestic and foreign reports of adverse experiences. 
1297 
1298 
1299  XI.   REQUESTS FOR WAIVERS TO POSTMARKETING SAFETY REPORTING 
1300  REQUIREMENTS 
1301 
1302  Under  314.90(a) and 600.90(a), applicants may ask the FDA to waive any 
1303  postmarketing safety reporting requirement that applies to the applicant under  314.80 
1304  and 600.80. The following paragraphs discuss certain postmarketing periodic safety 
1305  reporting requirements for which the FDA is currently granting waivers. 
1306 
1307  A.  Submission of FDA Form 3500A for Nonserious, Expected Adverse 
1308  Experiences 
1309 
1310  Applicants are encouraged to request a waiver for submission of FDA Form 3500As for 
1311  individual case safety reports of nonserious, expected adverse experiences that, at a 
1312  minimum, contain the four basic elements (see section IV.B in this guidance). In such 
1313  cases, applicants should maintain records of these nonserious, expected adverse 
1314  experiences in their corporate drug or biological product safety files. The FDA may 
1315  request that an applicant submit to the Agency FDA Form 3500As of one or more of these 
1316  adverse experiences. The agency would expect these forms to be submitted within 5 
1317  calendar days after receipt of the request. 
1318 
1319  Applicants who obtain a waiver for the requirement to submit individual case safety reports 
1320  of nonserious, expected adverse experiences would still be expected to submit information 
1321  on these adverse experiences to the FDA in the summary tabulations section of 
1322  postmarketing periodic reports (see section V.B.2.a in this guidance). 
1323 
1324  At this time, the FDA does not intend to grant waiver requests for new biological molecular 
1325  entities within one year of licensure or for blood products, plasma derivatives, or vaccines. 
1326  The Agency believes that it is important to continue periodic review of all individual case 
1327  safety reports of adverse experiences for these products to identify safety problems due to 
1328  lot-to-lot variations and also to monitor the safety of newly approved biological products. 
1329 
1330  B.  Submission of PSUR format for the Periodic Report 
1331 
1332  Applicants can request a waiver of the requirement to submit postmarketing periodic 
1333  safety reports in the format described in the regulations. Instead, applicants can prepare 
1334  these reports using the PSUR (Periodic Safety Update Report) format described in the 
1335  ICH E2C guidance. In addition, the Agency recommends the following: 
1336 
1337     If all dosage forms and formulations for the active substance, as well as 
1338  indications, are combined in one PSUR, this information should be 
32
  Draft  Not for Implementation 
1339  separated into specific sections of the report when such separation is 
1340  appropriate to accurately portray the safety profile of the specific dosage 
1341  forms. For example, one should not combine information from ophthalmic 
1342  drop dosage forms and solid oral dosage forms. One copy of the PSUR 
1343  should be submitted for each approved NDA or ANDA whose product is 
1344  covered in the PSUR as well as an additional copy for review by the 
1345  postmarketing pharmacovigilance office. 
1346 
1347     Copies of the FDA Form 3500A or VAERS form that are required by the 
1348  regulations must be included. 25  These forms should be included with the 
1349  PSUR as an appendix. You can request a waiver for submission of certain 
1350  nonserious, expected adverse experiences on an FDA Form 3500A as 
1351  described in the previous section. 
1352 
1353     A summary tabulation should be included as an appendix listing all 
1354  spontaneously reported U.S. individual case safety reports from consumers if 
1355  such cases are not already included in the PSUR. Summary tabulations 
1356  should be presented by body system of all adverse experience terms and 
1357  counts of occurrences and be segregated by type (i.e., serious/unexpected; 
1358  serious/expected; nonserious/unexpected; and nonserious/expected), 
1359 
1360     A narrative should be included as an appendix that references the changes, 
1361  if any, to the approved U.S. labeling for the dosage forms covered by the 
1362  PSUR based on new information in the PSUR. A copy of the most recently 
1363  approved U.S. labeling for the product(s) covered by the PSUR should be 
1364  included. 
1365 
1366  C.  Submission Date and Frequency for PSUR Reports 
1367 
1368  Applicants can request a waiver to submit PSURs to the FDA based on the month and day 
1369  of the international birth date of the product instead of the month and day of the anniversary 
1370  date of U.S. approval of the product.26  The waiver request should specify that these 
1371  PSURs would be submitted to the FDA within 60 calendar days of the data lock point (i.e., 
1372  month and day of the international birth date of the product or any other day agreed on by 
1373  the applicant and the FDA).27 
1374 
1375  Applicants can also request a waiver to submit PSURs to the FDA at a frequency other 
1376  than those required under   314.80(c)(2)(i) and 600.80(c)(2)(i). 
1377 
                                                
25 See  314.80(c)(2)(ii)(b) and 600.80(c)(2)(ii)(B). 

26 The international birth date for a product is the date the first regulatory authority in the world approved the 

first marketing application for a human drug product containing the drug substance or a human biological 

product.
 
27 The data lock point is the date designated as the cut-off date for data to be included in a PSUR. 
33
  Draft  Not for Implementation 
1378  D.  How and Where to Submit Waiver Requests 
1379 
1380  1.  Marketed human drug products 
1381 
1382  For waivers under  314.90(a), applicants should submit a written waiver request 
1383  (include the products name(s), date(s) of U.S. approval, and the application 
1384  number(s)) to: 
1385 
1386  Director 
1387  Office of Post-Marketing Drug Risk Assessment 
1388  Center for Drug Evaluation and Research 
1389  Food and Drug Administration 
1390  5600 Fishers Lane, HFD-400 
1391  Rockville, MD 20857 
1392 
1393  2.  Licensed biological products 
1394 
1395  For waivers under  600.90(a), applicants should submit a written waiver request 
1396  (include the product name(s), date(s) of U.S. approval, and the application 
1397  number(s)) to: 
1398 
1399  Director 
1400  Office of Biostatistics & Epidemiology 
1401  Center for Biologics Evaluation and Research 
1402  Food and Drug Administration 
1403  140l Rockville Pike, HFM-220 
1404  Rockville, MD 20852-1448 
1405 
1406 
1407  XII.  VALIDATION OF ADVERSE EXPERIENCE COMPUTER SYSTEMS 
1408 
1409  If an electronic record of an adverse experience is created, modified, maintained, 
1410  archived, retrieved, or transmitted, the applicant is required, among other things, to employ 
1411  procedures to ensure that records are trustworthy, reliable, and consistent with FDA's 
1412  ability to promote and protect public health (21 CFR part 11). Those procedures must 
1413  include validation of systems to ensure accuracy, reliability, consistent intended 
1414  performance, and the ability to discern invalid or altered records. 
34
  Draft  Not for Implementation 
1415  APPENDIX A: GLOSSARY 
1416 
1417  Adverse Experience  - Any adverse event associated with the use of a drug or biological 
1418  product in humans, whether or not considered product-related, including the following: An 
1419  adverse event occurring in the course of the use of a drug product in professional practice; 
1420  an adverse event occurring from drug overdose whether accidental or intentional; an 
1421  adverse event occurring from drug abuse; an adverse event occurring from drug 
1422  withdrawal; and any failure of expected pharmacological action. Reporting an adverse 
1423  experience does not necessarily reflect a conclusion by the applicant or the FDA that the 
1424  product caused or contributed to the adverse experience. Adverse experience is 
1425  synonymous with adverse drug experience, adverse biological experience, adverse 
1426  product experience, and adverse event. 
1427 
1428  Affiliate  - Any individual or entity related by employment or organizational structure to the 
1429  applicant, including all subsidiaries, whether domestic or foreign. 
1430 
1431  Applicant  - An individual or entity who holds the new drug application (NDA), abbreviated 
1432  new drug application (ANDA), or the biologics license application (BLA). For purposes of 
1433  this guidance, this term includes any person whose name appears on the label of a 
1434  marketed drug or licensed biological product as its manufacturer, packer, distributor, 
1435  shared manufacturer, joint manufacturer, or any participant involved in divided 
1436  manufacturing. 
1437 
1438  Causality Assessment  - Determination of whether there is a reasonable possibility that 
1439  the product is etiologically related to the adverse experience. Causality assessment 
1440  includes, for example, assessment of temporal relationships, dechallenge/rechallenge 
1441  information, association with (or lack of association with) underlying disease, presence (or 
1442  absence) of a more likely cause, and physiologic plausibility. 
1443 
1444  Challenge  - Administration of a suspect product by any route. 
1445 
1446  Dechallenge  - Withdrawal of a suspect product from a patient's therapeutic 
1447  regimen. 
1448 
1449  Negative Dechallenge  - Continued presence of an adverse experience after 
1450  withdrawal of the suspect product. 
1451 
1452  Positive Dechallenge  - Partial or complete disappearance of an adverse 
1453  experience after withdrawal of the suspect product. 
1454 
1455  Rechallenge  - Reintroduction of a suspect product suspected of having caused an 
1456  adverse experience following a positive dechallenge. 
1457 
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1458  Negative Rechallenge  - Failure of the product, when reintroduced, to produce 
1459  signs or symptoms similar to those observed when the suspect product was 
1460  previously introduced. 
1461 
1462  Positive Rechallenge  - Reoccurrence of similar signs and symptoms upon 
1463  reintroduction of the suspect product. 
1464 
1465  Disability - A substantial disruption in one's ability to conduct normal life functions. 
1466 
1467  Expected Adverse Experience - Adverse experience listed in the current FDA-approved 
1468  labeling for the drug or licensed biological product. This would include any section of the 
1469  labeling that refers to adverse experience information. 
1470 
1471  Initial Reporter  - The original source of information concerning an adverse experience 
1472  (e.g., consumer, healthcare professional). 
1473 
1474  Life-threatening Adverse Experience - An adverse experience that, in the view of the 
1475  initial reporter, places the patient at immediate risk of death from the adverse experience 
1476  as it occurred. It does not include an adverse experience that, had it occurred in a more 
1477  severe form, might have caused death. 
1478 
1479  Serious Adverse Experience - An adverse experience occurring at any dose that results 
1480  in any of the following outcomes: 
1481 
1482     Death 
1483 
1484     Life-threatening adverse experience 
1485 
1486     Initial inpatient hospitalization 
1487 
1488     Prolongation of hospitalization 
1489 
1490     Significant or persistent disability/incapacity 
1491 
1492     Congenital anomaly/birth defect (including that occurring in a fetus); 
1493 
1494     Important medical events, based upon appropriate medical judgment, that may 
1495  jeopardize the patient or subject and may require medical or surgical intervention to 
1496  prevent one of the outcomes listed above. 
1497 
1498  Spontaneous Report - A communication from an individual (e.g. health care 
1499  professional, consumer) to a company or regulatory authority that describes a suspected 
1500  adverse experience. It does not include cases identified from information solicited by the 
1501  applicant such as individual cases or findings derived from a study. 
1502 
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1503  Study  - Any organized data collection system (e.g., adverse experience information 
1504  derived from a clinical trial, patient registry including pregnancy registries). Reports from 
1505  company sponsored patient support programs and disease management programs should 
1506  be handled as if they were study reports and not as spontaneous reports. 
1507 
1508  Suspect Product  - Drug or biological product associated with an adverse experience as 
1509  determined by the initial reporter, regardless of the opinion of the applicant. 
1510 
1511  Unexpected Adverse Experience - Adverse experience not included in any section of 
1512  the current FDA-approved labeling for the drug or licensed biological product.  This 
1513  includes an adverse experience that may differ from a labeled adverse experience 
1514  because of greater severity or specificity (e.g., abnormal liver function versus hepatic 
1515  necrosis). Adverse experiences listed as occurring with a class of drugs or biological 
1516  products but not specifically mentioned with a particular drug or biological product are 
1517  considered unexpected (e.g., rash with antibiotic X would be unexpected if the labeling 
1518  said "rash may be associated with antibiotics"). This is because the labeling does not 
1519  specifically state "rash is associated with antibiotic X." Reports of death from an adverse 
1520  experience are considered unexpected unless the possibility of a fatal outcome from that 
1521  adverse experience is stated in the labeling. 
1522 
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1523  APPENDIX B: REPORT CHECKLIST 
1524 
1525  Before mailing your postmarketing safety reports to the FDA, you should make sure that 
1526  the following questions have been addressed: 
1527 
1528  A.  For All FDA Form 3500A Reports 
1529 
1530  l.  Have you completed a separate FDA Form 3500A for each patient? 
1531 
1532  2.  Have you included the manufacturer report number in item G9 on FDA Form 
1533  3500A? (Note: For followup reports, this number should be identical to the 
1534  manufacturer report number on the initial report.) 
1535 
1536  3.  Have you clearly marked the report "Periodic" or "15-Day" as appropriate in 
1537  item G7 on FDA Form 3500A? 
1538 
1539  4.  Have you clearly marked the report "Initial" or "Followup" as appropriate in 
1540  item G7 on FDA Form 3500A? Do not package and send a 15-day followup 
1541  report with a non-15 day followup report. 
1542 
1543  5.   Have you included the name, address, and telephone number of the initial 
1544  reporter in item E1 on FDA Form 3500A? 
1545 
1546  6.  Have you left all the boxes in item B2 of the FDA Form 3500A blank for a 
1547  nonserious adverse experience? A box should only be checked in item B2 if 
1548  the outcome for the adverse experience is serious. 
1549 
1550  7.  Have you included all relevant attachments and eliminated unnecessary 
1551  attachments? 
1552 
1553  Attachments can include copies of: 
1554 
1555     hospital discharge summaries 
1556     autopsy/biopsy reports 
1557     death certificates 
1558     relevant office visit notes 
1559     summaries of relevant laboratory tests and other diagnostic 
1560  procedures, particularly pre- and post-drug values. 
1561 
1562  Each page of an attachment should identify the manufacturer report number (i.e., 
1563  reported in item G9 on FDA Form 3500A) for that case. 
1564 
1565  In general, attachments should not include: 
1566 
1567     lengthy legal records 
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1568     complete medical records 
1569 
1570 
1571  8.  If two or more products produced by your company were suspected by the 
1572  initial reporter: 
1573 
1574     Have you completed only one FDA Form 3500A? (You should not 
1575  prepare more than one FDA Form 3500A even if more than one of 
1576  the suspect products was produced by your company.) 
1577 
1578     Have you identified all the suspect products in item C1 on FDA Form 
1579  3500A? 
1580 
1581     Have you indicated on FDA Form 3500A the product considered 
1582  most suspect by the initial reporter and prepared the report 
1583  accordingly? (If the initial reporter ranked them equally, you should 
1584  submit an FDA Form 3500A to the file of the first suspect product in 
1585  alphabetical order. You should list the adverse experience(s) for each 
1586  of the other suspected product(s) in the narrative summary section of 
1587  the periodic report.) 
1588 
1589  9.  Have you completed an FDA Form 3500A for another applicant's drug? 
1590  (You should send the report to the FDA if the applicant of the suspect product 
1591  is unknown or the report is for a serious, unexpected adverse experience 
1592  occurring during the conduct of a study. For all other cases, you should send 
1593  the report to the applicant holder of the suspect drug and not to the FDA.) 
1594 
1595  B.  For 15-Day Reports 
1596 
1597  1.  Have you clearly marked "15-Day Report" in item G7 on the FDA Form 
1598  3500A? 
1599 
1600  2.  Have you packaged the 15-day report (FDA Form 3500A initial or followup) 
1601  separately? (Do not package and send an initial 15-day report with a 15-day 
1602  followup report. You should not submit copies of 15-day reports with a 
1603  periodic report.) 
1604 
1605  3.  Have you submitted the report in duplicate? (Exceptions: for prescription 
1606  drugs marketed for human use without an approved application and for drugs 
1607  with approved ANDAs, only a single copy should be sent.) 
1608 
1609  4.  Have you clearly marked the outside mailing envelope "15-Day Report? 
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1610 
1611  C.  For Periodic Reports 
1612 
1613  1.  Have you included the four types of information required for a periodic report 
1614  and clearly separated the four sections with marked tabs? 
1615 
1616  2.  Have you submitted the report in duplicate? (Exception: For drugs with 
1617  approved ANDAs, only a single copy should be sent). 
1618 
1619  3.  Have you eliminated all unnecessary attachments to FDA Form 3500As? 
1620 
1621  D.  For Followup Reports 
1622 
1623  l.  Have you included the manufacturer report number in item G9 on FDA Form 
1624  3500A? (Note: this number should be identical to the manufacturer report 
1625  number on the initial report). 
1626 
1627  2.  Have you marked Afollowup@ in item G7 on FDA Form 3500A and indicated 
1628  what number followup report it is? 
1629 
1630 
40