Investigating and Reporting Adverse 
Reactions Related to Human Cells, 
Tissues, and Cellular and Tissue-Based 
Products (HCT/Ps) Regulated Solely 
under Section 361 of the Public Health 
Service Act and 21 CFR Part 1271  
 
 
Guidance for Industry 
 
 
 
 
 
 
 
Additional copies of this guidance are available from the Office of Communication, Outreach, 
and Development (OCOD), 10903 New Hampshire Ave., Bldg. 71, Rm. 3128, Silver Spring, 
MD 20993-0002, or by calling 1-800-835-4709 or 240-402-8010, or email ocod@fda.hhs.gov, or 
from the Internet at 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guida
nces/default.htm. 
 
For questions on the content of this guidance, contact OCOD at the phone numbers or email 
address listed above. 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Biologics Evaluation and Research 
March 2016  Contains Nonbinding Recommendations 
 
Table of Contents 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
A.  What is the Scope of this Guidance? ................................................................... 2 
B.  Who Should Read this Guidance? ....................................................................... 3 
III.  REGULATORY REQUIREMENTS REGARDING INVESTIGATING AND 
REPORTING ADVERSE REACTIONS ....................................................................... 3 
A.  What is an Adverse Reaction under 21 CFR Part 1271? .................................. 3 
B.  Which HCT/Ps are Subject to Adverse Reaction Reporting Requirements 
under 21 CFR 1271.350(a)? ................................................................................. 4 
C.  Which Adverse Reactions Related to 361 HCT/Ps Must I Investigate and 
Report under 21 CFR 1271.350(a)? .................................................................... 4 
D.  Who Must Report Adverse Reactions Related to 361 HCT/Ps under 21 CFR 
1271.350(a)? ........................................................................................................... 5 
E.  When Must I Submit Reports of Adverse Reactions Related to 361 HCT/Ps 
to FDA? .................................................................................................................. 5 
F.  How Must I Submit Reports of Adverse Reactions Related to 361 HCT/Ps to 
FDA? ...................................................................................................................... 5 
IV.  ADVERSE REACTION INVESTIGATION ................................................................. 6 
A.  What Information About the Recipient Should I Review as Part of the 
Investigation of an Adverse Reaction? ................................................................ 6 
B.  What Information Should I Review About the Donor Whose HCT/Ps are 
Involved in an Adverse Reaction? ....................................................................... 6 
C.  What Recovery Information Should I Review in My Investigation of an 
Adverse Reaction? ................................................................................................ 7 
D.  What Processing Information Should I Review in My Investigation of an 
Adverse Reaction? ................................................................................................ 7 
E.  What Environmental Control and Monitoring Information Should I Review 
in My Investigation of an Adverse Reaction?..................................................... 8 
F.  What Storage and Distribution Information Should I Review in My 
Investigation of an Adverse Reaction? ................................................................ 9 
G.  What Tracking Information Should I Review in My Investigation of an 
Adverse Reaction? ................................................................................................ 9 
H.  What Labeling Information Should I Review in My Investigation of an 
Adverse Reaction? .............................................................................................. 10 
I.  What Complaint File Information Should I Review in My Investigation of an 
Adverse Reaction? .............................................................................................. 10 
J.  What Information Pertaining to Adverse Reactions Concerning 361 HCT/Ps 
Should I Share with Other Establishments? .................................................... 10 
V.  ADVERSE REACTION REPORTING ........................................................................ 11 
A.  What Information Should I Report on Form FDA 3500A? ............................ 11 
B.  How Do I Report Adverse Reactions Involving Multiple HCT/Ps? ............... 15 
i  Contains Nonbinding Recommendations 
 
C.  How Do I Report Adverse Reactions/Events for Other HCT/Ps that are not 
Regulated as 361 HCT/Ps, but are Regulated as Drugs, Medical Devices, or 
Biological Products? ........................................................................................... 15 
D.  Who Can I Contact if I Have Additional Questions Concerning the 
Reporting of an Adverse Reaction Related to a 361 HCT/P? ......................... 16 
E.  What Happens to MedWatch Form FDA 3500A Reports After I Submit 
Them to FDA? ..................................................................................................... 16 
VI.  IMPLEMENTATION .................................................................................................... 16 
VII.  REFERENCES ................................................................................................................ 17 
ii  Contains Nonbinding Recommendations 
 
Investigating and Reporting Adverse Reactions Related to Human 
Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) 
Regulated Solely under Section 361 of the Public Health Service Act 
and 21 CFR Part 1271  
 
 
Guidance for Industry 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or 
Agency) on this topic.  It does not establish any rights for any person and is not binding on FDA 
or the public.  You can use an alternative approach if it satisfies the requirements of the 
applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff 
responsible for this guidance as listed on the title page. 
 
 
I.  INTRODUCTION 
 
We, FDA, are issuing this guidance to provide establishments1 that manufacture human cells, 
tissues, and cellular and tissue-based products (HCT/Ps) with recommendations for complying 
with the requirements under Title 21 of the Code of Federal Regulations Part 1271 (21 CFR Part 
1271) for investigating and reporting adverse reactions involving communicable disease in 
recipients of HCT/Ps that are regulated solely under section 361 of the Public Health Service Act 
(PHS Act) and 21 CFR Part 1271 (hereafter referred to throughout this guidance as 361 
HCT/Ps.  In addition, this guidance provides updated information specific to reporting adverse 
reactions related to HCT/Ps to supplement the general instructions accompanying the MedWatch 
mandatory reporting form, Form FDA 3500A. 
 
This guidance provides recommendations for complying with the requirements under 21 CFR 
Part 1271, Subparts D and E, for investigating and reporting of complaints of adverse reactions 
involving communicable disease in recipients of 361 HCT/Ps.  This guidance does not apply to 
reproductive HCT/Ps or to tissues regulated under 21 CFR Part 1270 and recovered before May 
25, 2005.  Furthermore, this guidance does not apply to health professionals who implant,  
                                                           
1 Establishment means a place of business under one management, at one general physical location, that engages in 
the manufacture of human cells, tissues, and cellular and tissue-based products.  Establishment includes:  (1) Any 
individual, partnership, corporation, association, or other legal entity engaged in the manufacture of human cells, 
tissues, and cellular and tissue-based products; and (2) Facilities that engage in contract manufacturing services for a 
manufacturer of human cells, tissues, and cellular and tissue-based products (21 CFR 1271.3(b)). 
1  Contains Nonbinding Recommendations 
 
transplant, infuse, or transfer HCT/Ps into recipients.2  This guidance supplements section XXII 
of the FDA guidance document entitled Guidance for Industry:  Current Good Tissue Practice 
(CGTP) and Additional Requirements for Manufacturers of Human Cells, Tissues, and Cellular 
and Tissue-Based Products (HCT/Ps) dated December 2011, by providing additional 
recommendations specific to your responsibilities to investigate complaints of adverse reactions 
concerning 361 HCT/Ps under 21 CFR 1271.160(b)(2), 21 CFR 1271.320 and 21 CFR 
1271.350(a).  In addition, this guidance supersedes the FDA guidance entitled Guidance for 
Industry:  MedWatch Form FDA 3500A:  Mandatory Reporting of Adverse Reactions Related to 
Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) dated November 
2005.  This guidance also finalizes the draft guidance of the same title dated February 2015.   
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the FDAs current thinking on a topic and should be 
viewed only as recommendations, unless specific regulatory or statutory requirements are cited.  
The use of the word should in FDAs guidances means that something is suggested or 
recommended, but not required. 
 
 
II.  BACKGROUND 
 
A.  What is the Scope of this Guidance? 
 
HCT/Ps are defined in 21 CFR 1271.3(d) as articles containing or consisting of human 
cells or tissues that are intended for implantation, transplantation, infusion, or transfer 
into a human recipient.  FDA has implemented a risk-based approach to the regulation of 
HCT/Ps.  Under the authority of section 361 of the PHS Act, FDA established regulations 
under 21 CFR Part 1271 for all HCT/Ps to prevent the introduction, transmission, and 
spread of communicable diseases. 
 
In 21 CFR 1271.10, the regulations identify the criteria for regulation solely under 
section 361 of the PHS Act and 21 CFR Part 1271.  An HCT/P is regulated solely under 
section 361 of the PHS Act and 21 CFR Part 1271 if it meets all of the criteria under  
                                                           
2 However, FDA notes that health professionals have an important role in identifying adverse reactions in recipients 
of HCT/Ps and reporting adverse reactions to manufacturers of HCT/Ps.  Further, manufacturers may seek to obtain 
additional information from health professionals such as recipient culture reports or recipient clinical records when 
investigating the possible transmission of communicable disease related to HCT/Ps that the manufacturer made 
available for distribution. 
2  Contains Nonbinding Recommendations 
 
21 CFR 1271.10(a).3  As stated in section I. of this guidance, an HCT/P that falls into this 
category is referred to as a 361 HCT/P. 
 
B.  Who Should Read this Guidance? 
 
This guidance is intended for any 361 HCT/P establishment that performs a 
manufacturing step and is responsible for complying with CGTP requirements4 pertaining 
to the review, evaluation, investigation, and reporting of complaints of adverse reactions 
under 21 CFR 1271.320 and 21 CFR 1271.350(a), with respect to 361 HCT/Ps.  It is also 
intended for those 361 HCT/P establishments that share information pertaining to:   
(1) the possible contamination of a 361 HCT/P; or (2) the potential for transmission of a 
communicable disease by a 361 HCT/P with other establishments  
(21 CFR 1271.160(b)(2)). 
 
In this guidance, you means the establishment that made the HCT/P available for 
distribution.  The term available for distribution means that the HCT/P has been 
determined to meet all release criteria (21 CFR 1271.3(z)). 
 
 
III.  REGULATORY REQUIREMENTS REGARDING INVESTIGATING AND 
REPORTING ADVERSE REACTIONS  
 
A.  What is an Adverse Reaction under 21 CFR Part 1271?  
 
An adverse reaction for 361 HCT/Ps is defined as a noxious and unintended response 
to any HCT/P for which there is a reasonable possibility that the HCT/P caused the 
response (21 CFR 1271.3(y)). 
 
We recognize that whenever an HCT/P recipient experiences an unintended response, 
there may be multiple possible causes.  Nevertheless, if one of the reasonable possibilities 
is that the HCT/P caused the response, then this would meet the definition of adverse 
reaction. 
 
                                                           
3 Under 21 CFR 1271.10(a), an HCT/P is regulated solely under section 361 of the PHS Act and the regulations in 
[21 CFR Part 1271] if it meets all of the following criteria:  (1) The HCT/P is minimally manipulated; (2) The 
HCT/P is intended for homologous use only, as reflected by the labeling, advertising, or other indications of the 
manufacturer's objective intent; (3) The manufacture of the HCT/P does not involve the combination of the cells or 
tissues with another article, except for water, crystalloids, or a sterilizing, preserving, or storage agent, provided that 
the addition of water, crystalloids, or the sterilizing, preserving, or storage agent does not raise new clinical safety 
concerns with respect to the HCT/P; and (4) Either:  (i) The HCT/P does not have a systemic effect and is not 
dependent upon the metabolic activity of living cells for its primary function; or (ii) The HCT/P has a systemic 
effect or is dependent upon the metabolic activity of living cells for its primary function, and:  (a) Is for autologous 
use; (b) Is for allogeneic use in a first-degree or second-degree blood relative; or (c) Is for reproductive use. 
4 The CGTP requirements govern the methods used in, and the facilities and controls used for, the manufacture of 
HCT/Ps.  Establishments that manufacture HCT/Ps, including establishments that manufacture 361 HCT/Ps, must 
follow those CGTP requirements that pertain to the operations they perform to prevent the introduction, 
transmission, or spread of communicable diseases by HCT/Ps (21 CFR 1271.150). 
3  Contains Nonbinding Recommendations 
 
B.  Which HCT/Ps are Subject to Adverse Reaction Reporting Requirements 
under 21 CFR 1271.350(a)? 
 
All non-reproductive 361 HCT/Ps are subject to the adverse reaction reporting 
requirements under 21 CFR 1271.350(a).  At this time, FDA does not require adverse 
reaction reporting for reproductive 361 HCT/Ps (e.g., oocytes, semen, and embryos), or 
for tissues regulated under 21 CFR Part 1270 and recovered before May 25, 2005.  
 
Provided that they meet all of the criteria listed in 21 CFR 1271.10(a), the following are 
examples of HCT/Ps that are subject to adverse reaction reporting under 21 CFR 
1271.350(a) and fall within the scope of this guidance:  
 
  Amniotic membrane  
  Bone  
  Cartilage  
  Cornea 
  Fascia 
  Ligament  
  Pericardium 
  Hematopoietic stem/progenitor cells derived from peripheral blood5 
  Hematopoietic stem/progenitor cells derived from cord blood6 
  Sclera  
  Skin  
  Tendon  
  Vascular graft 
  Heart valve 
  Dura mater 
 
C.  Which Adverse Reactions Related to 361 HCT/Ps Must I Investigate and 
Report under 21 CFR 1271.350(a)? 
 
Under 21 CFR 1271.350(a)(1), you must investigate any adverse reaction involving a 
communicable disease related to an HCT/P that you made available for distribution.  
Your investigation must begin as soon as practical (21 CFR 1271.350(a)(3)).  In addition, 
under 21 CFR 1271.350(a)(1), you must report to FDA an adverse reaction involving a 
communicable disease if it: 
 
  Is fatal;  
  Is life-threatening;  
                                                           
5 Hematopoietic stem/progenitor cells derived from peripheral or cord blood may be regulated as a 361 HCT/P if the 
product meets the criteria under 21 CFR 1271.10(a) and either is for autologous use or is for allogeneic use in a first-
degree or second-degree blood relative. 
6 Id. 
4  Contains Nonbinding Recommendations 
 
  Results in permanent impairment of a body function or permanent damage to a 
body structure; or 
  Necessitates medical or surgical intervention, including hospitalization. 
 
D.  Who Must Report Adverse Reactions Related to 361 HCT/Ps under 21 CFR 
1271.350(a)? 
 
Under 21 CFR 1271.350(a)(1), if you are the establishment that made the HCT/P 
available for distribution, you must report to FDA any adverse reaction involving a 
communicable disease related to the HCT/P that you have determined met the criteria for 
reporting under 21 CFR 1271.350(a) (see section III.C. of this guidance).  
 
E.  When Must I Submit Reports of Adverse Reactions Related to 361 HCT/Ps 
to FDA? 
 
You must submit to FDA each report of an adverse reaction that you determine meets the 
criteria for reporting under 21 CFR 1271.350(a) within 15 calendar days of initial receipt 
of the information about the adverse reaction (see 21 CFR 1271.350(a)(2)).  Under  
21 CFR 1271.350(a)(3), you must, as soon as practical, investigate all adverse reactions 
that are the subject of these 15-day reports and must submit to FDA follow-up reports 
within 15 calendar days of the receipt of new information or as requested by FDA.  If 
additional information is not obtainable, a follow-up report may be required that 
describes briefly the steps taken (e.g., phone call, email, registered mail) to seek 
additional information and the reasons why it could not be obtained (see 21 CFR 
1271.350(a)(3)).  This might include situations where you are unable to obtain the 
additional information you need to complete your investigation, such as clinical 
information about the recipient, in spite of repeated attempts. 
 
F.  How Must I Submit Reports of Adverse Reactions Related to 361 HCT/Ps to 
FDA? 
 
You must submit two copies of each adverse reaction report on a Form FDA 3500A 
(21 CFR 1271.350(a)(5)).7  Send these copies to: 
 
U.S. Food and Drug Administration,  
Center for Biologics Evaluation and Research, 
Document Control Center, 
10903 New Hampshire Avenue, 
WO71, G112, 
Silver Spring, MD 20993-0002. 
 
You may obtain copies of Form FDA 3500A from Center for Biologics Evaluation and 
Research (CBER) at the address listed above or electronically at:  
                                                           
7 We encourage manufacturers to use Form FDA 3500A whenever reporting adverse reactions to FDA, even if they 
are reporting voluntarily, to help ensure that FDA has sufficient information to evaluate the reported event or 
reaction.    
5  Contains Nonbinding Recommendations 
 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM048334.p
df.  
General instructions for completing Form FDA 3500A are available at 
http://www.fda.gov/Safety/MedWatch/HowToReport/.  However, section V. of this 
guidance gives you additional recommendations specific to HCT/Ps to help you complete 
Form FDA 3500A and to help ensure that you provide FDA with critical information. 
 
 
IV.  ADVERSE REACTION INVESTIGATION  
 
A.  What Information About the Recipient Should I Review as Part of the 
Investigation of an Adverse Reaction? 
 
Your investigation should include the evaluation of pertinent information about the 
recipients adverse reaction that might be informative about possible etiologies of the 
adverse reaction.  Pertinent information may include: 
 
  The time course, symptoms, and outcome of the reaction; 
  The recipients medical and social/behavioral history (including pre-existing 
medical conditions and travel history); 
  Relevant test results; and 
  History of transfusions, infusions, transplants, implants, and transfers that may 
have been a source for communicable disease transmission. 
 
We recognize that you might not be able to obtain detailed clinical and behavioral risk 
factor information about the recipient; however, you should make diligent efforts (e.g., 
phone call, email, registered mail) to obtain relevant information in order to make an 
appropriate assessment of the possible etiologies of the adverse reaction.8 
 
B.  What Information Should I Review About the Donor Whose HCT/Ps are 
Involved in an Adverse Reaction? 
 
You should review all information used to make the donor-eligibility determination (or 
any donor information that may have become available after the determination was made) 
and verify that screening and testing were performed in accordance with regulatory 
requirements.  This would include review of information pertaining to whether the donor 
received transfusions or infusions that may have caused plasma dilution or may have 
been a source for communicable disease transmission if the complaint involves a disease 
that is potentially transmissible through transfusion.  Part 1271, Subpart C and FDAs 
guidance document entitled Guidance for Industry:  Eligibility Determination for 
Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) 
                                                           
8 The Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule specifically permits covered 
entities (such as pharmacists, physicians or hospitals) to report adverse events and other information related to the 
quality, effectiveness and safety of FDA-regulated products both to the manufacturers and directly to FDA. 
Information on HIPAA compliance for reporters to FDA MedWatch is available at: 
http://www.fda.gov/Safety/MedWatch/HowToReport/ucm085589.htm.  
6  Contains Nonbinding Recommendations 
 
dated August 2007, describe requirements and recommendations, respectively, for 
making a donor-eligibility determination.  
 
C.  What Recovery Information Should I Review in My Investigation of an 
Adverse Reaction? 
 
You should review whether the facility where recovery of the HCT/P took place met the 
general requirements for HCT/P facilities under 21 CFR 1271.190.  In addition, you 
should review: 
 
  Whether the recovery was performed by a method appropriate to controlling 
contamination; 
  Whether there were deviations from established procedures that may have 
increased the risk of contamination or cross-contamination; 
  Whether the supplies and reagents used during recovery were in compliance with 
21 CFR 1271.210; and 
  Whether the recovery was performed within your established time and 
temperature limits for recovery.  
 
D.  What Processing Information Should I Review in My Investigation of an 
Adverse Reaction? 
 
Under 21 CFR 1271.3(ff), processing means any activity performed on an HCT/P, 
other than recovery, donor screening, donor testing, storage, labeling, packaging, or 
distribution, such as:  
  Testing for microorganisms;  
  Preparation;  
  Sterilization;  
  Steps to inactivate or remove adventitious agents;  
  Preservation for storage; and  
  Removal from storage. 
 
Investigation of an adverse reaction related to a 361 HCT/P should include the review of 
processing records to determine whether there were any deviations or departures from 
your established procedures that may have resulted in contamination or cross-
contamination of the HCT/P involved in the adverse reaction.  The investigation should 
specifically include the following, as applicable: 
 
  The review of records related to the evaluation of the incoming bioburden, such as 
the results of recovery or procurement cultures, or findings on inspection of the 
HCT/P packaging or container for damage and contamination.  
  The review of pre- and post-processing culture results, if applicable, and the 
determination as to whether any microorganisms present on those cultures were 
also present on recipient cultures.  Although some microbiology laboratories do 
not routinely identify the species of certain microorganisms, speciation is 
desirable as it aids in the investigation of adverse reactions. 
7  Contains Nonbinding Recommendations 
 
  The determination as to whether multiple cellular products were collected at 
different times from the same donor and combined to attain a certain therapeutic 
dose, and a review of the results of cultures performed on each separate product, 
if available. 
  A verification that the process used for removal or inactivation of microorganisms 
was validated and performed as established in standard operating procedures.  
This verification should include a comparison of the list of representative 
challenge microorganisms that were used in your process validation to the type of 
microorganism(s) involved in the adverse reaction.  
  The review of records of sterilization and/or disinfection process failures (i.e., 
positive microbiological testing results following sterilization or disinfection of an 
HCT/P) within the timeframe spanning an appropriate period before and after the 
suspect HCT/P was manufactured and a determination as to whether your 
establishment has experienced sterilization or disinfection process failures 
involving the same microorganism as identified in the recipient adverse reaction. 
An appropriate period should be supported by a risk-based analysis that includes 
the volume of processing cultures performed, but it should be no less than 7 days. 
  A determination as to whether any HCT/Ps from the donor were discarded during 
or after processing because they did not meet your pre-established acceptance 
criteria related to communicable diseases (e.g., organism considered 
unacceptable, sterilization or disinfection process failures, contamination). 
 
E.  What Environmental Control and Monitoring Information Should I Review 
in My Investigation of an Adverse Reaction? 
 
Under 21 CFR 1271.195(a), where environmental conditions could reasonably be 
expected to cause contamination or cross-contamination of HCT/Ps or equipment, or 
accidental exposure of HCT/Ps to communicable disease agents, you must adequately 
control environmental conditions and provide proper conditions for operations.   
 
Under 21 CFR 1271.195(c), you must monitor environmental conditions where 
environmental conditions could reasonably be expected to cause contamination or cross-
contamination of HCT/Ps or equipment, or accidental exposure of HCT/Ps to 
communicable disease agents, and you also must provide environmental monitoring for 
microorganisms, where appropriate.   
 
As part of your investigation, you should review environmental control and monitoring 
records from all areas where the involved HCT/Ps were processed, including records 
pertaining to: 
 
  Temperature and humidity controls; 
  Ventilation and air filtration; 
  Air samples; 
  Work surfaces; 
  Sinks and drains; 
  Personnel;  
8  Contains Nonbinding Recommendations 
 
  Maintenance of equipment; and 
  Cleaning and disinfection of rooms and equipment.   
 
You also should determine: 
 
  What types of microorganisms have been detected;  
  Whether the same microorganism responsible for the recipient infection has been 
cultured during routine environmental monitoring; and 
  Whether results reached or exceeded your established action levels in the general 
timeframe surrounding the processing of the implicated HCT/P.  
 
Even if the microorganisms cultured from the environment and from the recipient are not 
the same, the recurrence or persistence of microorganisms in the environment near or 
above established action levels may indicate a general problem within your 
establishment. 
 
F.  What Storage and Distribution Information Should I Review in My 
Investigation of an Adverse Reaction? 
 
You should review storage and distribution records to determine whether the HCT/P was 
stored under appropriate conditions (e.g., stored within defined temperature limits); 
whether there was a possibility of mix-up, contamination, or cross-contamination; 
whether the HCT/P was properly made available for distribution (e.g., met release 
criteria); and whether the HCT/P was shipped under established conditions (21 CFR 
1271.260 and 1271.265). 
 
G.  What Tracking Information Should I Review in My Investigation of an 
Adverse Reaction? 
 
You should review tracking information to identify the following pertaining to the donor 
of the HCT/P involved in an adverse reaction:   
 
  Number of HCT/Ps produced and distributed;  
  Number of HCT/Ps reported as implanted;  
  Number of HCT/Ps that remain in inventory; and  
  Number or types of HCT/Ps you sent to other establishments for further 
manufacture.   
 
Such tracking information facilitates timely corrective actions, including notification of 
consignees as appropriate (21 CFR 1271.160(b)(2)(iii)). 
 
9  Contains Nonbinding Recommendations 
 
H.  What Labeling Information Should I Review in My Investigation of an 
Adverse Reaction? 
 
You should review records pertaining to the information in the product label to determine 
whether it was labeled appropriately, including warnings and instructions for use related 
to prevention of the introduction, transmission, or spread of communicable diseases (see 
21 CFR 1271.250, and 1271.370(b) and (c)).  
 
I.  What Complaint File Information Should I Review in My Investigation of an 
Adverse Reaction? 
 
Under 21 CFR 1271.320(b), you must maintain a record of complaints that you receive in 
a file designated for complaints.  As part of every investigation, you should review this 
file to determine if other relevant complaints of adverse reactions have been reported to 
your establishment.  This may include other complaints involving the same donor, 
complaints involving the same infectious agent or microorganism, or complaints 
involving the same reporting facility or surgeon.  Should you find other relevant 
complaints, you should review the relevant documentation from the investigation(s) of 
these complaints, including any results or findings, to determine if there are any 
correlations with the current complaint under investigation. 
 
J.  What Information Pertaining to Adverse Reactions Concerning 361 HCT/Ps 
Should I Share with Other Establishments? 
 
If you are an establishment that performs any step in the manufacture of HCT/Ps, under 
21 CFR 1271.160(a), you must maintain a quality program intended to prevent the 
introduction, transmission, or spread of communicable diseases through the manufacture 
and use of HCT/Ps.  Among other things, one of the functions your quality program must 
perform is the establishment and maintenance of procedures for sharing with other 
establishments information pertaining to the possible contamination of the HCT/P or 
pertaining to the potential  transmission of communicable disease by the HCT/P with 
other establishments that are known to have recovered HCT/Ps from the same donor, and 
with other establishments that are known to have performed manufacturing steps with 
respect to the same HCT/P (21 CFR 1271.160(b)(2)(i) and (ii)).  We recommend that the 
shared information include any pertinent information that you have collected from your 
investigation of an adverse reaction and note that these procedures can be designed so 
that patient confidentiality is not compromised.  Sharing this information should assist 
other establishments in taking appropriate action(s).  We also recommend that you seek 
information regarding any complaints that the other establishments who have recovered 
or performed manufacturing steps on HCT/Ps from the same donor may have received 
related to the HCT/Ps.9 
 
                                                           
9 We refer you to the FDA guidance entitled Guidance for Industry:  Current Good Tissue Practice (CGTP) and 
Additional Requirements for Manufacturers of Human Cells, Tissues, and Cellular and Tissue-Based Products 
(HCT/Ps) dated December 2011, for further recommendations pertaining to sharing information with, and receiving 
information from, other establishments. 
10  Contains Nonbinding Recommendations 
 
 
V.  ADVERSE REACTION REPORTING 
 
A.  What Information Should I Report on Form FDA 3500A?  
 
If you are an establishment that makes the 361 HCT/P available for distribution, you 
should use the information that you collected from your investigation of the adverse 
reaction to complete Sections A, B, C, E, and G, as well as the Other Remarks section 
of Form FDA 3500A.  If any items in those sections do not apply to you or the adverse 
reaction, indicate these as being not applicable (N/A).  The following recommendations 
are specific to the information you should provide to complete the sections applicable to 
361 HCT/Ps; you also may need to refer to the general instructions for completing Form 
FDA 3500A available at  
http://www.fda.gov/downloads/Safety/MedWatch/HowToReport/DownloadForms/UCM
387002.pdf.  
 
Section A:  Patient Information 
Information in this section pertains to the recipient of the HCT/P. 
A1:  Patient Identifier.  Use recipients initials or some other identifier that will 
facilitate follow-up if requested. Complete a separate form for each recipient. 
A2:  Age or Date of Birth.  Provide the most precise information available. For 
age, indicate time units used (e.g., years, months, and days). 
A3:  Sex.  Enter the recipients gender. 
A4:  Weight.  Provide the weight if it is relevant to the adverse reaction.  Indicate 
the weight units used (e.g., pounds, kilograms).  
A5a:  Ethnicity.  Choose only one response. 
A5b:  Race.  Choose all that apply. 
 
Section B:  Adverse Event or Product Problem  
B1:  Adverse Event and/or Product Problem.  The term adverse event as used 
on the form is applicable to HCT/P adverse reactions; check this box to report an 
adverse reaction.  FDA does not require reporting of 361 HCT/P problems that 
did not result in or contribute to an adverse reaction. 
B2:  Outcomes Attributed to Adverse Event.  Check off all that apply for 
outcomes attributed to the adverse reaction.  Refer to the general instructions that 
accompany the Form FDA 3500A for descriptions of the outcome categories.  
B3:  Date of Event.  Provide the actual or best estimate of the date of first onset 
of the adverse reaction, such as the approximate date of onset of symptoms or the 
date the health professional identified the infection. 
B4:  Date of this Report.  Provide the date the report is filled out. 
B5:  Describe Event or Problem.  Describe the adverse reaction in detail using 
the words of the individual who reported the adverse reaction to the manufacturer.  
Include a description of what happened and a summary of all clinical information 
relevant to the event (e.g., recipients medical status prior to the event; signs 
and/or symptoms; differential diagnosis for the event in question; clinical course; 
treatment; outcome).  If available and if relevant, include synopses of any office 
11  Contains Nonbinding Recommendations 
 
visit notes or the hospital discharge summary.  To save time and space (and if 
permitted by the institution), you may attach copies of these records and simply 
refer to them in your response.  Include information about any environmental 
exposures that may have influenced the event (e.g., for an adverse reaction 
involving West Nile Virus (WNV), note whether the recipient lives in or has 
traveled to an area with high WNV activity).  Include the Manufacturer Report 
Number(s) in this field to identify other MedWatch reports filed regarding the 
same donor. 
B6:  Relevant Tests/Laboratory Data, Including Dates.  Provide results of the 
recipients relevant tests and laboratory data, including relevant negative tests and 
laboratory findings, and dates performed.  This includes recipient cultures or 
serology performed before or after receipt of the product, or tests performed to 
evaluate the reaction.  Copies of any reports may be submitted as attachments.  In 
cases where cultures were not obtained from the recipient, make note of that in 
this field. 
B7:  Other Relevant History, Including Preexisting Medical Conditions.   
This item should include information about the recipient and the donor. 
  Provide any relevant information about the recipients history that has 
not already been requested in Section B, including preexisting medical 
conditions, behavioral risk factors, and history of transfusion of blood 
and/or blood products. 
  Provide any relevant information about the donor.  Such information 
may include relevant donor medical and social history, donor 
screening test results, and pre- and post-processing culture results.  
Include a statement about whether the donor record review revealed 
any problems with donor screening, testing, or eligibility 
determination, and whether the donor received blood or blood 
products. 
 
Section C:  Suspect Product(s) 
Provide information about the 361 HCT/P that is suspected of causing the adverse 
reaction in this section.  Up to two (2) suspect products may be reported on one 
form 
C1:  Name, Manufacturer/Compounder, Strength.  Space provided to 
identify two products.  Provide the common name of the HCT/P, followed by 
Tissue or Cell in parentheses, for example: 
  Demineralized bone (Tissue) 
  Cornea (Tissue) 
  Hematopoietic stem/progenitor cells derived from peripheral blood 
(Cell) 
You also can indicate if the HCT/P has a proprietary or trade name, in addition to 
the common name of the HCT/P. Provide the name of the manufacturer. 
Lot #.  Provide the lot number here. 
NDC # or Unique ID.  Provide the unique identification number for the 
HCT/P to facilitate tracking. 
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C2:  Concomitant Medical Products and Therapy Dates.  List and provide 
therapy dates for any other medical products (drugs, biological products, medical 
devices, blood or blood products) that were administered to the recipient at the 
time of receipt of the HCT/P. 
C3:  Dose, Frequency & Route Used.  This is applicable for cells.  Please 
provide information on the dose, frequency and route used. 
C4:  Therapy Dates.  Provide date of implantation, transplantation, or infusion 
(Line #1) and date of explantation (Line #2), if applicable.  
C5:  Diagnosis for Use.  Provide the diagnostic reason for HCT/P implantation, 
transplantation, or infusion.  
C6:  Is the Product Compounded?  Leave Blank 
C7:  Is the Product Over-the-Counter?  Leave Blank 
C8:  Expiration Date.  Provide the date of expiration on the HCT/P label, if any. 
C9:  Event Abated After Use Stopped or Dose Reduced?  Check the box 
Doesn't Apply. 
C10:  Event Reappeared After Reintroduction?  Check the box Doesnt 
Apply. 
 
Section E:  Initial Reporter 
E1:  Name and Address, Phone #.  Provide the name, mailing address, and 
phone number of the individual who initially reported the adverse reaction to the 
manufacturer or distributor so that individual can be contacted if follow-up is 
necessary to obtain additional clinical information related to the recipients 
adverse reaction.  We recommend that you also provide the email address and fax 
number of the initial reporter, if known. 
E2:  Health Professional?  Indicate whether the initial reporter is a health 
professional (check Yes or No). 
E3:  Occupation.  Indicate the initial reporters occupation (e.g., physician, 
nurse, dentist, etc.). 
E4:  Initial Reporter Also Sent Report to FDA.  Indicate whether the initial 
reporter also notified or sent a report to FDA or check Unk if unknown. 
 
Section G:  All Manufacturers 
G1:  Contact Office  Name/Address/Email Address.  Provide the full name 
and address of the manufacturer reporting site, including the name of the contact 
at that site.  Include the email address of the contact. 
G2:  Phone Number.  Provide the telephone number of the contact at the 
manufacturer reporting site who is knowledgeable about the report. 
G3:  Report Source.  Check the box(es) that describe how the manufacturer 
became aware of the reported adverse reaction or where the information 
originated.  See the MedWatch instructions for more detailed definitions of report 
sources: 
http://www.fda.gov/downloads/Safety/MedWatch/HowToReport/DownloadForm
s/UCM387002.pdf. 
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G4:  Date Received by Manufacturer.  Provide the date the manufacturer 
initially received information that the adverse reaction occurred, or the date the 
manufacturer received follow-up information (for follow-up reports). 
G5:  Does not apply (leave blank).  
G6:  Does not apply (leave blank).  
G7:  Type of Report.  Check off 15-day as well as Initial for initial reports 
of adverse reactions related to HCT/Ps.  Check off Follow-Up if the report is a 
follow-up to a previously submitted report.  You should provide additional or 
corrected information on the previously reported event.  You should include 
information that was submitted in the original report if the information is still 
correct.  
G8:  Adverse Event Term(s).  Include a list of adverse event terms that most 
accurately characterize the adverse event described in the narrative format in box 
B5.  Terms should be listed with the most important term(s) first.  The 
terminology may be an accepted standard (e.g., MedDRA or WHOART), a 
verbatim term, or the manufacturers own terminology.  For more information on 
MedDRA coding, see the MedDRA Term Selection:  Points to Consider dated 
October 1, 2012, at 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/MedDRA/MedDR
A_Documents/MedDRA_Term_Selection/Release_4.4_based_on_v.15.1/TermSe
lection_PTC_R4.4_October.2012.pdf. 
G9:  Manufacturer Report Number.  The report number should consist of three 
numbers separated by dashes.  The first number will be the 10-digit FDA 
Establishment Identifier (FEI) number, which was assigned to you as part of the 
Human Cells and Tissue Establishment Registration System (HCTERS).  The 
second number should be the year that you are submitting the report.  The last 
number should be a consecutive 5-digit number for each report filed during the 
year by the manufacturer.  Example: 1234567890-2005-00005. 
  In the upper right corner of the front page in the field Mfr Report # enter 
the same manufacturer report number. 
  For a follow-up report, the manufacturer report number should be identical 
to the number assigned to the initial report. 
 
Section Other Remarks on page 3 of Form FDA 3500A 
In this section, include statements summarizing the findings from review of 
manufacturing records, including information as to: 
  Any problems with the donor eligibility determination; 
  Any problems with the tissue recovery protocols; 
  Any deviations or departures from established procedures; 
  Any microorganisms present on donor tissue or in cell product pre- or 
post-processing culture results that are also present on recipient cultures; 
  Any sterilization or disinfection process failures your establishment 
experienced within the timeframe spanning at least 7 days before and after 
the suspect HCT/P was manufactured involving the same microorganism 
as identified in the recipient adverse reaction; 
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  Any problems with environmental monitoring; indicate what types of 
microorganisms have been detected, and whether results reached or 
exceeded action levels in a general timeframe surrounding the processing 
of the implicated HCT/P; and 
  Any other complaints involving the same donor or complaints of the same 
microorganism involving tissues processed in the same general timeframe 
as those from the implicated donor. 
 
B.  How Do I Report Adverse Reactions Involving Multiple HCT/Ps?  
 
If a reportable adverse reaction involves two or more 361 HCT/Ps transplanted in the 
same recipient, only one Form FDA 3500A should be completed.  The Form FDA 3500A 
should list the names and lot numbers of all HCT/Ps. 
 
If multiple recipients experience adverse reactions related to HCT/Ps from the same 
donor, you should submit a separate Form FDA 3500A for each recipient.  Include the 
Manufacturer Report Number(s) in field B5 of Form FDA 3500A to identify the other 
Forms FDA 3500A you submitted regarding the same donor. 
 
C.  How Do I Report Adverse Reactions/Events for Other HCT/Ps that are not 
Regulated as 361 HCT/Ps, but are Regulated as Drugs, Medical Devices, or 
Biological Products? 
 
If your establishment manufactures and makes available for distribution other HCT/Ps 
that do not meet the criteria specified in 21 CFR 1271.10(a) for regulation solely under 
section 361 of the PHS Act, then the adverse reaction report requirements in  
21 CFR 1271.350 are not applicable.  Those other HCT/Ps are regulated as either drugs, 
medical devices, or biological products and therefore are subject to the reporting 
requirements for drugs, medical devices, or biological products under the Federal Food, 
Drug, and Cosmetic Act and/or section 351 of the PHS Act and the applicable regulations 
in Title 21 of the CFR.  For those types of HCT/Ps, we refer you to the following, 
relevant sections of the CFR for reporting pre- and post-marketing adverse reactions to 
FDA: 
 
Medical Devices: 
 
21 CFR Part 803 (Medical Device Reporting)  
Medical Device Reporting - General Information 
http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm. 
 
21 CFR Part 812 (Investigational Device Exemptions)  
 
Investigational Drugs (including Investigational Biological Drugs): 
 
21 CFR 312.32 (IND safety reporting) and 21 CFR 312.64 (Investigator reports)  
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Prescription Drugs: 
 
21 CFR 314.80 (Postmarketing reporting of adverse drug experiences)  
 
Licensed Biological Drugs (Postmarket Biological Drug Products): 
 
21 CFR 600.80 (Postmarketing reporting of adverse experiences)  
 
D.  Who Can I Contact if I Have Additional Questions Concerning the 
Reporting of an Adverse Reaction Related to a 361 HCT/P? 
 
You may send questions concerning reporting adverse reactions related to 361 HCT/Ps to 
FDAs Tissue Safety Team (TST) at the following email address:  TST@cber.fda.gov.  
 
E.  What Happens to MedWatch Form FDA 3500A Reports After I Submit 
Them to FDA? 
 
CBER has established Standard Operating Procedures and Policies (SOPP) 8508 for 
handling adverse reaction reports related to 361 HCT/Ps (see  
http://www.fda.gov/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/pr
oceduressopps/ucm073048.htm).  The reports are reviewed by FDAs TST which 
conducts further information gathering and recommends interventions, if necessary. 
 
 
VI.  IMPLEMENTATION 
 
We recommend that you implement the recommendations in this guidance as soon as feasible, 
but not later than six months after the issuance date of this guidance. 
 
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VII.  REFERENCES  
 
1.  Food and Drug Administration.  Guidance for Industry:  Eligibility Determination for Donors 
of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) (August 2007).   
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInf
ormation/Guidances/Tissue/UCM091345.pdf.  
 
2.  Food and Drug Administration.  Guidance for Industry:  Current Good Tissue Practice 
(CGTP) and Additional Requirements for Manufacturers of Human Cells, Tissues, and 
Cellular and Tissue-Based Products (HCT/Ps) (December 2011). 
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInf
ormation/Guidances/Tissue/UCM285223.pdf. 
 
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