Rabies:  Developing 
Monoclonal Antibody 
Cocktails for the Passive 
Immunization Component of 
Post-Exposure Prophylaxis 
Guidance for Industry 
 
 
 
 
DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit electronic comments to http://www.regulations.gov.  Submit written 
comments to the Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers 
Lane, Rm. 1061, Rockville, MD  20852.  All comments should be identified with the docket 
number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document, contact Stephanie Troy at 240-402-4656.  
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
July 2021 
Clinical/Antimicrobial 
34605388dft.docx 
07/13/21   
Rabies:  Developing 
Monoclonal Antibody 
Cocktails for the Passive 
Immunization Component of 
Post-Exposure Prophylaxis 
Guidance for Industry 
 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor 
Silver Spring, MD  20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
July 2021 
Clinical/Antimicrobial 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION ........................................................................................... 1 
II.  BACKGROUND.............................................................................................. 2 
III.  DEVELOPMENT PROGRAM ....................................................................... 4 
A.  General Considerations ...................................................................................... 4 
1  Nonclinical Virology Development Considerations ................................................... 4 
a.  Epitope mapping ............................................................................................ 4 
b.  Antiviral activity in cell culture ........................................................................ 4 
c.  Animal challenge studies................................................................................. 5 
2. Early-Phase Clinical Development Considerations ................................................... 5 
3. Efficacy Considerations ........................................................................................ 6 
4. Safety Considerations ........................................................................................... 7 
B.  Phase 3 Efficacy Trial Considerations.................................................................. 8 
1. Trial Design, Including Randomization, Stratification, and Blinding............................ 8 
2. Trial Population and Location ............................................................................... 8 
3. Entry Criteria...................................................................................................... 9 
4. Dose Selection................................................................................................... 10 
5. Use of Active Comparators.................................................................................. 10 
6. Efficacy Endpoints ............................................................................................. 10 
7. Trial Procedures and Timing of Assessments.......................................................... 11 
8. Endpoint Adjudication ........................................................................................ 11 
9. Statistical Considerations.................................................................................... 11 
a.  Analysis populations .................................................................................... 11 
b.  Efficacy analyses ......................................................................................... 11 
c.  Handling of missing data............................................................................... 12 
d.  Statistical considerations for a trial to support a first-line indication ..................... 12 
10.  Risk-Benefit Considerations ............................................................................ 13 
C.  Other Considerations ....................................................................................... 13 
1. Nonclinical Safety Considerations ........................................................................ 13 
2. Chemistry, Manufacturing, and Controls Considerations ......................................... 15 
a.  Candidate selection ...................................................................................... 15 
b.  Control strategy: potency assays..................................................................... 16 
c.  Control strategy: ratio of mAbs in cocktail ....................................................... 16 
3. Labeling Considerations ..................................................................................... 16 
4. Postmarketing Considerations ............................................................................. 16 
REFERENCES ......................................................................................................... 17 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Rabies:  Developing Monoclonal Antibody Cocktails for the 
2  Passive Immunization Component of Post-Exposure Prophylaxis 
3  Guidance for Industry1 
4   
5   
6   
7  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
8  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
9  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
10  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
11  for this guidance as listed on the title page. 
12   
13   
14   
15  I.  INTRODUCTION  
16   
17  The purpose of this guidance is to help sponsors in the development of anti-rabies virus 
18  monoclonal antibody (mAb) cocktails as an alternative to anti-rabies virus immunoglobulin 
19  (RIG) as the passive immunization component of post-exposure prophylaxis (PEP) for the 
20  prevention of rabies when given immediately after contact with a rabid or possibly rabid animal.  
21  This draft guidance is intended to serve as a focus for continued discussions among the Division 
22  of Antivirals, sponsors, the academic community, and the public.2  This guidance does not 
23  address the development of rabies vaccines, products to treat rabies, or mAbs for other 
24  indications.  The recommendations in this guidance relate to studies to be submitted in support of 
25  a biologics license application (BLA) submission under section 351 of the Public Health Service 
26  Act (42 U.S.C.  262) and implementing regulations at 21 CFR part 601.  
27   
28  This guidance does not address general issues of statistical analysis or clinical trial design.  
29  Those topics are addressed in the ICH guidances for industry E9 Statistical Principles for 
30  Clinical Trials (September 1998), E9(R1) Statistical Principles for Clinical Trials: Addendum: 
31  Estimands and Sensitivity Analysis in Clinical Trials (May 2021), and E10 Choice of Control 
32  Group and Related Issues in Clinical Trials (May 2001), respectively.3 
33   
34  The contents of this document do not have the force and effect of law and are not meant to bind 
35  the public in any way, unless specifically incorporated into a contract. This document is intended 
36  only to provide clarity to the public regarding existing requirements under the law. FDA 
37  guidance documents, including this guidance, should be viewed only as recommendations, unless 
 
1 This guidance has been prepared by the Office of New Drugs, Office of Infectious Diseases, Division of Antivirals 
in the Center for Drug Evaluation and Research at the Food and Drug Administration. 
 
2 FDA encourages sponsors to contact the division to discuss specific issues that arise during the development of 
rabies mAb cocktails. 
 
3 We update guidances periodically.  For the most recent version of a guidance, check the FDA guidance web page 
at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
38  specific regulatory or statutory requirements are cited. The use of the word should in Agency 
39  guidance means that something is suggested or recommended, but not required.  
40   
41  II.  BACKGROUND 
42   
43  Rabies has an almost 100% case fatality rate after clinical symptoms develop and there is no 
44  proven treatment.  However, timely administration of rabies PEP is nearly 100% effective in 
45  preventing clinical rabies (WHO 2018).  Globally, approximately 20 million people per year 
46  receive PEP after potential rabies virus exposure (WHO 2013), including approximately 55,000 
47  people in the United States (Pieracci et al. 2019).  Despite available prophylaxis, approximately 
48  59,000 people die from rabies worldwide each year (Hampson et al. 2015, WHO 2018), usually 
49  either because PEP was not administered or because PEP was administered incorrectly (WHO 
50  2018). 
51   
52  PEP consists of three components for patients not previously vaccinated against rabies4: 
53   
54  1.  Thoroughly washing the wound  
55  2.  Promptly initiating a rabies vaccine series 
56  3.  Promptly administrating RIG in and around the wound 
57    In the United States, RIG is recommended in any situation for which PEP is 
58  considered appropriate (in patients not previously vaccinated against rabies).  Outside 
59  the United States, RIG is included for only World Health Organization (WHO) 
60  category III exposures, which include any transdermal bites or scratches, 
61  contamination of mucous membrane or broken skin with saliva from animal licks, or 
62  exposures due to direct contact with bats.   
63   
64  Although thoroughly washing the wound and promptly completing a modern rabies vaccination 
65  series alone have been estimated to prevent rabies in approximately 99% of people exposed to 
66  rabies virus (WHO 2018), RIG is vital to rabies prevention after more severe exposures 
67  (Baltazard and Bahmanyar 1955).  RIG is considered particularly important after bites to the 
68  head and neck for which it may take less time for the rabies virus to travel from the wound to the 
69  brain.  People vaccinated with a rabies vaccine series develop rabies virus neutralizing antibodies 
70  (RVNAs) >0.5 IU/mL, the level WHO uses as a measure of adequate vaccine response, within 7-
71  14 days (WHO 2018).  RIGs chief contribution is providing neutralization activity in the period 
72  before the vaccine-induced RVNAs develop.  
73   
74  RIG is produced from the pooled serum of individuals hyperimmunized against the rabies virus, 
75  and currently is either of human (HRIG) or equine (ERIG) origin.  HRIG and ERIG are 
76  considered to have equal effectiveness, but the safety profile of the two products may differ.  
77  Only HRIG is commercially available in the United States.  Globally, in developing countries 
78  where rabies is endemic, ERIG is used more often. 
79   
 
4 In previously vaccinated individuals, PEP consists of wound washing and an abbreviated vaccine series without 
RIG.  In individuals who have not previously been vaccinated, RIG should be administered concurrently with the 
first dose of vaccine. 
2  Contains Nonbinding Recommendations 
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80  Globally, RIG is used in less than 2% of rabies virus exposures because of several factors, 
81  including RIGs dependence on the cold chain and logistical issues such as limited supply.  In 
82  the United States where RIG is generally available, an alternative to RIG would be useful in case 
83  of RIG shortage and to eliminate the theoretical risk of transmission of blood-borne pathogens.  
84  For these reasons, mAb cocktails are being developed as an alternative to RIG as the passive 
85  component of PEP.  WHO has recommended that mAb cocktails contain at least two mAbs that 
86  target different, nonoverlapping antigenic sites on the rabies virus envelope G glycoprotein, the 
87  protein that is the sole target of the RVNAs elicited by vaccine administration (WHO 2013). 
88   
89  The development pathway for rabies mAb cocktails is challenging because of many complicating 
90  factors including the following: 
91   
92    Without RIG, wound washing and rabies vaccination by themselves are ~99% effective 
93  at preventing clinical rabies.  Complete PEP with RIG increases this rate to ~99.9%, but 
94  the exact contribution of RIG to the effectiveness of PEP is unknown.  Consequently, 
95  trial sizes required to power for noninferiority versus RIG with mortality as an endpoint 
96  are infeasible, even if a noninferiority margin could be determined, whereas placebo-
97  controlled trials would likely be considered unacceptable based on expert input.  These 
98  topics were discussed during an FDA public workshop and advisory committee meeting.5 
99   
100    Multiple factors affect the risk of rabies development after potential exposure through an 
101  animal bite, which makes comparison to a historical control challenging.  Whether the 
102  bite was from a rabid animal is usually not known, and the likelihood of the animal being 
103  rabid varies widely by location.  Other factors include the location of the bite on the 
104  body, number and depth of bites, viral inoculum in the saliva of the biting animal, type of 
105  rabies vaccine used as part of PEP, host factors, and the time interval between the bite 
106  and initiation of PEP. 
107   
108    Selecting an appropriate dose for the mAb cocktail is challenging, as too high a dose 
109  could interfere with the vaccine response and thus increase the risk of developing rabies. 
110   
111    The mAb cocktails are qualitatively different from HRIG preparations, so they will have 
112  a different development pathway.  A chief concern with mAb cocktails is diminished 
113  breadth of activity and durability against different rabies virus strains, as mAb cocktails 
114  could contain as few as two antibodies compared with polyclonal RIG.  RVNA levels, 
115  which have been used as an endpoint in many HRIG trials, do not measure breadth of 
116  activity.  For new HRIG preparations standardized to the same potency as a marketed 
117  HRIG product, and with similar RVNA profiles, it was reasonable to assume that these 
118  new products would likely have similar efficacy and breadth of activity to the marketed 
119  HRIG product.  This assumption cannot be extrapolated to mAb cocktails. 
 
5 Materials for the 2017 workshop Developing Rabies Monoclonal Antibody Products as a Component of Rabies 
Post-exposure Prophylaxis are available at https://www.fda.gov/drugs/news-events-human-drugs/developing-rabies-
monoclonal-antibody-products-component-rabies-post-exposure-prophylaxis.  Materials for the 2019 Antimicrobial 
Drugs Advisory Committee are available at https://www.fda.gov/advisory-committees/advisory-committee-
calendar/april-25-2019-antimicrobial-drugs-advisory-committee-meeting-announcement-04252019-04252019. 
 
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
120   
121  Because of the unique complexities of drug development for rabies mAb cocktails, FDA 
122  convened discussions with multiple stakeholders, including a public workshop in 20176 and an 
123  advisory committee meeting in 2019.7  These discussions helped FDA formulate recommended 
124  regulatory pathways for rabies mAb cocktail development.  At these discussions there was 
125  consensus that superiority trials of mAb cocktails versus placebo, for the passive PEP 
126  component, are likely to be considered unacceptable and that adequately powered noninferiority 
127  trials of mAb cocktail versus RIG are not logistically feasible.  In addition, there was agreement 
128  that surrogate endpoints of protection are not established for the passive component of PEP.  
129  Therefore, FDA is recommending an approach combining nonclinical and clinical data to 
130  demonstrate substantial evidence of effectiveness for rabies mAb cocktails. 
131   
132  III.  DEVELOPMENT PROGRAM 
133   
134  A.  General Considerations 
135   
136  Development of mAbs for use in rabies PEP requires careful balancing and integrated 
137  assessment of data from nonclinical studies, healthy volunteer clinical trials, and clinical trials 
138  enrolling persons with known or suspected rabies exposure.  Because adverse outcomes from 
139  decreased performance of the passive component of PEP can be lethal but rare and difficult to 
140  attribute causally, sponsors should consider other available types of data at each step in the 
141  development sequence.  Some of these interrelationships will be emphasized in the following 
142  sections. 
143   
144  1  Nonclinical Virology Development Considerations 
145   
146  a.  Epitope mapping 
147   
148  Sponsors should characterize the epitope of each mAb, including identifying amino acids critical 
149  for neutralization (e.g., contact residues).  These studies should include selecting and 
150  characterizing neutralization-resistant variants in cell culture, ideally using multiple resistant 
151  variants that were independently selected from antigenically diverse viruses.  Sponsors should 
152  determine the frequency of amino acid polymorphisms at critical amino acid positions in 
153  circulating rabies virus strains. 
154   
155  b.  Antiviral activity in cell culture 
156   
157  The neutralizing activity of the mAb cocktail, the individual mAb constituents of the cocktail, 
158  and an HRIG comparator should be evaluated in cell culture against a panel of rabies virus 
159  strains representative of the antigenic diversity of circulating strains.  The panel should include 
160  strains from multiple host species (e.g., bats, dogs, foxes, raccoons, skunks) and from multiple 
161  locations (i.e., the United States and areas in Asia and Africa where rabies is endemic).  In 
162  addition, the panel should include strains with polymorphisms at amino acid positions critical for 
 
6 See footnote 5. 
 
7 See footnote 5. 
4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
163  neutralization by each mAb.  The results of the neutralization assays should be reported as the 
164  50% effective concentration (i.e., EC  values reportedas ng/mL and/or International Units 
50  
165  [IU]/mL).  Ideally, the mAb cocktail will demonstrate a breadth of neutralizing activity that is at 
166  least as broad as that of HRIG.  Sponsors should consider evaluating potential Fc-mediated 
167  mechanisms of antiviral activity (e.g., antibody-dependent cellular cytotoxicity), if applicable.  
168   
169  c.  Animal challenge studies 
170   
171  Animal models of rabies PEP (e.g., hamster, dog) should demonstrate that the mAb cocktail at 
172  the to-be-marketed concentration and dose is superior to placebo and similar to or better than 
173  HRIG in reducing mortality.8  These animal challenge studies should test various concentrations 
174  and doses of the mAb cocktail and be conducted both with and without a concomitant rabies 
175  vaccine.  Studies comparing the effects of the mAb cocktail and HRIG on vaccine response in 
176  the animal models should be completed, and sponsors should consider a comparison of the 
177  prophylactic windows of the mAb cocktail and HRIG.  Selecting rabies virus challenge strains 
178  should depend on human exposure risks (e.g., dog and bat strains) and susceptibility of the mAbs 
179  based on cell culture data; ideally, these studies will include challenge strains that are among the 
180  least susceptible to neutralization in cell culture to increase confidence that reductions in 
181  mortality with the challenge strains could be extrapolated to other, more susceptible strains.  
182   
183  2.  Early-Phase Clinical Development Considerations 
184   
185  Trials in healthy subjects not exposed to rabies virus should evaluate the pharmacokinetics, 
186  RVNA levels, and initial safety and tolerability of the mAb cocktail versus HRIG both when 
187  administered alone and when administered with a rabies vaccine series.   
188   
189  A dose-ranging trial of the mAb cocktail versus HRIG in the absence of a rabies vaccine in 
190  healthy volunteers should include both intramuscular and subcutaneous administration to reflect 
191  how these products could be administered for PEP.  Blood samples should be collected at 
192  multiple time points to accurately capture the peak RVNA levels and the RVNA concentration-
193  time profile and to fully characterize the pharmacokinetic profile of each mAb.  Important 
194  endpoints include demonstration of the following for the doses of the mAb cocktail chosen for 
195  further development: 
196   
197    Similar or higher RVNA levels (in IU/mL) for the mAb cocktail versus HRIG at each of 
198  multiple time points through Day 14 (i.e. throughout the earliest time period when 
199  passive antibodies may be the principal contributor to neutralizing activity, as well as the 
200  period from Day 7 to Day 14 when vaccine-induced RVNAs would be expected to 
201  become apparent in most people with vaccine coadministration).  
202   
203  A second trial in healthy volunteers should compare various doses of the mAb cocktail versus 
204  HRIG versus placebo when administered in combination with a rabies vaccine series.  If various 
 
8 We support the principles of the 3Rs, to reduce, refine, and replace animal use in testing when feasible.  FDA 
encourages sponsors to consult with us if they wish to use a nonanimal testing method they believe is suitable, 
adequate, validated, and feasible.  We will consider if such an alternative method could be assessed for equivalency 
to an animal test method.   
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205  rabies vaccines and routes of vaccine administration (intramuscular or intradermal) are expected 
206  to be used in the phase 3 trials, each of these rabies vaccines and routes of vaccine administration 
207  should be tested with the mAb cocktail in the phase 1 healthy volunteer trials to assess for 
208  acceptable levels of vaccine interference.  If FDA-approved rabies vaccines will not be used in 
209  the phase 3 trials, the potential for interference with FDA-approved rabies vaccines should be 
210  evaluated in healthy volunteer trials.  Important endpoints in the healthy volunteer trials in which 
211  the mAb cocktail or HRIG is administered with a rabies vaccine series include demonstration of 
212  the following for the dose of mAb cocktail chosen for further development in trials in potentially 
213  rabies-exposed subjects: 
214   
215    Comparable RVNA levels for the mAb cocktail versus HRIG at earlier time points (up to 
216  7 days), before RVNAs produced by vaccine would be expected to predominateThere 
217  is no established protective threshold at early time points, but HRIG is considered to be 
218  effective. 
219   
220    Comparable vaccine interference to that observed with HRIGThe proportion of 
221  subjects with RVNA levels 0.5 IU/mL at Day 14 was used to measure vaccine 
222  interference for a recently FDA-approved HRIG product.  However, if the mAb cocktails 
223  alone increase RVNA levels to 0.5 IU/mL at Day 14 and later, there could be complete 
224  interference with vaccine response, which would not be detected using this method.  In 
225  this situation, vaccine interference could be measured by assessing the proportion of 
226  subjects with RVNA levels 0.5 IU/mL at a later time point when the mAb contribution 
227  to the RVNA levels would be expected to be much less than 0.5 IU/mL. 
228   
229    Comparable Day 14 RVNA geometric mean titers for the mAb cocktail versus the HRIG 
230  groups, acknowledging that these RVNAs would be a combination of vaccine-induced 
231  RVNA and RVNA from passive immunization with mAb cocktail or HRIGBased on 
232  the pathophysiology of rabies virus infection, total RVNA at this time point would be 
233  important for rabies virus neutralization regardless of the RVNA source. 
234   
235  3.  Efficacy Considerations 
236   
237  A traditional approval can potentially be based on a multicenter clinical trial enrolling subjects 
238  with suspected rabies exposure, if those trial results are supported by evidence from the cell 
239  culture, animal model data, and healthy volunteer data described above.  Initial BLA submissions 
240  for rabies mAb cocktails could be submitted for either a second-line or a first-line indication 
241  depending on the number of subjects enrolled and the level of efficacy demonstrated, as 
242  described in more detail in section III. B.  Discussions in this guidance assume a trial to support a 
243  second-line indication would be performed first, before proceeding to a larger trial to support 
244  advancing to a first-line indication.   
245   
246  In either scenario, because diminished efficacy of rabies mAb cocktails could result in death, 
247  rabies mAb cocktail development should proceed in a stepwise fashion to minimize risk to trial 
248  subjects.  The mAbs initially chosen for cocktail development should be complementary in terms 
249  of neutralization activity and have activity against a diverse panel of rabies virus strains.  Broad 
250  coverage is particularly important for development in the United States, where rabies deaths have 
6  Contains Nonbinding Recommendations 
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251  been reported from domestic exposures (predominantly due to bat, raccoon, fox, and skunk 
252  strains) and exposures during international travel due to canine strains (Pieracci et al. 2019).  In 
253  addition, mAb choice should consider the amino acid sequence and whether any residues in the 
254  complementarity-determining regions could undergo posttranslational modifications that might 
255  affect antigen binding.  After sponsors have chosen mAbs, data should be obtained from cell 
256  culture activity studies, animal challenge studies, toxicology studies, and clinical trials in healthy 
257  volunteers not exposed to rabies virus (both with and without rabies vaccine).  These data can 
258  inform dose selection and provide support for antiviral activity and breadth of coverage.  The 
259  next step is a clinical trial of the mAb cocktail versus RIG, in combination with wound washing 
260  and a rabies vaccine series, in potentially rabies virus-exposed subjects.   
261   
262  It is not feasible to adequately power a clinical trial to demonstrate noninferiority of mAb 
263  cocktails versus RIG, both in combination with rabies vaccine and wound washing, for an 
264  endpoint of rabies-free survival.  The exact contribution of the passive immunization component 
265  of PEP is unknown but is believed to be very small compared with the contribution of wound 
266  washing and administration of a rabies vaccine.  In addition, patients presenting with WHO 
267  category III rabies virus exposures will be highly heterogenous with regard to their actual risk of 
268  developing clinical rabies in the absence of the mAb cocktail or RIG.  It is also not feasible to 
269  adequately power a clinical trial to demonstrate superiority of mAb cocktails versus RIG because 
270  PEP including RIG is nearly 100% effective.   
271   
272  Consequently, evaluation of efficacy will rely on a clinical trial demonstrating an acceptable 
273  rabies-free survival rate in subjects presenting with WHO category III rabies virus exposures in 
274  rabies-endemic countries9 who receive the mAb cocktail in place of RIG as part of PEP.  
275  However, a double-blinded, randomized, active-controlled design comparing the mAb cocktail 
276  with RIG, both in combination with wound washing and rabies vaccine, is still recommended to 
277  adequately characterize safety and to confirm comparable early RVNA levels and vaccine 
278  interference when the mAb cocktail or RIG are administered in and around the wound.  In 
279  addition, including an active control would serve as a point of reference in the event of PEP 
280  failures to better determine if the failures were due to decreased efficacy of the mAb cocktail 
281  versus unforeseen factors such as an unexpectedly low vaccine response or a novel viral strain.  
282    
283  4.  Safety Considerations 
284   
285  Generating a robust safety database from adequately blinded, well-controlled human trials in 
286  appropriate populations is important because of the wide variety of affected populations and 
287  possible exposures that would qualify for PEP.  An application for a new mAb cocktail for the 
288  passive immunization component of PEP should include safety data from at least 1,000 subjects 
 
9 For the purposes of this guidance document, rabies-endemic countries are considered to be countries in which 
rabies circulates in the dog population and dog bites are known to pose a meaningful risk of rabies transmission and 
death for humans.  Reasons for recommending that substantial proportions of clinical trials be conducted in such 
rabies-endemic countries include the following: (1) canine rabies is critically important to the total global burden of 
human rabies exposures in need of PEP and (2) assumptions and estimates regarding likelihood of human rabies 
deaths after an exposure with receipt of PEP are based mostly on experience with dog bites in rabies-endemic 
countries, so interpretation of trial results may be subject to more uncertainty of expected outcomes after other types 
of known or suspected rabies exposures. 
 
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289  who received the mAb cocktail dose proposed for marketing.  A safety database larger than 
290  1,000 subjects may be necessary if significant safety signals are identified in development.  This 
291  total can include healthy subjects from the phase 1 trials as well as potentially rabies virus-
292  exposed subjects in both rabies-endemic countries and non-rabies-endemic countries.  If the 
293  mAb cocktail is already approved in other countries, and there are postmarketing data that are 
294  well-characterized in terms of number of patients dosed, number of rabies deaths, and serious 
295  adverse events, these data may be considered for use as part of the safety database if the Agency 
296  agrees. 
297   
298  B.  Phase 3 Efficacy Trial Considerations 
299   
300  With the exception of section III. B. 9. d, the following sections describe Agency 
301  recommendations for a trial designed to support a second-line indication.   
302   
303  1.  Trial Design, Including Randomization, Stratification, and Blinding 
304   
305  The trial should be a multicenter, double-blind, randomized controlled trial of the mAb cocktail 
306  versus RIG, each in combination with thorough wound washing and rabies vaccine series, in 
307  subjects with WHO category III rabies virus exposure.  FDA recommends 1:1 randomization for 
308  the clinical trial to support licensure.  The trial should be designed such that at least 750 subjects 
309  with WHO category III exposure in rabies-endemic countries are treated with PEP including the 
310  mAb cocktail and followed for at least one year to demonstrate a rabies-free survival rate 
311  >99.5%10.  This means that the trial should enroll at least 1,500 subjects with WHO category III 
312  exposure in rabies-endemic countries, with additional enrollment in non-rabies-endemic 
313  countries for an adequate safety evaluation. 
314   
315  Stratification should be considered for factors influencing the risk of rabies development, such as 
316  the time interval between exposure and randomization ( or >24 hours), the location of the bite 
317  or bites (above versus below the neck), and the number of bites.  Sponsors should carefully 
318  document all components of PEP for all enrolled cases.  If any subject develops rabies, review of 
319  the PEP administration for that case should be conducted and documented in a blinded fashion 
320  by experts unaware of the subjects treatment assignment. 
321   
322  2.  Trial Population and Location 
323   
324  To draw conclusions about mAb cocktail efficacy from clinical trial survival results, the trial 
325  should predominantly enroll subjects in rabies-endemic countries.  When a patient presents for 
326  rabies PEP, it is generally not known whether the exposure was from a rabid animal.  This is also 
327  expected to be the case in a clinical trial.  The likelihood that the exposure was from a rabid 
328  animal varies widely by location, with the risk being much higher in rabies-endemic countries.  
329  FDA prefers that the trial enroll subjects in several rabies-endemic countries with different 
330  endemic rabies virus strains.  However, FDA encourages sponsors to include some trial sites in 
 
10 The 2019 advisory committee concurred that approval based on lack of rabies mortality in a trial that randomizes 
at least 750 subjects to receive the mAb cocktail as part of PEP would be sufficient for a second-line indication in 
situations where HRIG is not available because survival with PEP including RIG is estimated to be >99.9%.   
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331  the United States and other non-rabies-endemic countries to allow for safety evaluation in a 
332  broad population. 
333   
334  The trial should start by enrolling adults with wounds considered lower risk for rabies 
335  development in the absence of RIG (such as wounds in the lower extremities).  Adolescents (for 
336  the purposes of this guidance, defined as pediatric subjects 12 years and older) may be included 
337  with adults from trial initiation, particularly if enrollment occurs at sites where RIG is otherwise 
338  not available.  If a prespecified interim analysis finds no reason to stop the trial, the trial should 
339  be expanded to enroll subjects with higher risk WHO category III exposures.  The trial should 
340  also be expanded to include pediatric subjects younger than adolescents (i.e., less than 12 years 
341  old) after the prespecified interim analysis, as approximately 40% of rabies cases occur in 
342  children (WHO 2018).  Available data can be leveraged for initial pediatric dosing, with 
343  pharmacokinetic and RVNA sampling in the initial pediatric cohort for dose confirmation.  
344  Sponsors are encouraged to engage in early discussions with the Agency about the appropriate 
345  time for including pediatric clinical trial subjects depending on available information from their 
346  development program.11 
347   
348  Enrolling a variety of subjects of different races, ethnicities, sex, and ages and with different 
349  comorbidities is particularly important for a trial evaluating mAb cocktails for rabies PEP 
350  because rabies PEP is needed by every segment of the population exposed to a rabid animal.  In 
351  addition, host factors such as age or genetic variations could influence the response to the rabies 
352  vaccine and by extension vaccine interference.   
353   
354  3.  Entry Criteria  
355   
356  Promptly administering PEP is critical for reducing the risk of clinical rabies disease.  
357  Consequently, trial entry criteria should be limited to factors that can be assessed in a short 
358  period of time (less than one hour).  Entry criteria should clearly define the types of exposures, 
359  including the allowable animals causing the exposure.  Baseline factors that are considered 
360  important but which cannot be ascertained in this short time frame, such as evidence of previous 
361  rabies vaccine administration, can be used to exclude subjects from the intention-to-treat (ITT) 
362  population if clearly defined in the protocol. 
363   
364  Passive immunization with RIG or a mAb cocktail may provide the most added benefit in 
365  subjects who present later after exposure.  Consequently, rabies-free survival in these subjects 
366  would best support the efficacy of the mAb cocktail, but enrollment of these subjects would be 
367  associated with the most risk if the mAb cocktail is less effective than RIG.  It would be 
368  reasonable to limit trial entry to subjects who present within two to three days of rabies virus 
369  exposure to balance the risk of treatment delay with the need for informative rabies-free survival 
370  data. 
371   
372   
373   
 
11 FDA regulations at 21 CFR Part 50, subpart D, contain additional safeguards for children enrolled in clinical 
investigations.  Clinical investigations involving greater than minimal risk but presenting the prospect of direct 
benefit to individual subjects may involve children as set forth in 21 CFR 50.52.  
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374  4.  Dose Selection 
375   
376  Sponsors should select the dose for the phase 3 trial based on data from the nonclinical studies 
377  and the phase 1 trials in healthy volunteers.  The selected dose should be high enough that it 
378  provides comparable breadth of neutralizing activity to HRIG in cell culture activity studies, 
379  similar reductions in mortality to HRIG in animal challenge studies, similar or higher RVNA 
380  levels through Day 14 compared with HRIG in phase 1 clinical trials without vaccine, and 
381  comparable early RVNA levels (up to Day 7) compared with HRIG in phase 1 clinical trials with 
382  vaccine.  However, the selected dose should be low enough that it provides similar or lower 
383  levels of vaccine interference to HRIG in the phase 1 clinical trials with vaccine. 
384   
385  5.  Use of Active Comparators  
386   
387  For approval considerations in the United States, because mAb cocktails may be used in place of 
388  HRIG, sponsors should use HRIG as the comparator in enough subjects to allow for a sufficient 
389  safety comparison.  However, in trials in rabies-endemic countries, comparisons evaluating 
390  rabies-free survival could be done using either HRIG or ERIG as the active comparator.  The 
391  choice of comparator at different study sites should consider local standard of care as well as 
392  input from local regulatory authorities and stakeholders.  Sponsors are encouraged to discuss the 
393  choice of active comparator at different study sites with the Agency early in the planning stages 
394  of clinical trials. 
395   
396  6.  Efficacy Endpoints 
397   
398  The following endpoints are recommended as evidence of efficacy: 
399   
400  1.  Comparable RVNA levels for the mAb cocktail versus RIG recipients at early time points 
401  (up to 7 days), before RVNAs produced by vaccine predominate. 
402   
403  2.  Comparable vaccine interference for the mAb cocktail versus RIG recipients.  Vaccine 
404  interference can be assessed by the proportion of subjects who develop vaccine-induced 
405  RVNAs 0.5 IU/mL, the threshold used by WHO as a measure of adequate vaccine 
406  response.  
407   
408  i.  For mAb cocktail products that lead to RVNA levels much lower than 0.5 IU/mL 
409  when administered alone, vaccine interference can be measured at Day 14 or Day 28. 
410   
411  ii.  For mAb cocktail products that result in RVNA levels close to or above 0.5 IU/mL 
412  when administered alone, vaccine interference should be measured at later time points 
413  when the mAb cocktails contribution to the RVNA levels are expected to be much 
414  less than 0.5 IU/mL (after five half-lives). 
415   
416  3.  Absence of rabies mortality through at least one year after PEP initiation.  The 
417  occurrence of one or more rabies deaths would raise significant review concerns. 
418   
419   
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420  7.  Trial Procedures and Timing of Assessments 
421   
422  The trial should follow subjects for at least one year to monitor for rabies deaths.  Descriptive 
423  details about the exposure should be recorded and should include whether the bite was provoked, 
424  the number of bites, location and depth of the bites (including pictures of the bites), the time 
425  interval between the exposure and PEP initiation, and the species or type of animal involved in 
426  the exposure.  Sponsors should make reasonable efforts to ascertain and record the rabies status 
427  of the animal involved in the exposure, as this data is critical to analysis of benefit.  In addition, 
428  sponsors should prospectively assess whether PEP was administered promptly and correctly and 
429  record this at the time PEP is administered.   
430   
431  8.  Endpoint Adjudication 
432   
433  The trial should include a plan for a thorough, unbiased, blinded adjudication of any deaths.   
434   
435  9.  Statistical Considerations 
436   
437  For considerations regarding statistical analysis methods, sponsors should refer to the FDA 
438  guidance for industry Providing Clinical Evidence of Effectiveness for Human Drug and 
439  Biological Products (May 1998).  
440   
441  a.  Analysis populations 
442   
443  In general, the primary efficacy analysis should include all subjects who are randomized and 
444  receive any part of the assigned therapy during the trial.  However, if subjects are excluded from 
445  the ITT population based on previous rabies vaccine administration or other baseline factors that 
446  could not be ascertained during screening, a modified ITT population can be considered for the 
447  primary efficacy analysis.  Sponsors can use a per-protocol population, which may be affected by 
448  post-randomization exclusions, as a secondary efficacy population.  
449   
450  b.  Efficacy analyses 
451   
452  The preferred co-primary endpoints for the phase 3 trial are described above in section III. B. 6.  
453  The following are recommendations for analyzing the primary efficacy endpoints: 
454   
455    For early RVNA levels, sponsors should justify criteria for comparability and choice of 
456  specific time points before trial initiation. 
457   
458    For vaccine interference, a noninferiority margin of at most 10%12 for the proportion of 
459  subjects with RVNA levels 0.5 IU/mL is generally clinically acceptable.  However, 
 
12 Studies of vaccine response after PEP regimens containing HRIG plus vaccine show a very high proportion of 
subjects with RVNA levels 0.5 IU/mL at Day 14.  For example, in the efficacy analysis population of a study in 
which 116 subjects were randomized to receive one of two HRIG products plus vaccine, all 59 subjects who 
received the first HRIG product had RVNA 0.5 IU/mL at Day 14 (100%, exact 95% CI 93.9-100%); 56/57 
receiving the second HRIG product had RVNA 0.5 IU/mL at Day 14 (98.2%, exact 95% CI 90.6-100%) (Matson 
et al. 2020). 
 
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460  sponsors should discuss their choice of noninferiority margin with the Agency before trial 
461  initiation. 
462   
463    A BLA submission for a second-line indication should be supported by a clinical trial 
464  demonstrating >99.5% rabies-free survival among subjects with WHO category III 
465  exposure in rabies-endemic countries treated with the mAb cocktail as part of PEP 13.  
466  This means the lower bound of the 95% confidence interval for the rabies-free survival 
467  would be >99.5% (using the Clopper-Pearson method).  A threshold of rabies-free 
468  survival of >99.5% was chosen because it is higher than the ~99% estimated rabies-free 
469  survival with wound washing and rabies vaccine alone (without RIG) but would not 
470  require trial sizes that may be prohibitively large.   
471   
472    Sponsors should perform the primary efficacy endpoints analyses within important 
473  subgroups based on demographic and baseline characteristics (e.g., sex, race, age, renal 
474  impairment, hepatic impairment, time interval between exposure and randomization (24 
475  hours or >24 hours), the location of the bite or bites (above versus below the neck), and 
476  the number of bites).  The purpose of these analyses is to explore the consistency of the 
477  primary efficacy endpoint results across these subgroups.  
478   
479  c.  Handling of missing data 
480   
481  Sponsors should make every attempt to limit discontinuation of subjects from the trial.  When the 
482  loss is unavoidable, sponsors should explain the causes of missing data and attempt to determine 
483  the final status of a subject who does not complete the protocol.  Analyses excluding subjects 
484  with missing data or other posttreatment outcomes can be biased because subjects who do not 
485  complete the trial may differ substantially in both measured and unmeasured ways compared 
486  with subjects who remain in the trial.  The primary method of handling missing data in the 
487  analysis should be prespecified in the protocol or the statistical analysis plan.  Sensitivity 
488  analyses should demonstrate that the primary analysis results are robust to the assumptions 
489  regarding missing data.   
490   
491  d.  Statistical considerations for a trial to support a first-line indication 
492   
493  To expand from a second-line to a first-line indication, applicants may conduct an additional 
494  clinical trial or may potentially use pooled data from several trials, data available from other 
495  countries in which the mAb cocktail was previously approved, or information from a registry 
496  after discussion with the Agency.  As previously discussed in section III. A. 3., data from a 
497  clinical trial supporting a first-line indication can be submitted either in a supplemental BLA 
498  after initial approval or in the original BLA.  This trial should include data from at least 6,000 
499  subjects receiving the mAb cocktail as part of PEP after WHO category III rabies virus exposure 
500  in rabies-endemic countries.  Because survival with PEP including RIG is estimated to be 
501  >99.9%, expanding to a first-line indication would require submission of additional clinical data 
502  demonstrating >99.9% rabies-free survival among subjects with WHO category III exposure in 
 
13 This guidance assumes a single multicenter trial would be conducted, but applicants may also potentially use 
pooled data from several trials if the total number of subjects meets the described requirements. 
 
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503  rabies-endemic countries treated with the mAb cocktail as part of PEP. If the true rabies-free 
504  survival rate of PEP containing the mAb cocktail is 99.99%, enrollment of at least 6,000 subjects 
505  provides at least 80% power to demonstrate a survival rate >99.9%.  
506   
507  The trial to support a first-line indication should be a randomized controlled trial to make the 
508  efficacy data more interpretable and to allow for a comparative safety evaluation.  Trial 
509  randomization should be preferably 3:1 (enrolling 8,000 subjects total), or at most no greater 
510  than a 6:1 ratio (enrolling 7,000 subjects total), of mAb cocktail versus the RIG comparator, both 
511  in combination with wound washing and vaccine.  The primary endpoint for a trial to expand 
512  from a second-line to a first-line indication should be rabies-free survival through at least one 
513  year after PEP initiation14.  The lower bound of the 95% confidence interval (using the Clopper-
514  Pearson method) for rabies-free survival will be used to evaluate whether the survival rate is 
515  >99.9%.   
516   
517  10.  Risk-Benefit Considerations 
518   
519  The benefit of a mAb cocktail for use in place of RIG is different in the United States than in 
520  rabies-endemic countries where RIG is not readily available.  In the United States, except for 
521  several brief shortages, HRIG has been readily available.  HRIG is believed to be highly 
522  effective and has an excellent safety profile.  Consequently, for FDA approval, a mAb cocktail 
523  should have a safety profile similar to HRIGs as well as efficacy similar to HRIGs.  In addition 
524  to an imbalance in rabies-free survival, any nonclinical or clinical data for the mAb cocktail that 
525  suggest new safety signals or issues that could decrease efficacy compared with HRIG could 
526  result in an unfavorable benefit-risk assessment.  Issues that could decrease efficacy include but 
527  are not limited to a shorter half-life or lower peak RVNA levels from the mAb cocktail alone that 
528  might result in a gap in RVNA coverage before the vaccine response manifests, higher rates of 
529  vaccine interference, or cell culture studies indicating decreased coverage of different rabies 
530  virus strains. 
531   
532  C.  Other Considerations 
533   
534  1.  Nonclinical Safety Considerations 
535   
536  The nonclinical safety assessment for the development of anti-rabies virus mAb cocktails should 
537  follow approaches outlined in the ICH guidance for industry S6(R1) Preclinical Safety Evaluation 
538  of Biotechnology-Derived Pharmaceuticals (May 2012).  
539   
540  For mAbs directed against rabies virus, sponsors can conduct toxicology studies in one species, 
541  as specified in ICH S6(R1).  For species selection for the nonclinical safety assessment, ICH 
542  S6(R1) notes that tissue cross reactivity (TCR) studies employing immunohistochemical 
543  techniques can be used by comparing tissue binding profiles between human and animal tissues 
544  when a pharmacologically relevant species cannot be identified by other approaches.  FDA 
545  recommends conducting a good laboratory practice compliant TCR study using a panel of 32 
 
14 If an applicant wishes to submit a BLA with data supporting a first-line indication without first submitting data to 
support a second-line indication, FDA recommends contacting the Agency early in development to discuss specifics 
of clinical trial design. 
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546  human tissues.  For the list of tissues and detailed technical information about 
547  immunohistochemistry studies, sponsors should refer to the guidance for industry Points to 
548  Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use 
549  (February 1997).  Sponsors should also consider alternative technologies, such as those 
550  employing protein microarrays, to evaluate off-target binding, but these technologies cannot 
551  replace the TCR study using immunohistochemical techniques unless appropriately justified.  
552  Although mAbs could be evaluated separately, it is typically sufficient to conduct the TCR study 
553  with the mAb cocktail at the intended clinical ratio. 
554   
555  If no off-target binding of significant clinical concern is observed in the TCR and/or alternative 
556  studies using human tissues/proteins (e.g., no or only minimal cytoplasmic binding observed), 
557  then conducting a short duration repeat-dose toxicology study (e.g., 3 week) in a single species 
558  should be sufficient.  Although rats have typically been used in this scenario, sponsors can select 
559  the species of their choice with justification.  Alternatively, if the mAbs bind to human tissues in 
560  the TCR study, sponsors should evaluate mAb binding to tissues from the nonclinical species to 
561  be used for toxicology testing.  As stated in ICH S6(R1), evaluating select animal tissues can 
562  also provide information on the extrapolation of toxicity observed.  Sponsors should conduct a 
563  TCR study using select tissues from several candidate species and include animal tissues that 
564  correspond to those where human tissue binding was observed.  Typically, sponsors can select a 
565  single species for toxicology testing in this scenario.  Although sponsors can select any animal 
566  species that demonstrates similar binding to that seen in human tissues, FDA strongly 
567  recommends that sponsors discuss species selection with the Agency to facilitate a final 
568  determination before initiating the toxicology study.  The amount of clinical concern of any off-
569  target human tissue/protein binding is determined on a case-by-case basis.  When binding of 
570  potential clinical concern is observed (e.g., cell membrane binding), the Agency may recommend 
571  additional studies to help inform the potential clinical relevance of the findings. 
572   
573  The design of the repeat-dose toxicology study should follow existing guidance found in ICH 
574  S6(R1).  For rabies mAbs, sponsors should consider the following: 
575   
576    A good laboratory practice compliant repeat-dose toxicology study of at least 3 weeks in 
577  duration (i.e., 3 weeks of treatment) that includes all standard toxicity endpoints 
578  including toxicokinetic analysis is recommended. 
579   
580    Including a recovery group with a treatment-free period of approximately 5 half-lives 
581  following the last mAb administration is recommended. 
582   
583    The route of administration in the toxicology studies should be the same as that planned 
584  for clinical trials in healthy subjects, typically intramuscular. 
585   
586    Dose selection should be justified according to ICH S6(R1) (i.e., the high dose should 
587  provide product exposure approximately 10 times greater than the maximal anticipated 
588  clinical exposure). 
589   
590    The same ratio of rabies mAbs selected for clinical administration should typically be 
591  administered in the toxicology study. 
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592   
593    The drug substance or substances used in the toxicology study (i.e., toxicology lot 
594  material) should be sufficiently representative of the good manufacturing practice-grade 
595  clinical material. 
596   
597    The intended clinical formulation should be administered in the toxicology study. 
598   
599    As discussed in ICH S6(R1), measurement of anti-drug antibodies should be conducted 
600  as specified.  Sponsors should collect appropriate samples during the study (e.g., at the 
601  end of both the treatment and the recovery periods) for possible anti-drug antibody 
602  analysis to help interpret the toxicology study results. 
603   
604    Local tolerance assessments should be included as part of the repeat-dose toxicology 
605  study. 
606   
607  Chronic repeat-dose, genotoxicity, and carcinogenicity studies are not necessary.  To inform 
608  potential reproductive and developmental effects, sponsors should conduct a TCR study using 
609  human fetal tissues or studies using alternative protein interaction technologies, with appropriate 
610  justification.  If no specific concerns are identified in the repeat-dose toxicology and TCR 
611  studies, developmental and reproductive toxicology studies are not necessary.  
612   
613  ICH S6(R1) states that, when animal models of disease are used to evaluate proof of principle, 
614  safety assessments can be included in the evaluation to provide information on potential target-
615  associated safety aspects.  Thus, FDA encourages sponsors to collect safety information of rabies 
616  mAbs in the animal challenge studies, as feasible.    
617   
618  2.  Chemistry, Manufacturing, and Controls Considerations 
619   
620  Sponsors should develop cocktails of at least two monoclonal antibodies that recognize distinct, 
621  nonoverlapping conserved epitopes of rabies virus glycoprotein.  All mAbs in the cocktail should 
622  be broadly neutralizing against rabies virus strains from multiple animal species and from 
623  multiple locations (see section III. A. 1. a.).  Combining the individual mAbs to make the 
624  cocktail may occur either at the formulated drug substance step in manufacturing or during drug 
625  product manufacturing. 
626   
627  a.  Candidate selection 
628   
629  During the candidate selection stage of development, FDA recommends that sponsors assess the 
630  variable (V) region amino acid sequences of the mAb candidates for potential sites of 
631  posttranslational modifications that could affect binding to the antigen.  Such posttranslational 
632  modifications include but are not limited to deamidation, oxidation, V-region glycosylation or 
633  glycation.  If any final candidates have amino acid residues prone to a posttranslational 
634  modification that could result in reduced potency of the product, these primary amino acid 
635  sequences should be engineered out of the sequence, provided that the amino acid is not crucial 
636  for binding specificity.  If the specific amino acid residue is crucial for activity of the mAb, 
637  formulation and forced degradation studies should be performed early in development to 
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638  determine levels of the posttranslational modification that may be present without a reduction in 
639  potency. 
640   
641  b.  Control strategy: potency assays 
642   
643  Potency for individual mAb drug substances and the mAb cocktail (either formulated drug 
644  substance or drug product) typically include a Binding enzyme-linked immunosorbent assay 
645  (ELISA) and a rapid fluorescent focus inhibition test (RFFIT).  Potency results for the Binding 
646  ELISAs are reported as a percentage of the reference standard.  Potency results for the RFFIT 
647  assay are typically reported as IU per mL.  For the RFFIT assay, the reference standard should be 
648  an international standard, such as the WHO International Standard Anti-Rabies Immunoglobulin, 
649  also known as SRIG, or the U.S. Standard Rabies Immunoglobulin.  Alternatively, an in-house 
650  reference standard may be qualified against one of the international reference standards.  
651  Sponsors should justify how the RFFIT potency results are reported and the chosen reference 
652  standard.  Potency of the individual mAbs based on the RFFIT assay should be considered when 
653  determining the ratio for combining the mAbs.  The advantage of using an international 
654  reference standard is that the potency of each mAb can be determined relative to the same 
655  standard.  
656   
657  c.  Control strategy: ratio of mAbs in cocktail 
658   
659  The ratio of the individual mAbs in the cocktail may be based on mass or potency.  Each mAb in 
660  the cocktail may have different potency in the RFFIT assay, which may be more apparent when 
661  using an international reference standard.  Sponsors should justify the ratio and develop an assay 
662  that can demonstrate lot-to-lot consistency.  
663   
664  3.  Labeling Considerations 
665   
666  To support the approval of a mAb cocktail as the passive component of PEP for the prevention 
667  of rabies, sponsors should demonstrate that the mAb cocktail has neutralizing activity equal to or 
668  superior to HRIG against a breadth of rabies virus strains found in the United States (bat, fox, 
669  skunk, and raccoon strains) and from international exposures in returning travelers (primarily 
670  dog strains).  FDA does not recommend limiting the indication to only a subset of rabies virus 
671  strains because the rabies virus strain would not be known at the time PEP is administered, and 
672  the species of animal that bites a patient will not necessarily correlate with the lineage of the 
673  rabies virus strain (Ma et al. 2018). 
674   
675  4.  Postmarketing Considerations 
676   
677  A plan should exist to monitor for rabies deaths as well as safety concerns that may emerge with 
678  use of the mAb cocktail in the postmarketing setting.  In addition, sponsors should have a plan 
679  and infrastructure to surveil new rabies virus strains and assess activity of the mAb cocktail 
680  against these new strains, which should be discussed with the Agency during product 
681  development. 
682     
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683  REFERENCES 
684   
685  Baltazard, M and M Bahmanyar, 1955, Field Trials with Rabies Vaccine on Persons Bitten by 
686  Rabid Wolves, Bull World Health Organ, 13:747772. 
687   
688  Hampson, K, L Coudeville, T Lembo, M Sambo, A Kieffer, M Attlan, J Barrat, JD Blanton, DJ 
689  Briggs, S Cleaveland, P Costa, CM Freuling, E Hiby, L Knopf, F Leanes, FX Meslin, A Metlin, 
690  ME Miranda, T Muller, LH Nel, S Recuenco, CE Rupprecht, C Schumacher, L Taylor, MAN 
691  Vigilato, J Zinsstag, and J Dushoff, 2015, Estimating the Global Burden of Endemic Canine 
692  Rabies, PLoS Negl Trop Dis, 9(4), e0003709. 
693   
694  Ma, X, BP Monroe, JM Cleaton, LA Orciari, P Yager, Y Li, JD Kirby, JD Blanton, BW 
695  Petersen, and RM Wallace, 2018, Rabies Surveillance in the United States During 2016, J Am 
696  Vet Med Assoc, 252(8):945957. 
697   
698  Matson MA, E Schenker, M Stein, V Zamfirova, HB Nguyen, and GE Bergman, 2020, Safety 
699  and Efficacy Results of Simulated Post-Exposure Prophylaxis with Human Immune Globulin 
700  (HRIG; KEDRAB) Co-Administered with Active Vaccine in Healthy Subjects: A Comparative 
701  Phase 2/3 trial, Hum Vaccin Immunother, 16(2):452459. 
702   
703  Pieracci, EG, CM Pearson, RM Wallace, JD Blanton, ER Whitehouse, X Ma, K Stauffer, RB 
704  Chipman, and V Olson, 2019, Vital Signs: Trends in Human Rabies Deaths and Exposures
705  United States, 19382018, MMWR Morb Mortal Wkly Rep, 68(23):524528. 
706   
707  WHO, 2013, WHO Expert Consultation on Rabies: Second Report, World Health Organ Tech 
708  Rep Ser, 1139. 
709   
710  WHO, 2018, Rabies Vaccines: WHO Position Paper-April 2018, 2018, Wkly Epidemiol Rec, 93, 
711  201220. 
712   
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