Clostridioides difficile 
Infection: Developing Drugs 
for Treatment, Reduction of 
Recurrence, and Prevention 
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DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 https://www.regulations.gov.  Submit written 
comments to the Dockets Management Staff (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 Ramya Gopinath at 240-402-5328.  
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
October 2022 
Clinical/Antimicrobial 
48983672dft.docx 
10/04/22   
Clostridioides difficile 
Infection: Developing Drugs 
for Treatment, Reduction of 
Recurrence, and Prevention 
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)  
 
October 2022 
Clinical/Antimicrobial 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  DEVELOPMENT PROGRAM ....................................................................................... 2 
A.  Trial Populations ............................................................................................................................ 2 
B.  Trial Design .................................................................................................................................... 3 
C.  Efficacy Considerations ................................................................................................................. 4 
1. Efficacy Assessments ........................................................................................................................ 4 
2. Statistical Considerations ................................................................................................................ 5 
D.  Safety Considerations .................................................................................................................... 5 
E.  Other Considerations ..................................................................................................................... 6 
APPENDIX .................................................................................................................................... 8 
 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Clostridioides difficile Infection: Developing Drugs  
2  for Treatment, Reduction of Recurrence, and Prevention 
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  This guidance outlines the Food and Drug Administrations (FDAs) current thinking regarding 
18  the clinical development of drugs2 to support an indication of treatment,3 reduction of 
19  recurrence,4 or prevention5 of Clostridioides difficile infection (CDI).6   
20   
21  CDI is a toxin-mediated disease caused by Clostridioides difficile (C. difficile), an anaerobic, 
22  gram-positive, spore-forming bacterium that produces two pathogenic enterotoxins, Toxin A 
23  (TcdA) and Toxin B (TcdB). Some C. difficile strains (e.g., 027/BI/NAP1) produce a third toxin 
24  called binary toxin, which has been associated with increased production of TcdA and TcdB and 
25  more severe CDI.  
26   
 
1 This guidance has been prepared by the Division of Anti-Infectives in the Center for Drug Evaluation and 
Research (CDER) at the Food and Drug Administration.  
 
2 In this guidance, the term drugs includes both small molecule drugs and therapeutic biological products regulated 
by CDER unless otherwise specified. This guidance does not apply to certain biological products such as fecal 
microbiota transplantation products, probiotics, and vaccines. 
 
3 In this guidance, treatment of Clostridioides difficile (C. difficile) infection (CDI) refers to treatment of an acute 
episode of CDI defined as greater than or equal to three unformed stools or greater than or equal to 200 milliliters 
(mL) of unformed stool (in subjects with a stool collection device) in a less than or equal to 24-hour period, 
associated with a stool test positive for C. difficile TcdA or TcdB using an accepted and prespecified testing method.  
 
4 Reduction of recurrence refers to reducing the risk of a subsequent CDI episode in subjects immediately after 
resolution of an episode of CDI.  
 
5 In this guidance, prevention refers to prevention of CDI in subjects with or without a history of CDI who are at risk 
for CDI (e.g., subjects on antibacterial therapy in the context of other predisposing factors such as increased age or 
immunosuppression). For subjects with a history of CDI, the sponsor should discuss with FDA the time between 
resolution of the previous episode and enrollment in a prevention trial. 
 
6 In this guidance, CDI includes symptomatic disease, not asymptomatic carriage. Sponsors that want to include 
study populations with asymptomatic carriage of Clostridioides difficile should consult with FDA. 
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27  Clinical manifestations of CDI may range from self-limited to unremitting diarrhea to colitis 
28  accompanied by features of systemic inflammatory response (e.g., fever, hypotension, 
29  tachycardia) to severe manifestations like toxic megacolon, intestinal perforation, septic shock, 
30  and death. Following resolution of the first episode, CDI recurs in 15 to 40 percent of patients 
31  with further recurrences occurring in an even higher proportion of those patients.7  
32   
33  Because clinical manifestations of CDI may not be limited to diarrhea alone, and in keeping with 
34  current terminology in treatment guidelines and literature, the term CDI rather than 
35  Clostridioides difficile-associated diarrhea is used in this guidance. 
36   
37  Because the design of clinical trials for CDI will depend on the goal of treatment, this guidance 
38  addresses the development of small molecule drugs and therapeutic biological products for the 
39  following indications: 
40   
41    Treatment of CDI 
42   
43    Reduction of recurrence8 of CDI following resolution9 of a CDI episode after treatment 
44  with a standard of care (SOC) regimen 
45   
46    Treatment of CDI and reduction of recurrence 
47   
48    Prevention of CDI in patients at risk5 
49   
50  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
51  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
52  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
53  the word should in Agency guidances means that something is suggested or recommended, but 
54  not required. 
55   
56   
57  II.  DEVELOPMENT PROGRAM 
58   
59  A.  Trial Populations 
60   
61  Sponsors developing drugs for CDI indications should consider enrolling the following clinical 
62  trial populations: 
63   
64    Trials for treatment: Subjects with CDI.7 
 
7 McFarland LV, Elmer GW, and Surawicz CM, 2002, Breaking the Cycle: Treatment Strategies for 163 Cases of 
Recurrent Clostridium Difficile Disease, Am J Gastroenterol, 97(7):176975. 
 
8 See footnote 4. Sponsors that want to include subjects with multiple recurrences following resolution of a CDI 
episode with SOC treatment should discuss this with FDA before trial enrollment.  
 
9 In this guidance, resolution of CDI is defined as less than three unformed stools or less than 200 mL of unformed 
stool (for subjects with a stool collection device) in a 24-hour period. 
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65   
66    Trials for treatment and reduction of recurrence: Subjects with CDI. 
67   
68    Trials for reduction of recurrence only: Subjects immediately after resolution of a CDI 
69  episode with an SOC regimen.   
70   
71    Trials for prevention: Subjects at risk of developing CDI5 
72   
73    Trials for all CDI indications should include older adults and immunosuppressed subjects 
74  and those with varying severity of illness, comorbidities, and concomitant medications, 
75  including antibacterial drugs and proton-pump inhibitors, among others. The 
76  representation of polymerase chain reaction (PCR) ribotypes in the trial population 
77  should reflect current CDI epidemiology. 
78   
79  B.  Trial Design 
80   
81  Sponsors developing drugs for CDI indications should consider the following clinical trial 
82  designs: 
83   
84    Trials should be randomized, double-blinded, and controlled.  
85   
86    Sponsors should use an active control in trials for CDI treatment and treatment and 
87  reduction of recurrence. Sponsors can use a placebo or active control in trials for 
88  prevention or reduction of recurrence only.   
89   
90    In trials for treatment and reduction of recurrence, the initial CDI episode should be 
91  treated with the investigational or comparator drug. In trials for reduction of recurrence 
92  only, the investigational and comparator drug (active or placebo) should be started as 
93  soon as possible after resolution of the initial CDI episode with an SOC regimen.  
94   
95    A noninferiority (NI) or superiority finding of the investigational drug to SOC is 
96  acceptable to support approval of a drug for treatment of CDI. FDA prefers a showing of 
97  superiority for drugs developed for treatment and reduction of recurrence, and reduction 
98  of recurrence only, unless the sponsor can justify an NI margin for these trials. As there 
99  are currently no suitable active comparators for CDI prevention trials, superiority trials 
100  are most appropriate for drugs developed for prevention of CDI.   
101   
102    The timing of assessments should be the same for all subjects defined based on a fixed 
103  timepoint from randomization. FDA recommends the following time point definitions: 
104   
105   End of treatment (EOT): the final day of the planned duration of therapy (or 
106  planned duration of the longest therapy if the treatment arms are not of the same 
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107  duration) timed from randomization. In general, the duration of therapy should be no 
108  more than 14 days.10  
109   
110   Test of cure (TOC): 2 days after the end of the planned duration of therapy (i.e., 2 
111  days after EOT). 
112   
113   Late follow-up (LFU): a fixed time point at least 4 weeks after the end of the 
114  planned duration of treatment (e.g., this would be at least 6 weeks after randomization 
115  for a 14-day planned duration of therapy). 
116   
117  C.  Efficacy Considerations 
118   
119  1.  Efficacy Assessments 
120   
121  Sponsors developing drugs for CDI indications should consider the following regarding a drugs 
122  efficacy: 
123   
124    In general, two adequate and well-controlled trials are needed to support the effectiveness 
125  of the investigational drug.11 One trial demonstrating evidence of efficacy for treatment 
126  alone and another trial for reduction of recurrence or for prevention of CDI alone may 
127  support two indications. If treatment and reduction of recurrence are evaluated in the 
128  same trial, two adequate and well-controlled trials would be needed.  
129   
130    In trials for treatment of CDI, the primary efficacy endpoint should be survival and 
131  resolution of diarrhea while on the randomized study treatment that is sustained after the 
132  EOT through the TOC visit without a requirement for additional CDI treatment. Sponsors 
133  can also consider sustained clinical response12 as an important secondary endpoint for 
134  trials for CDI treatment only. 
135   
136    In trials for treatment and reduction of recurrence, the sponsor should assess two 
137  coprimary endpoints that include the efficacy of treatment of CDI at TOC and sustained 
138  clinical response as described above.  
139   
140    In trials for reduction of CDI recurrence only, sponsors should define the primary 
141  efficacy endpoint as survival without recurrent CDI or requirement for additional CDI 
 
10 Sponsors proposing a drug regimen requiring more than 14 days of treatment to resolve CDI should discuss this 
with FDA before trial enrollment because the proposed NI margin may not be applicable. 
 
11 See the guidances for industry Providing Clinical Evidence of Effectiveness for Human Drug and Biological 
Products (May 1998) and Integrated Summary of Effectiveness (October 2015) and the draft guidance for industry 
Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products (December 2019). 
When final, this guidance will represent the FDAs current thinking on this topic. 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.  
 
12 Sustained clinical response is defined as being a success at TOC and survival without recurrent CDI or additional 
CDI treatment for at least 4 weeks after the EOT visit. 
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142  treatment for at least 4 weeks after the EOT. In trials for CDI prevention, the primary 
143  efficacy endpoint should be the occurrence of an episode of CDI within a predefined trial 
144  period. The sponsor should discuss with FDA the duration of the prevention trial and 
145  approaches to handling deaths in the efficacy analyses (see section II., C., 2. Statistical 
146  Considerations).  
147   
148    Subjects in CDI prevention, treatment, or treatment and reduction of recurrence trials 
149  should not receive oral or rectal vancomycin, intravenous or oral metronidazole, 
150  fidaxomicin, rifaximin, tigecycline, nitazoxanide, or fusidic acid for more than 24 hours 
151  before randomization. Sponsors should discuss with FDA the inclusion of subjects with a 
152  history of fecal transplantation or bezlotoxumab use.  
153   
154    Sponsors should discuss with FDA the use of patient-reported outcome measures in 
155  clinical trials for CDI. 
156   
157  2.  Statistical Considerations 
158   
159  FDA recommends the following statistical considerations for sponsors developing drugs for CDI 
160  indications: 
161   
162    An NI margin of 10 percent for the primary efficacy endpoint for clinical response in 
163  trials for CDI treatment with vancomycin as the active comparator is supported by 
164  historical evidence (see the Appendix). For CDI treatment trials using an active 
165  comparator other than vancomycin, the sponsor should provide additional justification of 
166  an NI margin.  
167   
168    If an NI trial is proposed for drugs developed for reduction of CDI recurrence, the 
169  sponsor should provide justification of an NI margin.  
170   
171    For CDI prevention trials, the statistical analysis plan should specify the approaches for 
172  handling deaths, which is considered an intercurrent event. Depending on the trial 
173  population (e.g., hematopoietic stem cell recipients), the number of deaths from 
174  underlying comorbidities may be greater than the rate of CDI and could complicate the 
175  interpretation of trial results, especially if there are differences between treatment groups 
176  in occurrence of death unrelated to CDI or death overall.   
177   
178  D.  Safety Considerations 
179   
180  Sponsors developing drugs for CDI indications should consider the following: 
181   
182    For drugs developed for CDI treatment and/or reduction of recurrence, the marketing 
183  application (new drug application or biologics license application) safety database should 
184  include at least 300 subjects exposed to the proposed investigational drug treatment dose 
185  and duration.   
186   
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187    Clinical programs for drugs developed solely for prevention of CDI may require a larger 
188  safety database. Sponsors should discuss the appropriate size of the premarket safety 
189  database with FDA during clinical development.  
190   
191  E.  Other Considerations 
192   
193  FDA recommends the following additional considerations for sponsors developing drugs for the 
194  treatment, treatment and reduction of recurrence, reduction of recurrence only, or prevention of 
195  CDI: 
196   
197  Relevant Nonclinical Safety Considerations 
198   
199    Sponsors of drugs developed for CDI indications should test the investigational drug in 
200  vitro and in animal models13 for general toxicity before submitting an initial 
201  investigational new drug application (IND). For recommendations on the types, duration, 
202  and timing of nonclinical studies needed to support clinical trials, see the International 
203  Council for Harmonisation guidance for industry M3(R2) Nonclinical Safety Studies for 
204  the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals 
205  (January 2010).  
206   
207    Because patients with CDI may have increased oral drug absorption due to disruption of 
208  the intestinal barrier, FDA recommends an intravenous toxicology study in at least one 
209  mammalian species to identify potential risk associated with enhanced absorption.  
210   
211    If the drug is to be used as part of a clinical regimen (e.g., in combination with an 
212  approved CDI treatment), nonclinical studies to evaluate toxicological effects of the 
213  proposed combination may be warranted. Sponsors should contact FDA to determine if 
214  nonclinical toxicology studies of the specific investigational drug combination regimen 
215  should be conducted.  
216   
217  Pharmacokinetic and Dose Selection Considerations 
218   
219    Drugs developed for CDI indications can be administered by various routes (e.g., 
220  intravenous, oral administration). Some of these drugs can be systemically available 
221  although some orally administered drugs may act locally in the gastrointestinal tract (site 
222  of action) with minimal systemic absorption. 
223   
224    During development, sponsors should adequately characterize the pharmacokinetics of 
225  the investigational drugs, as appropriate, based on the route of administration. The 
226  characterization includes, but is not limited to, assessment of drug-drug interaction 
227  potential and the evaluation of the effect of renal and hepatic impairment on the 
228  pharmacokinetics of the drug. Of particular relevance for CDI drug development, 
 
13 We support the principles of the 3Rs (reduce, refine, and replace) for animal use in testing when feasible. We 
encourage sponsors to consult with review divisions when considering a nonanimal testing method believed to be 
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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229  pharmacokinetic assessments for locally acting orally administered drugs should include, 
230  but are not to be limited to, systemic absorption in healthy subjects and CDI patients and 
231  effect of food on the systemic absorption, drug metabolism and drug-drug interaction 
232  potential in the gastrointestinal tract, as well as the extent and duration of drug excretion 
233  in stool. Given that CDI is most common in older adults, sponsors should evaluate the 
234  pharmacokinetics of the investigational drugs in this population to assist the assessment 
235  of safety and efficacy.  
236   
237    Appropriate dose-ranging studies should be conducted to aid dose selection. For 
238  systemically available drugs, sponsors can use assessment of blood/plasma 
239  concentrations in dose-ranging studies to explore the exposure-response relationships for 
240  safety and/or efficacy. 
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241  APPENDIX 
242   
243  Justification for a Noninferiority Margin for Trials for Treatment of Clostridioides difficile 
244  Infection1 
245   
246  Sponsors can estimate the treatment effect of an active control (M ) in the treatment of 
1
247  Clostridioides difficile (C. difficile) infection (CDI) using the results of two identical phase 3 
248  three-arm trials comparing vancomycin, metronidazole, and tolevamer for treatment of CDI.2 
249  Tolevamer is a polymer that was hypothesized to bind and neutralize C. difficile toxins. The 
250  trials demonstrated superiority of both vancomycin and metronidazole over tolevamer. 
251  Therefore, tolevamer may be considered a putative placebo for the purposes of estimating the 
252  treatment effects of potential active controls. Given that in a prior phase 2 trial tolevamer 
253  demonstrated dose-response efficacy in resolution of CDI, it can be assumed that tolevamer is 
254  not worse than placebo.3  
255   
256  The phase 3 trials of tolevamer had a similar design and were randomized, double-blind, and 
257  active-controlled trials conducted between 2005 and 2007. One trial enrolled subjects in the 
258  United States and Canada (Study 301, NCT00106509) and another trial enrolled subjects in 
259  Europe, Australia, and Canada (Study 302, NCT00196794). Subjects 18 years of age and older 
260  were randomly assigned in a 2:1:1 ratio to receive tolevamer liquid every 8 hours for 14 days, 
261  vancomycin 125 milligram (mg) capsule every 6 hours for 10 days, or metronidazole 375 mg 
262  capsule every 6 hours for 10 days. 
263   
264  CDI was defined as three or more bowel movements in a 24-hour period with a loose or watery 
265  consistency, a positive C. difficile toxin assay result (enzyme immunoassay or cellular 
266  cytotoxicity assay) or pseudomembranes on endoscopy. 
267   
268  Subjects with fulminant CDI, intestinal ileus, continued exposure to CDI-inducing antibacterial 
269  drugs for more than 7 days, receipt of more than 48 hours of oral vancomycin or intravenous or 
270  oral metronidazole, or other effective alternate treatment for CDI within 5 days of enrollment 
271  were excluded.  
272   
273  The primary efficacy endpoint was clinical success, defined as resolution of diarrhea and absence 
274  of severe abdominal discomfort due to CDI for more than 2 consecutive days including Day 10. 
 
1 For prevention of Clostridioides difficile infection (CDI), FDA recommends a superiority design. For reduction of 
CDI recurrence, FDA recommends a superiority design, but if the sponsor decides to conduct a noninferiority (NI) 
trial for this indication, the sponsor will need to provide a justification for an NI margin. See the guidance for 
industry Non-Inferiority Clinical Trials to Establish Effectiveness (November 2016). We update guidances 
periodically.  To make sure you have the most recent version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
 
2 Johnson S et al., 2014, Vancomycin, Metronidazole, or Tolevamer for Clostridium difficile Infection: Results From 
Two Multinational, Randomized, Controlled Trials, Clin Infect Dis, 59(3):34554. 
 
3 Louie TJ et al., 2006, Tolevamer, a Novel Nonantibiotic Polymer, Compared With Vancomycin in the Treatment 
of Mild to Moderately Severe Clostridium difficile-Associated Diarrhea, Clin Infect Dis, 43(4): 41120. 
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275  Resolution of diarrhea was defined as attainment of bowel movements with a hard or formed 
276  consistency or two or fewer watery bowel movements in a 24-hour period.  
277   
278  Key demographics of the trial populations are presented in Table 1. As subjects were similarly 
279  matched across the three treatment arms within each trial, the combined data for the trials are 
280  presented. Overall, the subject populations in the trials reflect subjects that are expected to enroll 
281  in modern CDI trials.  
282   
283  Table 1: Key Demographics in Phase 3 Historical Trials (Full Analysis Set)* 
284   
Key Demographics  Study 301  Study 302 
N=543  N=528 
Age, mean and range  62 (18-99)  68 (18-97) 
> 65  252 (46%)  323 (61%) 
Female  285 (52%)  284 (54%) 
Inpatient  306 (56%)  482 (91%) 
First episode of CDI  384 (71%)  436 (83%) 
CDI severity** 
  Mild  136 (25%)  172 (33%) 
  Moderate  221 (41%)  228 (43%) 
  Severe  185 (34%)  128 (24%) 
  Missing  1  0 
Binary toxin C. difficile strain  136 (25%)  40 (8%) 
285  Johnson S et al., 2014, Vancomycin, Metronidazole, or Tolevamer for Clostridium difficile Infection: Results From 
286  Two Multinational, Randomized, Controlled Trials, Clin Infect Dis, 59(3):34554. 
287   
288  * Full analysis set = All randomized subjects who received any treatment and had any postdose evaluation. 
289  ** CDI = Clostridioides difficile infection; Mild= Three to five bowel movements (BM)/day, white blood cell counts 
290  (WBC) less than or equal to 15,000/cubic millimeter (mm3), mild or absent abdominal pain due to CDI; Moderate = 
291  six to nine BM/day, WBC 15,00120,000/mm3, mild, moderate, or absent abdominal pain due to CDI; Severe = 10 
292  or more BM/day, WBC greater than or equal to 20,001/mm3, severe abdominal pain due to CDI; any characteristics 
293  could be used to assign a severity category, and the more severe category was used when characteristics overlapped. 
294   
295  The clinical success rates in the phase 3 tolevamer trials are presented in Table 2 (treatment 
296  differences and confidence intervals are not provided in the original paper). 
297   
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298  Table 2: Clinical Success Rates in Phase 3 Historical Trials (Full Analysis Set)* 
299   
Study  Drug  Clinical Success Rate  Treatment Difference 
(95% CI) 
Tolevamer  124/266  46.6%   
301  Vancomycin  109/134  81.3%  35% (25%, 43%) 
Metronidazole  103/143  72.0%  25% (15%, 34%) 
Tolevamer  112/268  41.8%   
302  Vancomycin  101/125  80.8%  39% (29%, 47%) 
Metronidazole  99/135  73.3%  32% (21%, 40%) 
300  Johnson S et al., 2014, Vancomycin, Metronidazole, or Tolevamer for Clostridium difficile Infection: Results From 
301  Two Multinational, Randomized, Controlled Trials, Clin Infect Dis, 59(3):34554. 
302   
303  * Full analysis set = All randomized subjects who received any treatment and had any postdose evaluation.  
304  ** Confidence interval (CI) was derived using method recommended in Newcombe RG, 1998, Interval Estimation 
305  for the Difference Between Independent Proportions: Comparison of Eleven Methods, Stat Med, 17(8): 87390. 
306   
307  The two trials provide a reproducible estimation of the treatment effect of oral vancomycin and 
308  oral metronidazole for treatment of CDI. However, metronidazole is not currently considered a 
309  first-line therapy for CDI whereas oral vancomycin remains the standard of care.4  
310   
311  A meta-analysis of the results of the two trials using the DerSimonian and Laird approach 
312  (random effect model) gives an estimate of the treatment effect for oral vancomycin of 37 
313  percent with a 95 percent confidence interval (CI) (30 percent, 43 percent).5 Thus, the treatment 
314  effect (M ) can be conservatively estimated at 30 percent based on the lower bound of the CI for 
1
315  the treatment difference between vancomycin and tolevamer.  
316   
317  These estimations of the treatment effect may be conservative as tolevamer may be more 
318  effective than placebo. However, there are uncertainties regarding possible departures from the 
319  constancy assumption and generalizability issues (i.e., it should be noted that in the tolevamer 
320  trials clinical success was defined as the resolution of diarrhea by the end of treatment (EOT); 
321  whereas in the current guidance, clinical success is defined as the resolution of diarrhea at the 
322  EOT sustained through 2 days immediately following EOT). To account for these uncertainties, 
323  the treatment effect of vancomycin should be somewhat discounted. We propose a 10 percent 
324  discounting, which, when applied to the 30 percent lower limit of the 95 percent CI of the M  of 
1
325  vancomycin over tolevamer from the meta-analysis of the tolevamer clinical trials, results in M  
1
326  of 27 percent. The derived M  supports a noninferiority (NI) margin of 10 percent while still 
1
327  preserving more than 60 percent of the treatment effect based on the endpoint of clinical success 
 
4 McDonald LC et al., 2018, Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 
2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of 
America (SHEA), Clin Infect Dis, 66(7): 987994. 
 
5 See the April 5, 2011, FDA briefing document for the Anti-Infective Drugs Advisory Committee meeting entitled 
Fidaxomicin for the Treatment of Clostridium difficile-Associated Diarrhea (CDAD) available at 
https://wayback.archive-
it.org/7993/20170405204844/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/
Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM249353.pdf. 
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328  as defined above. If the sponsor uses active comparators other than vancomycin in CDI treatment 
329  trials, the sponsor may need to provide additional justification of an NI margin.  
11