Guidance for Industry
 
 
Safety, Efficacy, and Pharmacokinetic 
Studies to Support Marketing of 
Immune Globulin Intravenous 
(Human) as Replacement Therapy for 
Primary Humoral Immunodeficiency 
 
 
 
 
 
 
 
 
Additional copies of this guidance are available from the Office of Communication, Training and 
Manufacturers Assistance (HFM-40), 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-
1448, or by calling 1-800-835-4709 or 301-827-1800, or from the Internet at 
http://www.fda.gov/cber/guidelines.htm. 
 
For questions on the content of this guidance, contact the Division of Blood Applications, Office 
of Blood Research and Review at 301-827-3543.  
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Biologics Evaluation and Research 
June 2008  Contains Nonbinding Recommendations 
 
 
Table of Contents 
 
 
I.  INTRODUCTION.............................................................................................................1 
II.  BACKGROUND...............................................................................................................1 
III.  GENERAL PRINCIPLES CONCERNING CLINICAL TRIAL DESIGN TO 
EVALUATE SAFETY, EFFICACY, AND PHARMACOKINETICS........................2 
A.  Safety......................................................................................................................2 
1.  General Principles Pertaining to Safety............................................................2 
2.  Guidance for Evaluation of Safety....................................................................3 
B.  Efficacy...................................................................................................................6 
1.  General Principles Pertaining to Efficacy.........................................................6 
2.  Guidance for Evaluation of Efficacy................................................................7 
C.  Pharmacokinetic Studies of IGIV........................................................................9 
1.  Guidance for Pharmacokinetic (PK) Studies....................................................9 
2.  PK Studies in the Pediatric Population...........................................................10 
IV.  APPENDIX .....................................................................................................................12 
V.  REFERENCES................................................................................................................14 
i  Contains Nonbinding Recommendations 
 
Guidance for Industry 
 
Safety, Efficacy, and Pharmacokinetic Studies to Support 
Marketing of Immune Globulin Intravenous (Human) as 
Replacement Therapy for Primary Humoral Immunodeficiency  
 
 
This guidance represents the Food and Drug Administrations (FDAs) 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.  You can use an alternative approach if the approach satisfies the 
requirements of the applicable statutes and regulations.  If you want to discuss an alternative 
approach, contact the appropriate FDA staff.  If you cannot identify the appropriate FDA staff, 
call the appropriate number listed on the title page of this guidance. 
 
 
I.  INTRODUCTION 
 
We, FDA, are providing you, Investigational New Drug Application (IND) sponsors and 
Biologics License Application (BLA) applicants, recommendations for testing the safety and 
efficacy of Immune Globulin Intravenous (Human) (IGIV) products as replacement therapy in 
primary humoral immunodeficiency.  The document provides guidance on general principles 
concerning clinical trial design to evaluate safety, efficacy, and pharmacokinetics of 
investigational IGIV products and is intended to assist you in the preparation of the 
clinical/biostatistical and human pharmacokinetic sections of a BLA.  This guidance does not 
address evidence of clinical efficacy for other indications, or other sections of a BLA such as 
chemistry, manufacturing, and controls and preclinical toxicology.    
 
This guidance finalizes the draft guidance of the same title dated November 2005 (70 FR 72124, 
December 1, 2005).   
 
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 
 
Polyclonal immune globulin preparations of human origin, including IGIV, have long been used 
as replacement therapy in patients with humoral immunodeficiencies.  IGIV products are 
prepared from large pools of plasma collected from large numbers of individual healthy donors, 
and therefore contain antibodies against many infectious agents.   
1  Contains Nonbinding Recommendations 
 
To date, all IGIV products licensed by FDA carry an FDA approved indication for use in 
primary humoral immunodeficiency.  Some IGIV products have additional approved indications, 
such as elevation of platelet counts to prevent and/or to control bleeding in immune/idiopathic 
thrombocytopenic purpura.  
 
At the FDA Blood Products Advisory Committee (BPAC) meeting held in March, 1999 (Ref. 1), 
we presented our preliminary recommendations for designing a pivotal clinical trial to evaluate 
the safety and efficacy of a new IGIV product for treatment of primary humoral 
immunodeficiency.  The presented design involved a prospective, randomized, double-blind, 
parallel, positive control, non-inferiority study in 80 subjects with a documented history of such  
immunodeficiency, in which the safety and efficacy of the test product was to be compared head-
to-head to a U.S. licensed IGIV product.  IND sponsors would evaluate efficacy by comparing 
the serious infection rate in each randomization group over an observation period of 12 months. 
 
Since the March 1999 BPAC meeting, we have determined that alternative clinical trial design 
proposals involving testing in smaller numbers of subjects with primary humoral  
immunodeficiency in an open-label, single-arm trial compared to a statistically modeled 
historical control might be sufficient to provide evidence of safety and efficacy.  At the March, 
2000 BPAC meeting (Ref. 2), we presented an alternate approach to clinical trial design to 
evaluate IGIV safety and efficacy in primary humoral immunodeficiency, and we describe a 
similar approach in Section III below.  Other approaches may also satisfy applicable 
requirements.   
 
Other FDA guidance documents contain helpful information for you to consider as you prepare 
BLAs.  These documents are available at http://www.fda.gov/cber/guidelines.htm. 
 
 
III.  GENERAL PRINCIPLES CONCERNING CLINICAL TRIAL DESIGN TO 
EVALUATE SAFETY, EFFICACY, AND PHARMACOKINETICS  
 
A.  Safety 
 
1.  General Principles Pertaining to Safety 
 
Historically, the observed incidence of adverse experiences (AEs) reported 
to occur in clinical trials of IGIV products has varied widely by product, 
maximal infusion rate, and patient population/indication being studied.  
For this reason, the safety profile of each IGIV product should be 
determined independently.  In previous experience, the proportion of 
infusions in a clinical trial population for which one or more adverse 
experiences has been reported to occur in association with the infusion(s) 
has seldom been reported to exceed approximately 0.20. 
 
 
 
2  Contains Nonbinding Recommendations 
 
2.   Guidance for Evaluation of Safety 
 
  We evaluate product safety based on the totality of pertinent safety 
findings and analyses. 
 
  We recommend a minimum of 30 subjects be studied at the highest 
dose to be recommended in the products labeling.  For adverse 
events that occur with a frequency of 10%, the probability of 
observing at least one event in this sample size is approximately 0.95. 
If an adverse event were not observed in this sample, then the 
probability of seeing that event is no more than 0.1 (i.e., the upper 
limit of 95% confidence interval for the observed rate of 0/30 is 0.1).   
 
  For purposes of this guidance, an AE is a treatment-emergent AE 
associated with the use of the IGIV, whether or not the AE is 
determined to be product related.     
 
  Under 21 CFR 312.32(a), a serious adverse drug experience (SAE) is 
any adverse drug experience occurring at any dose that results in any 
of the following outcomes:  death, a life-threatening adverse drug 
experience, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant disability/incapacity, or a 
congenital anomaly/birth defect.  Important medical events that may 
not result in death, be life-threatening, or require hospitalization may 
be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed 
in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or 
at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or 
drug abuse.  
 
  It is important for protocols to define and capture all AEs associated 
with the use of the product, regardless of the investigators opinion 
regarding whether the AE is product-related.  Where appropriate, 
analyses of AEs should take into account the observed intra-subject 
correlation of the same type or any type of AE, as such within-subject 
events may not be independent.  Methodology for these analyses 
should be described in the statistical analysis plan. 
 
  Your protocol should define criteria for establishing an AE as an 
infusional AE (i.e., an AE temporally associated with an infusion).  
We recommend you list AEs individually by body system with 
subject identification numbers and report the overall incidences of all 
AEs that occur during or within:  (a) 1 hour, (b) 24 hours, and (c) 72 
3  Contains Nonbinding Recommendations 
 
hours following an infusion of test product, regardless of other factors 
that may impact a possible causal association with product 
administration.  The ADVERSE REACTIONS section of the 
products draft package insert submitted with any IGIV BLA should 
summarize:  (a) the total number of AEs that occur during or within 
72 hours of an infusion, (b) the total number of infusions, and (c) the 
mean number of such temporally-associated AEs per infusion (i.e., 
(a)/(b)) that were seen in the clinical trial(s).    
 
  One safety endpoint for clinical trials of IGIV should consist of the 
observed proportion of infusions with one or more temporally-
associated AEs (including AEs that you or your investigator 
determine not to be product-related).  We believe that an appropriate 
target for this safety endpoint is an upper one-sided 95% confidence 
limit of less than 0.40.  The methodology for computing such 
confidence limits should be described in the statistical analysis plan. 
It may be appropriate to modify this target as experience with various 
IGIV products further increases.  
 
  According to the available literature, the intensity (i.e., severity) of 
many AEs associated with infusion of IGIV is dependent on the rate 
of infusion (Ref. 3).  For this reason, your protocols should provide 
explicit directions for starting and raising/adjusting infusion rates, 
including the timeframes for incremental changes and the size of 
infusion rate increments.  A forced titration schedule may be 
appropriate, with explicit provisions for downward adjustment of the 
infusion rate, or temporary or permanent cessation of the infusion, 
depending on the nature and/or severity of temporally-associated 
(infusional) AEs.  Protocols should provide for the systematic 
evaluation of AEs as a function of infusion rate.  
 
  For AEs that occur during infusion, it is important that the protocol 
and the case report form (CRF) are designed to capture:  (1) the 
infusion rate in effect at the time of onset of AEs; (2) the time of 
onset of AEs; and (3) the time AEs change materially in intensity 
and/or resolve.  
 
  We consider subject diaries kept in real time to be important source 
documents for the complete collection of AE data.  You should 
provide an explanation for any discrepancies between subject diary 
entries and CRF entries made by the clinical investigator, sub-
investigators, or his/her designee(s). 
 
  We discourage the use of premedication in clinical trials designed to 
evaluate the safety of biologic products, except in cases where such 
premedication is important to the safety of trial subjects.  In such 
4  Contains Nonbinding Recommendations 
 
instances, you should record the use of any premedications and their 
possible impact on the study data and evaluate their possible impact 
in the final study report.  
 
  Routine hematology1 and serum chemistry2 tests, and urinalysis3 
should be obtained at baseline and periodically during the period of 
test product administration.  
 
  We recommend laboratory measurements intended to aid the 
detection/evaluation of intravascular hemolysis during and after the 
period of test product administration.  In addition to the routine 
hematology, chemistry, and urinalysis testing noted above, 
measurements of serum haptoglobin, plasma-free hemoglobin, urine 
hemosiderin, and direct anti-globulin (DAT, Coombs) testing should 
be obtained at baseline and follow-up.  We recommend that study 
protocols specify measurement of specific eluted antibodies in the 
event of positive Coombs test measurements, in addition to retesting.   
A drop in hemoglobin of 2 g/dL or greater, in conjunction with both a 
drop in serum haptoglobin to below the lower limit of normal and a 
rise in serum LDH from baseline, would suggest intravascular 
hemolysis.  
 
  We recommend that your final study report include: 
 
o  For each subject and for the study as a whole, the number of 
infusions administered, the total number of AEs reported at any 
time during the study (including AEs that you or the investigator 
determine were not product-related), the number of AEs 
temporally associated with infusions, and the number and 
percentage of infusions temporally associated with one or more 
AEs.  For AEs that occur during infusion, you should report and 
analyze:  (1) the infusion rate in effect at the time of onset of AEs; 
(2) the time of onset of AEs; and (3) the time AEs change 
materially in intensity and/or resolve.  It is important to our 
review that you also provide listings of SAEs, AEs by severity, 
AEs by body system, and your determination of which AEs were 
product-related, and which were not.   
 
o  The mean number of AEs temporally associated with infusions 
per infusion.  As previously noted, this is given by (a)/(b) where:  
(a) equals the total number of AEs that occur during or within 72 
hours of an infusion, and (b) equals the total number of infusions.  
                                                 
1 Includes complete blood count with white blood cell differential and platelet count. 
2 Includes serum electrolytes, glucose, blood urea nitrogen, creatinine, alanine aminotransferase, aspartate 
aminotransferase, lactate dehydrogenase, and total bilirubin. 
3 Includes microscopic examination of urine sediment. 
5  Contains Nonbinding Recommendations 
 
o  The proportion of infusions administered to subjects for which 
infusional AEs have been reported.  
 
o  The proportion of subjects who experience one or more AEs at 
any time during the course of the trial. 
 
o  For each AE, indicate which infusion of investigational product 
this occurred with or followed (i.e., 1st infusion, 2nd infusion, etc.).  
The AE listings should include separate reports of all AEs and of 
AEs judged by investigators to be associated with the infusion of 
the product, even if you determine the AE not to be product-
related.  You are encouraged to include in the protocol criteria or 
guidelines for the causality assessment of all AEs, whether 
temporally associated with infusion(s) or not. 
 
o  It is important for protocols to define and capture all AEs 
associated with the use of the product, regardless of the 
investigators opinion regarding whether the AE is product-
related.  In addition to reporting the verbatim AE terminology as 
entered on the case report forms, we recommend you report and 
analyze AEs according to a set of standard AE terms using a 
coding dictionary, such as the Medical Dictionary for Regulatory 
Activities (medDRA).4   
 
o  Where appropriate, analyses of AEs should take into account the 
observed intra-subject correlation of the same type or any type of 
AE, as such within-subject events may not be independent.  
Methodology for these analyses should be described in the 
statistical analysis plan. 
 
B.  Efficacy 
 
1.  General Principles Pertaining to Efficacy 
 
Historically, IGIV products have been used to reduce the frequency of 
serious bacterial infections in patients with primary humoral 
immunodeficiency.  To evaluate the efficacy of an investigational IGIV, 
we recommend that clinical trials compare the frequency of serious 
bacterial infections during a period of regular administration of the test 
product to a historically-based standard.   
 
The available literature suggests that prior to the routine institution of 
immunoglobulin replacement therapy, patients with 
hypogammaglobulinemia and agammaglobulinemia due to primary 
humoral immunodeficiency experienced approximately four or more 
                                                 
4 http://www.meddramsso.com/MSSOWeb/faq/meddra.htm 
6  Contains Nonbinding Recommendations 
 
serious acute bacterial infections per year (Ref. 4).  That number contrasts 
with an observed serious infection frequency of less than 0.5 per year 
during periods of regular (generally every 3 to 4 weeks) administration of 
IGIV, 200 to 600 mg/kg per infusion.  The available data do not permit 
identification of a trough total immunoglobulin G (IgG) level (pre-next-
dose) or pathogen-specific plasma IgG level which, if achieved and 
maintained, would ensure optimal protection from the risk of serious 
bacterial infection.  Preliminary data from clinical trials suggest that, 
within the commonly prescribed IGIV dosage range, subjects with higher 
trough levels may experience greater protection from bacterial infections.  
We encourage you to study the relationships among dose of your product, 
trough level, and risk of serious and non-serious bacterial infections. 
 
More data are needed to better understand the quantitative relationships 
among trough total and pathogen-specific plasma IgG levels and serious 
infection risk.  We encourage you to initiate exploratory analyses of your 
clinical trial data to evaluate the relationship of both serious and non-
serious infections to the pharmacokinetic parameters, the total IgG levels, 
the levels of the various subclasses of IgG and, if possible, the levels of 
selected specific antibodies such as anti-pneumococcal capsular 
polysaccharide and anti-Haemophilus influenzae antibodies.  
 
2.  Guidance for Evaluation of Efficacy 
 
  We recommend that you measure the rate of serious bacterial 
infections during regularly repeated administration of the 
investigational IGIV product in adult and pediatric subjects for 12 
months (to avoid seasonal biases) and compare the observed infection 
rate to a relevant historical standard, as discussed in this same section, 
or to a concurrent control group.   
 
  In ensuring compliance with the requirements of the Pediatric 
Research Equity Act of 2007 (Title IV of the Food and Drug 
Administration Amendments Act of 2007), we recommend that you 
discuss with the reviewing division at the IND stage your plans for 
pediatric studies.   
 
  We recommend that the protocol prospectively provide specific 
diagnostic criteria for each type of serious infection to be included in 
the primary efficacy analysis (e.g., rate of serious infections).  
Diagnostic criteria should not be overly restrictive so that you capture 
all infections of interest.  Clinical investigators at different sites should 
use uniform diagnostic criteria.  The Appendix outlines diagnostic 
criteria for each of the serious infection types that should be included 
in the analysis.   
 
7  Contains Nonbinding Recommendations 
 
  The protocol should prospectively define the study analyses.  We 
expect that the data analyses presented in the BLA will be consistent 
with the analytical plan submitted to the IND.  Based on our 
examination of historical data, we believe that a statistical 
demonstration of a serious infection rate per person-year less than 1.0 
is adequate to provide substantial evidence of efficacy.  You may test 
the null hypothesis that the serious infection rate is greater than or 
equal to 1.0 per person-year at the 0.01 level of significance or, 
equivalently, the upper one-sided 99% confidence limit would be less 
than 1.0.     
 
  You should employ a sufficient number of subjects to provide at least 
80% power with one-sided hypothesis testing and an alpha = 0.01.  
Although the responsibility for choosing the sample size rests with 
you, we anticipate that studies employing a total of approximately 40 
to 50 subjects would generally prove adequate to achieve the requisite 
statistical power, given the design specifications listed in this same 
section.  When describing your statistical plan, we recommend that 
you pay particular attention to how you will take into account the 
observed intra-subject correlation of serious acute infection events 
because such within-subject events may not be independent.  
 
  We recommend that you provide in the BLA descriptive statistics for 
the number of serious infection episodes per person-year during the 
period of study observation.  Additional information important to our 
review includes a frequency table giving the number of subjects with 
0, 1, 2... serious infections, a description of each serious infection, and 
summary statistics for the length of observation of each subject.  
 
  We recommend that you obtain and analyze secondary endpoints, 
including candidate surrogate efficacy endpoints.  Secondary 
endpoints would normally include trough total IgG and specific 
antibody levels, all infections of any kind/seriousness, non-serious 
infections (total and by category, including acute sinusitis, 
exacerbation of chronic sinusitis, acute otitis media, acute bronchitis, 
infectious diarrhea, etc.), time to resolution of infections, antibiotic 
treatment (oral, parenteral, oral plus parenteral, prophylactic, and 
therapeutic), hospitalizations due to infection, episodes of fever, days 
lost from school and/or work due to infections and their treatment, and 
additional quality of life measures.  You should prospectively define 
these secondary endpoints and their corresponding statistical analyses 
in the study protocol.   
   
 
   
8  Contains Nonbinding Recommendations 
 
C.  Pharmacokinetic Studies of IGIV 
 
1.  Guidance for Pharmacokinetic (PK) Studies  
 
We recommend that you submit PK data in your BLA to describe the 
distribution, metabolism, and elimination of IGIV products.  These data 
will provide a basis for historical comparison between the investigational 
IGIV product and licensed IGIVs, as well as help determine the optimum 
dosing schedule for the product. 
 
We recommend that you obtain PK data from at least 18-20 adult subjects 
with primary humoral immune deficiency (either previously untreated or 
previously treated patients).  PK parameters should be calculated for the 
overall PK study subject cohort, as well as for subgroups according to 
IGIV infusion dosing schedule (e.g., subjects dosed every 3 versus every 4 
weeks).  You may obtain the data as part of the Phase 3 clinical trials 
conducted to establish efficacy and safety.  Suitable PK studies can be 
single arm studies compared with historical data or they can be either 
crossover or parallel studies if you choose to include a licensed product 
arm as a positive control.  If you use the historical control approach, your 
PK study should be part of a single arm 12-month Phase 3 study in which 
the following measurements should be included: 
     
  The steady-state trough total IgG levels obtained from the previously 
used IGIV. 
 
  Sufficient plasma total IgG and selected specific (e.g., anti-
pneumococcal capsular polysaccharide and anti-Haemophilus 
influenzae) antibody levels to derive a plasma concentration-time 
curve, half-life, area under the curve (AUC ; AUC ), volume of 
0-t 0-infinity
distribution, concentration maximum (C ), and elimination rate 
max
constant(s).  The serum samples for these antibody measurements 
should be made after a washout period lasting 3 to 5 estimated half-
lives, during which time subjects receive the investigational IGIV on a 
regular basis.  You should justify the choice of PK model used to 
derive the PK parameters. 
 
  You should measure the trough total IgG levels prior to each infusion 
during the study.  IgG subclass levels should be measured at least once 
after steady state is estimated to have been achieved (i.e., after 
approximately 5 half lives have elapsed during regular periodic 
administration of the test product).  It may be appropriate to identify in 
the study protocol and provide justification for the minimum trough 
level value that is acceptable.  Your study report should include the 
proportion of subjects who failed to meet the target trough level at any 
time point equal to or subsequent to 5 estimated half-lives.  If you elect 
9  Contains Nonbinding Recommendations 
 
not to include a concurrent control for your PK study/sub-study 
design, we recommend you compare and relate your observed trough 
IgG level data to that of currently licensed historical control IGIV 
products.   
 
  You should develop a prospective plan for defining the recommended 
dosing schedule based on the observed/calculated PK parameters and 
include the plan in the PK study protocol.  For patients who are 
previously untreated, we recommend you determine the time to reach 
steady state. 
 
2.  PK Studies in the Pediatric Population  
 
The following definitions of pediatric populations are described in the 
FDA guidance entitled General Considerations for Pediatric 
Pharmacokinetic Studies for Drugs and Biological Products (Ref. 5).  
 
  Neonate:  birth to 1 month 
  Infant:  1 month to 2 years 
  Child:  2 to 12 years 
  Adolescent:  12 years to <16 years 
 
If possible and needed, the PK study of an IGIV product should be 
conducted across all pediatric age groups.  An appropriate PK study could 
involve administering either a single dose in naive subjects who have 
not been receiving regular IGIV replacement therapy, or multiple doses of 
the test IGIV over a time period of 3 to 5 terminal elimination half-lives, 
with PK sampling following the last dose.  The sample size should consist 
of 6 to 12 subjects in a given pediatric age group.  Two methods can be 
used for the estimation of PK parameters: 
 
  The standard 2-stage PK approach (model-independent and/or model-
dependent approach) (Refs. 6 through 8)  
 
  The standard 2-stage PK approach is the usual approach for the 
estimation of PK parameters.  In this approach, frequent blood 
sampling is required.  Blood samples should be collected over 
specified intervals depending on the elimination half-life of the drug.  
It is important in this approach to include enough subjects (e.g., 6 to 
12) to give a reasonable estimate of variability.  
 
 
 
 
 
10  Contains Nonbinding Recommendations 
 
  The population PK approach (Refs. 9 and 10)  
 
An alternate approach in many pediatric situations is the population 
PK approach.  This approach involves sparse blood sampling from a 
larger population than would be used in a standard PK study to 
estimate PK parameters.  The population PK approach is more 
practical in pediatric populations (especially neonates and very young 
children) than the 2-stage PK approach because it allows for infrequent 
sampling, sometimes as few as 2 to 4 samples per subject.  Because a 
relatively large number of subjects is studied, estimates of both 
population means and individual values (POSTHOC Bayesian)5, as 
well as estimates of intra- and inter-subject variability can be obtained 
if the population PK study is properly designed (Refs. 11 through 13).  
 
More details for conducting PK studies in pediatric populations can be 
found in the FDA guidance entitled, General Considerations for 
Pediatric Pharmacokinetic Studies for Drugs and Biological Products 
(Ref. 5). 
                                                 
5 The term POSTHOC Bayesian refers to individual subject estimates of PK parameters.  
11  Contains Nonbinding Recommendations 
 
IV.  APPENDIX     Diagnostic Criteria for Serious Infection Types  
 
 
Infection:  Bacteremia/sepsisa 
(cid:131)  Symptoms:  chills, rigors  
(cid:131)  Physical findings: fever, hypothermia, tachycardia, tachypnea, hypocarbia, hypotension 
(systolic blood pressure <90 mm Hg or a reduction of >40 mm Hg from baseline in the 
absence of other causes of hypotension), altered mental status, petechiae, purpura, 
oligouria, cutaneous vasodilation/vasoconstriction 
(cid:131)  Laboratory tests:  positive blood cultureb, leukocytosis (white blood cell (WBC) count 
> 12,000/mm3), differential WBC count demonstrating  >10% immature (band) 
neutrophils, leukopenia, thrombocytopenia, coagulopathy, lactic acidosis 
Infection: Bacterial Meningitis 
(cid:131)  Symptoms:  headache, stiff neck, mental status changes, irritability, decreased feeding 
(infants), photophobia, nausea/vomiting, rigors, seizures 
(cid:131)  Physical findings:  Kernigs sign, Brudzinskis sign, meningococcal rash, fever of >38 C 
oral or >39C rectal 
(cid:131)  Laboratory tests:  positive cerebrospinal fluid  (CSF) Gram stain and/or culture 
and/or positive CSF bacterial antigen assay, positive blood culturec, CSF leukocytosis 
with neutrophil predominance, decrease in CSF glucose 
Infection: Osteomyelitis/Septic Arthritis 
(cid:131)  Symptoms:  pain, decreased range of motion, tenderness, edema, redness, warmth over 
the involved site (local inflammatory symptoms/signs may be lacking in adults.) 
(cid:131)  Physical findings:  evidence of soft tissue infection adjacent to the involved bone/joint, 
drainage from sinus tract from involved bone, fever of >38C oral or >39C rectal 
(cid:131)  Laboratory tests:  positive blood culture, positive probe to bone, positive bone aspirate 
culture, positive bone biopsy culture, positive bone histopathology, positive joint fluid 
Gram stain and culture 
Imaging studies:  positive X-ray, nuclear medicine bone scan, magnetic resonance imaging 
(MRI) scan, or computed tomography (CT) scan showing bony destruction with radiolucent 
areas; for chronic osteomyelitis: sequestra, involucra 
 
                                                 
Note:  Items in bold are considered essential diagnostic features.   
 
a Two of the following should be present to make the diagnosis of sepsis in adults:  temperature >38C oral/ > 39C 
rectal or <36C oral or < 37C rectal; heart rate >90 beats/min; respiratory rate >20 breaths/min, or PaCO  <32 mm 
2
Hg; WBC count >12,000/mm3, <4,000/mm3, or >10% immature (band) forms (Ref. 14).  For pediatric subjects, we 
recommend you employ the definition of sepsis using age-specific criteria as recommended by the International 
Consensus Conference on Pediatric Sepsis (Ref. 15). 
b Indwelling catheter- or vascular access device-related blood-borne infections are not included because evidence is 
lacking that these are preventable with IGIV replacement therapy.  For subjects without indwelling catheters or 
vascular access devices, a single blood culture positive for a pathogenic organism will meet the diagnostic criteria 
for bacteremia.  (Multiple blood cultures are typically obtained in cases of suspected bacteremia/sepsis, as per 
standard medical practice, and the finding of a single positive culture should prompt additional confirmatory 
cultures).  Subjects meeting criteria for positive blood culture but without 2 or more of the sepsis criteria listed 
above will be classified as having bacteremia. 
c  A blood culture positive for growth of Streptococcus pneumoniae, Neisseria meningitides, or Haemophilus 
influenzae, in combination with CSF leukocytosis and/or decrease in CSF glucose, can serve to confirm the 
diagnosis of acute bacterial meningitis (Ref. 16).  
12  Contains Nonbinding Recommendations 
 
Infection: Bacterial Pneumoniad 
(cid:131)  Symptoms:  productive cough/change in character of sputum, dyspnea or tachypnea, 
chills, chest pain, rigors, headache, fatigue, sweats, anorexia, myalgias 
(cid:131)  Physical findings:  rales; pulmonary consolidation as reflected by: dullness on percussion, 
bronchial breath sounds, egophony; fever >38C oral or > 39C rectal, or <36C, 
hypothermia (temperature < 36C oral or < 37C rectal) 
(cid:131)  Laboratory tests:  leukocytosis, differential WBC count of >10% band neutrophils, 
leukopenia, hypoxemia (PaO < 60 mm Hg on room air), positive blood culture, Gram 
2 
stain and culture of deep expectorated sputume, positive culture with or without positive 
Gram stain of transtracheal aspirate, pleural fluid culture, lung biopsy, bronchoscopy with 
bronchoalveolar lavage (BAL) or protected brush sampling,  
(cid:131)  Imaging studies:  Pulmonary infiltrate with consolidation on chest X-Ray (CXR)  
(new in comparison with baseline CXR) 
 
Infection:  Visceral Abscess 
(cid:131)  Symptoms:  abdominal pain, anorexia, weight loss, cough/pleuritic chest pain (hepatic 
abscess), rigors (seldom present) 
(cid:131)  Physical findings:  intermittent fevers (temperature >38C oral or >39C rectal), 
abdominal tenderness, palpable mass, hepatomegaly, jaundice 
(cid:131)  Laboratory tests:  positive Gram stain and/or culture from the infected site, with 
isolation of an appropriate pathogen, positive blood culture, leukocytosis with 
accompanying left shift, differential WBC count of >10% immature (band) neutrophils, 
elevated serum amylase concentration (pancreatic abscess), elevated alkaline phosphatase 
concentration (hepatic abscess) pyuria in renal abscess 
(cid:131)  Imaging studies:  typical findings on ultrasound, CT scan, MRI scan, or radionuclide 
scan 
 
Note:  Items in bold are considered essential diagnostic features.   
 
 
 
 
                                                 
d For the diagnosis of pneumonia in adults, commonly at least 2 of the listed symptoms and/or signs should be 
present in conjunction with at least one laboratory and one imaging studies diagnostic element.  However, for the 
purposes of counting serious infection episodes in a clinical trial of IGIV, the finding of a new pulmonary infiltrate 
with consolidation on CXR is considered sufficient.  To establish the diagnosis of bacterial pneumonia for pediatric 
patients, most of the same diagnostic criteria listed may be used, with the following exceptions: Because pediatric 
patients may not produce a sputum specimen for culture, blood cultures or serology may be substituted to identify 
the etiologic bacterial pathogen.  In infants age 3 to 24 months, who tend to have a higher baseline temperature, 
fever is defined as a rectal temperature >38.3C (101F).  In children >2 years, fever is more commonly defined as a 
rectal temperature >38C (100.4F).  In pediatric patients, elevations of WBC counts >15,000/mm3 are frequent but 
could be variable in patients with bacterial pneumonia, or leukopenia with WBC count <5000/mm3 may be 
observed, usually associated with severe infection (Ref. 17). 
e We recommend a deep expectorated sputum gram stain to demonstrate the presence of microorganisms on 
examination of 10-20 oil immersion microscopic fields and <10 squamous epithelial cells and >25 
polymorphonuclear leukocytes at 10X low power magnification to determine suitability of sputum culture (Ref. 17). 
13  Contains Nonbinding Recommendations 
 
V.  REFERENCES 
 
1.  FDA Blood Products Advisory Committee Meeting, March, 1999 Transcript. 
http://www.fda.gov/ohrms/dockets/ac/99/transcpt/3504t2.pdf  
 
2.  FDA Blood Products Advisory Committee Meeting, March, 2000 Transcript. 
http://www.fda.gov/ohrms/dockets/ac/00/transcripts/3603t2a.pdf   
 
3.  Nydegger, UE, Mohacsi, PJ, (ed. Simon, TL, Dzik, WH, Snyder EL, et al).  
Immunoglobulins in Clinical Medicine.  In: Rossis Principles of Transfusion Medicine 
(3rd edition).  Lippincott, Williams, & Wilkins, 2002.  
 
4.  Bruton, OC. Agammaglobulinemia.  Pediatrics. 1952; 9: 722-28. 
 
5.  FDA Guidance General Considerations for Pediatric Pharmacokinetic Studies for Drugs 
and Biological Products, Draft Guidance, November 1998.  This draft guidance, when 
finalized, will represent FDAs current thinking on this topic.  
http://www.fda.gov/cber/gdlns/pedphrm.htm 
 
6.   Gibaldi M, Perrier D.  Noncompartmental analysis based on statistical moment theory.  
In: Pharmacokinetics (2nd edition).  Mercel Dekker, 1982.   
 
7.  Shargel L, Yu ABC.  Introduction to Pharmacokinetics. In: Applied Biopharmaceutics 
and Pharmacokinetics (3rd edition).  Appleton & Lange, 1993. 
 
8.  Mahmood I.  Pharmacokinetics.  In: Clinical pharmacology of therapeutic proteins.  Pine 
House Publishers, 2006. 
 
9.  Williams PJ, Ette EI.  The role of population pharmacokinetics in drug development in 
light of the Food and Drug Administrations Guidance for Industry:  population 
pharmacokinetics.  Clin Pharmacokinet. 2000; 39 (6): 385-95.   
 
10.  Duan J.  Population Pharmacokinetics.  In: Clinical pharmacology of therapeutic proteins.  
Pine House Publishers, 2006. 
 
11.  Peck CC, Chen BC.  Influence of sampling time of drug levels in Bayesian 
pharmacokinetic control of drug therapy.  Clin Pharmacol Therap.  1985; 37:220.  
 
12.  Mahmood I.  Impact of random and fixed (optimal) sampling approach on the Bayesian 
estimation of clearance.  Int J Clin Pharmacol Ther. 2003; 41(9):392-6. 
 
14  Contains Nonbinding Recommendations 
 
13.  Mahmood I, Tammara V.  A comparison of two sparse sampling population 
pharmacokinetic approaches for the estimation of pharmacokinetic parameters in 
children.  Int J Clin Pharmacol Ther. 2004; 42(4):240-5.  
 
14.  Levy MM, Fink MP, Marshall JC, et al.  2001 SCCM/ESICM/ACCP/ATS/SIS 
International Sepsis Definitions Conference. Crit Care Med 2003; 31:1250-1256. 
 
15.  International Consensus Conference on Pediatric Sepsis.  Pediatric Crit Care Med 2005; 
  6:2-8. 
 
16.  FDA Guidance for Industry Acute Bacterial Meningitis  Developing Antimicrobial 
Drugs for Treatment, Draft Guidance, July 1998.  This draft guidance, when finalized, 
will represent FDAs current thinking on this topic.  
http://www.fda.gov/cder/guidance/2573dft.pdf  
 
17.  FDA Guidance for Industry Community Acquired Pneumonia  Developing 
Antimicrobial Drugs for Treatment, Draft Guidance, July 1998.  This draft guidance, 
when finalized, will represent FDAs current thinking on this topic. 
http://www.fda.gov/cder/guidance/2570dft.pdf 
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