Demonstrating Substantial Evidence of 
Effectiveness With One Adequate and 
Well-Controlled Clinical Investigation 
and Confirmatory Evidence 
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DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only.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 90 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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 (CDER) Office of New Drug Policy, Eithu 
Lwin, 301-796-0728, or (CBER) Office of Communication, Outreach and Development, 800-
835-4709 or 240-402-8010.  
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Oncology Center of Excellence (OCE) 
Center for Biologics Evaluation and Research (CBER) 
Center for Drug Evaluation and Research (CDER) 
 
September 2023 
Clinical/Medical 
 
44625092dft.docx 
09/11/23   
Demonstrating Substantial Evidence of 
Effectiveness With One Adequate and 
Well-Controlled Clinical Investigation 
and Confirmatory Evidence 
Guidance for Industry 
 
 
Additional copies are available from: 
 
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Center for Drug Evaluation and Research 
Food and Drug Administration 
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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 
 
and/or 
 
Office of Communication, Outreach and Development  
Center for Biologics Evaluation and Research 
 Food and Drug Administration 
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Silver Spring, MD 20993-0002 
Phone: 800-835-4709 or 240-402-8010 
Email: ocod@fda.hhs.gov 
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Oncology Center of Excellence (OCE) 
Center for Biologics Evaluation and Research (CBER) 
Center for Drug Evaluation and Research (CDER) 
 
September 2023 
Clinical/Medical 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND AND SCOPE ....................................................................................... 1 
II.  GENERAL CONSIDERATIONS REGARDING CONFIRMATORY EVIDENCE 
AND THE DEMONSTRATION OF SUBSTANTIAL EVIDENCE OF 
EFFECTIVENESS ............................................................................................................ 4 
III.  TYPES OF CONFIRMATORY EVIDENCE ................................................................ 5 
A.  Clinical Evidence from a Related Indication ............................................................................... 5 
B.  Mechanistic or Pharmacodynamic Evidence .............................................................................. 6 
C.  Evidence from a Relevant Animal Model .................................................................................... 8 
D.  Evidence from Other Members of the Same Pharmacological Class ........................................ 9 
E.  Natural History Evidence ............................................................................................................ 10 
F.  Real-World Data/Evidence ......................................................................................................... 10 
G.  Evidence from Expanded Access Use of an Investigational Drug ........................................... 11 
IV.  PROCESS CONSIDERATIONS ................................................................................... 12 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Demonstrating Substantial Evidence of Effectiveness With One 
2  Adequate and Well-Controlled Clinical Investigation and 
3  Confirmatory Evidence 
4  Guidance for Industry1 
5   
6   
7   
8  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
9  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
10  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
11  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
12  for this guidance as listed on the title page.   
13   
14   
15   
16  I.  INTRODUCTION  
17   
18  This guidance (the Confirmatory Evidence guidance) complements the draft guidance for 
19  industry Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological 
20  Products (December 2019) (the 2019 Effectiveness draft guidance)2 and the guidance for 
21  industry Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products 
22  (May 1998) (the 1998 Effectiveness guidance).  This guidance provides recommendations for 
23  sponsors to consider when planning a drug3 development program. 
24   
25  In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
26  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
27  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
28  the word should in Agency guidances means that something is suggested or recommended, but 
29  not required.  
30   
31   
32  II.  BACKGROUND AND SCOPE 
33   
34  In 1962, Congress required for the first time that drugs be shown to be effective as well as safe.  
35  A drugs effectiveness must be established by substantial evidence, which is defined as 
 
1 This guidance has been prepared by the Office of New Drug Policy in the Center for Drug Evaluation and 
Research in cooperation with the Center for Biologics Evaluation and Research at the Food and Drug 
Administration. 
 
2 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. 
 
3 For the purposes of this guidance, all references to drugs include both human drugs and biological products, unless 
otherwise specified. 
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36  [E]vidence consisting of adequate and well-controlled investigations, including clinical 
37  investigations, by experts qualified by scientific training and experience to evaluate the 
38  effectiveness of the drug involved, on the basis of which it could fairly and responsibly be 
39  concluded by such experts that the drug will have the effect it purports or is represented to have 
40  under the conditions of use prescribed, recommended, or suggested in the labeling or proposed 
41  labeling thereof.4 
42   
43  FDA has interpreted this substantial evidence requirement as generally requiring two adequate 
44  and well-controlled clinical investigations, each convincing on its own, to establish effectiveness.  
45  Nevertheless, as noted in the 1998 Effectiveness guidance, FDA has also been flexible within the 
46  limits imposed by the statute where data on a particular drug were convincing. In 1997, Congress 
47  amended section 505(d) to confirm FDAs interpretation of the statutory requirements, making 
48  clear that FDA may consider data from one adequate and well-controlled clinical investigation 
49  and confirmatory evidence to constitute substantial evidence if FDA determines that such data 
50  are sufficient to establish effectiveness.5  Specifically, Congress added to section 505(d) that 
51   
52  If [FDA] determines, based on relevant science, that data from one adequate and well-
53  controlled clinical investigation and confirmatory evidence (obtained prior to or after 
54  such investigation) are sufficient to establish effectiveness, [FDA] may consider such 
55  data and evidence to constitute substantial evidence. 
56   
57  FDA issued the 1998 Effectiveness guidance in response to this legislative change.  The 1998 
58  guidance provides examples of the types of evidence that could be considered confirmatory 
59  evidence, with a specific focus on adequate and well-controlled trials of the test agent in related 
60  populations or indications, as well as a number of illustrations of a single adequate and well-
61  controlled trial supported by convincing evidence of the drugs mechanism of action in treating a 
62  disease or condition. 
63   
64  Although FDAs evidentiary standard for effectiveness has not changed since 1998, drug 
65  development and science have continued to evolve, leading to changes in the nature of drug 
66  development programs submitted to the Agency. In 2019, the Agency concluded that more 
67  guidance was needed on the flexibility in the amount and type of evidence needed to meet the 
68  substantial evidence standard. The 2019 Effectiveness draft guidance discusses a number of 
69  approaches that can yield evidence that meets the statutory standard for substantial evidence, and 
70  in particular addresses the agencys consideration of various trial designs, trial endpoints, and 
71  statistical methodologies, reflecting the Agencys long-standing flexibility when considering the 
72  types of data and evidence that can meet the substantial evidence requirement. 
73   
74  Given the range of topics addressed by the 2019 Effectiveness draft guidance, its discussion of 
75  meeting the substantial evidence standard based on one adequate and well-controlled clinical 
 
4 Under section 351 of the Public Health Service Act (PHS Act) (42 U.S.C. 262), licenses for biologics have been 
issued only upon a showing that the products are safe, pure, and potent.  Potency has long been interpreted to 
include effectiveness (21 CFR 600.3(s)).  FDA has also generally considered substantial evidence of effectiveness to 
be necessary to support licensure of a biological product under section 351 of the PHS Act. 
 
5 The Food and Drug Administration Modernization Act of 1997 (FDAMA) (Pub. L. 105115), 
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76  investigation plus confirmatory evidence was necessarily brief.  This guidance supplements the 
77  discussion in the 2019 Effectiveness draft guidance by providing further detail on the use of data 
78  drawn from one or more sources (e.g., clinical data, mechanistic data, animal data) to 
79  substantiate the results of one adequate and well-controlled clinical investigation.   
80   
81  This guidance describes factors to consider when assessing whether a single adequate and well-
82  controlled clinical investigation and confirmatory evidence are sufficient to demonstrate 
83  substantial evidence of effectiveness.  It also provides examples of types of data that could be 
84  considered confirmatory evidence.  This guidance also emphasizes the importance of early 
85  engagement with the Agency for sponsors that intend to establish substantial evidence of 
86  effectiveness with one adequate and well-controlled clinical investigation and confirmatory 
87  evidence. 
88   
89  This guidance does not discuss the development paradigm in which, under certain circumstances, 
90  a single multicenter trial can satisfy the legal requirement for substantial evidence of 
91  effectiveness; that scenario is discussed in the 2019 Effectiveness draft guidance.  This guidance 
92  also does not discuss approval of a different dose, regimen, or dosage form based on a previous 
93  finding of effectiveness of an approved drug, or other regulatory considerations beyond the scope 
94  of the substantial evidence determination under section 505(d) of the Act.  In addition, in some 
95  situations, a sponsor may intend to rely on data submitted in other applications to support a new 
96  drug application. This guidance does not address certain regulatory considerations that apply to 
97  reliance on certain types of information in certain applications (e.g., reliance on a previous 
98  finding of safety and effectiveness for a drug the applicant does not own or to which it has no 
99  right of reference in a 505(b)(2) application).6 
100   
101  The finding of substantial evidence of effectiveness is necessary but not sufficient for FDA 
102  approval.  An approval decision, among other things, also requires a determination that a drug is 
103  safe for its intended use.7  As all drugs can have adverse effects, evaluating whether a drug is 
104  safe involves weighing whether the benefits of the drug outweigh its risks.  In some cases, one 
105  adequate and well-controlled clinical investigation and confirmatory evidence may demonstrate 
106  effectiveness, but the clinical trial may not have enrolled a sufficient number of participants or 
107  have treated them for a sufficient duration to conclude that the drug is safe.  A second clinical 
108  trial may be needed to ensure a safety database of adequate size and duration to support an 
109  appropriate benefit-risk assessment.  Considerations for a safety evaluation, a benefit-risk 
110  analysis, and their impact on the acceptability of one trial with confirmatory evidence to support 
111  approval are beyond the scope of this guidance.  
112   
113   
 
6 For discussion of this topic, see the draft guidance for industry Applications Covered by Section 505(b)(2) 
(October 1999).  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.  Note, also, that use of certain sources of information may not be 
permitted under certain regulatory pathways, but that discussion is beyond the scope of this guidance. 
 
7 Section 505(d) of the FD&C Act.  
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114  II.  GENERAL CONSIDERATIONS REGARDING CONFIRMATORY EVIDENCE 
115  AND THE DEMONSTRATION OF SUBSTANTIAL EVIDENCE OF 
116  EFFECTIVENESS 
117   
118  The substantial evidence of effectiveness standard in the FD&C Act (see section II) refers to 
119  both the quantity and quality of the evidence.  As noted above, the number of trials required to 
120  demonstrate substantial evidence of effectiveness can vary across development programs.  The 
121  2019 Effectiveness draft guidance discusses, in part, the features of adequate and well-controlled 
122  clinical investigations,8 with a focus on trial design, endpoints, and statistical considerations.  A 
123  clinical investigations particular set of features will result in a greater or lesser degree of 
124  certainty about effectiveness. 
125   
126  When one adequate and well-controlled clinical investigation and confirmatory evidence are 
127  considered together to assess effectiveness, the quality and quantity of confirmatory evidence are 
128  also important considerations.  Confirmatory evidence should be evidence generated from 
129  quality data derived from an appropriate source (see section III).      
130   
131  The quantity (e.g., number of sources) of confirmatory evidence necessary to support 
132  effectiveness may vary across development programs.  Importantly, the quantity of confirmatory 
133  evidence needed in a development program will be impacted by the features of, and results from, 
134  the single adequate and well-controlled clinical investigation that the confirmatory evidence is 
135  intended to substantiate.  It may be possible for a highly persuasive adequate and well-controlled 
136  clinical investigation to be supported by a lesser quantity of confirmatory evidence, whereas a 
137  less-persuasive adequate and well-controlled clinical investigation may require a greater quantity 
138  of compelling confirmatory evidence to allow for a conclusion of substantial evidence of 
139  effectiveness. 
140   
141  Sponsors must include in their marketing submissions a description and analysis of all data or 
142  information relevant to an evaluation of the safety and effectiveness of the drug product, from 
143  any source, foreign or domestic, to avoid selecting only those sources that favor a conclusion of 
144  effectiveness.9  The results of a clinical investigation or confirmatory evidence can be called into 
145  question by conflicting evidence unless there is a sufficient scientific justification that may 
146  explain the disparate findings.   
147   
148  When evaluating whether to approach establishing substantial evidence of effectiveness with one 
149  adequate and well-controlled clinical investigation and confirmatory evidence, sponsors should 
150  consider the clinical context for the proposed therapy.  Disease- or condition-specific 
151  considerations (e.g., unmet need, size of the patient population) may be relevant to whether such 
152  an approach is appropriate. Furthermore, although safety considerations are beyond the scope of 
153  this guidance, decision making about a drug development program should also take into account 
154  the data necessary to demonstrate that a drug is safe for the intended use.   
155   
 
8 See 21 CFR 314.126(b) for additional information on the features of adequate and well-controlled investigations. 
 
9 See 21 CFR 314.50(d)(5)(iv). 
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156  Sponsors who plan to establish substantial evidence of effectiveness with a single adequate and 
157  well-controlled clinical investigation and confirmatory evidence should discuss their proposed 
158  approach with FDA early in development, such as at a pre-IND meeting and no later than when 
159  the sponsor is seeking feedback regarding the clinical investigation (e.g., at the end-of-phase 2 
160  meeting; see section IV).10  When meeting with FDA, sponsors should be prepared to provide a 
161  rationale for their chosen approach to development, along with descriptions of the planned single 
162  adequate and well-controlled clinical investigation and planned confirmatory evidence.  The goal 
163  of such engagement is to allow the sponsor and Agency an opportunity to evaluate whether a 
164  development program consisting of a single adequate and well-controlled clinical investigation 
165  and confirmatory evidence could demonstrate substantial evidence of effectiveness.  Ultimately, 
166  whether a single adequate and well-controlled clinical investigation and confirmatory evidence 
167  are sufficient to demonstrate substantial evidence of effectiveness will depend on the results 
168  generated by the development program.   
169   
170   
171  III.  TYPES OF CONFIRMATORY EVIDENCE 
172   
173  This section provides examples of types of confirmatory evidence that can, in appropriate 
174  circumstances, be used to substantiate one adequate and well-controlled clinical investigation to 
175  demonstrate substantial evidence of effectiveness.  This section is not intended to provide an 
176  exhaustive list.  We note that some of these examples involve data that are frequently generated 
177  during a conventional drug development program, and that such data may or may not be 
178  appropriate as confirmatory evidence depending on the specific development program under 
179  consideration.  Whether confirmatory evidence and the adequate and well-controlled clinical 
180  investigation provide substantial evidence of effectiveness is determined case by case, for each 
181  application, in the context of the application as a whole. 
182   
183  A.  Clinical Evidence from a Related Indication 
184   
185  Under certain circumstances, evidence of effectiveness of a drug from a clinical investigation for 
186  a particular indication can provide confirmatory evidence of effectiveness to support approval of 
187  the drug in a different but closely related indication. 
188   
189  A common example of this approach is the submission of a new drug application or a biologics 
190  license application for a new indication for an already approved therapy, where one adequate and 
191  well-controlled clinical investigation of the drug for the new indication is supported by the 
192  results from the clinical investigation or investigations that formed the basis of the previous 
193  approval (for a different but closely related indication).  In another example, one adequate and 
194  well-controlled clinical investigation in each of two related, unapproved indications can serve as 
195  confirmatory evidence for the other indication, thereby supporting concurrent approval of the 
196  drug for both indications.  
197   
198  Among the factors critical to determining whether an indication is closely related, and whether a 
199  drugs effectiveness for that indication can provide confirmatory evidence for a trial that studied 
 
10 See the draft guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA 
Products (December 2017).  When final, this guidance will represent the FDAs current thinking on this topic. 
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200  the drug for a different indication, are the degree of similarity between the indications, the degree 
201  of similarity in the drugs mechanism of action in the diseases, and the degree of similarity 
202  between the efficacy endpoints in the two diseases. 
203   
204  Examples of when clinical trial data from a related indication may be appropriate for use as 
205  confirmatory evidence include when the new indication is: 
206   
207    A different stage of the same disease (e.g., for initial treatment of a particular type of 
208  cancer, where the previously approved indication was for a treatment-refractory form of 
209  that cancer) 
210   
211    A different but closely related disease, for example: 
212   
213    Infections at different anatomical sites caused by similar pathogens against which the 

214  drug is active (e.g., bone/joint infections and acute bacterial skin and skin structure 
215  infections) 
216   
217    Diseases with a common precursor targeted by the product (e.g., genital warts and 

218  cervical cancer both prevented by human papillomavirus vaccine through prevention 
219  of infection) 
220   
221    Diseases with similarities in their underlying pathophysiology (e.g., rheumatoid 

222  arthritis and psoriatic arthritis) 
223   
224  B.  Mechanistic or Pharmacodynamic Evidence 
225   
226  Under certain circumstances, strong mechanistic evidence of the drugs treatment effect in a 
227  particular disease may be appropriate to use as confirmatory evidence.  In such cases, (1) the 
228  pathophysiology of the disease should be well understood and (2) the drugs mechanism of 
229  action should be both clearly understood and shown to directly target the major driver or drivers 
230  of the disease pathophysiology.  When the drugs mechanism of action affects several 
231  pathophysiologic pathways and it is not clear which pathway is important to disease occurrence 
232  and/or progression, mechanistic data may not provide sufficient confirmatory evidence to 
233  support approval, and additional evidence from other sources may be needed.  Similarly, when a 
234  disease has multiple causal pathways that lead directly to disease occurrence or progression and 
235  the drug only impacts one causal pathway, mechanistic data may not provide sufficient 
236  confirmatory evidence. 
237   
238   
239   
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240  Mechanistic evidence is generally obtained from clinical testing using a relevant and well-
241  understood pharmacodynamic endpoint11 not accepted by itself as an endpoint to establish 
242  evidence of effectiveness.  Mechanistic evidence can also be obtained from in vitro testing (e.g., 
243  if the disease is caused by a genetic defect that results in defective function of an anion 
244  transporter on epithelial cells, in vitro evidence in a relevant cell line and at relevant 
245  concentrations demonstrating that the drug directly augments transporter function).  The quality 
246  and strength of mechanistic data exist on a spectrum, ranging from exploratory in nature to 
247  results that demonstrate clear evidence for a particular pathophysiological mechanism of disease 
248  and the drugs effect on the established mechanism.   
249   
250  Examples of when mechanistic data may be appropriate for use as confirmatory evidence include 
251  the following: 
252   
253    When the disease is caused by a single gene and/or enzyme defect and the drugs 
254  mechanism of action corrects the enzymatic or genetic defect or its sequelae.  For 
255  example: 
256   
257    An enzyme replacement therapy that corrects the underlying enzymatic deficiency in 

258  a lysosomal storage disease at the affected target tissues or organs (e.g., laronidase in 
259  mucopolysaccharidosis type I) 
260   
261    A small-molecule drug that increases a metabolite, or decreases a precursor, in a 

262  disease caused by an enzymatic block in its biosynthetic pathway, resulting in 
263  absence or reduced levels of that metabolite (e.g., uridine replacement in hereditary 
264  orotic aciduria), and/or elevation of the precursor chemical 
265   
266    An antisense oligonucleotide directed at a specific gene variant or molecular genetic 

267  mechanism causing an inborn error of metabolism or genetic disease (e.g., 
268  overexpression of a gene leading to overexpression of an enzyme), where 
269  biochemical data in the target organ shows expected changes in gene expression (e.g., 
270  knockdown of the gene expression in the tissue and decreased enzyme activity) 
271   
272    Nonclinical data demonstrating concentration-dependent inhibition of cell 

273  proliferation or signaling correlating with inhibition of an oncogene-dependent 
274  pathway (e.g., single driver mutation) in a specific cancer type 
275   
276    When the therapy is a chelating or binding agent, where there is a body of evidence 
277  describing the clinical consequences of excessive amounts of a substrate (e.g., iron, 
 
11 In some settings where the pathophysiology of a disease is not well understood, a pharmacodynamic biomarker 
might not elucidate a drugs mechanism of action but could still provide information about a clinical outcome.  In an 
appropriate case, the results of a single adequate and well-controlled clinical investigation could be substantiated by 
the confirmatory evidence provided by the pharmacodynamic data.  Demonstration of a well-characterized 
exposure-response relationship for the pharmacodynamic biomarker may be particularly persuasive as confirmatory 
evidence when such data suggest that the effect observed in a successful adequate and well controlled clinical 
investigation is more likely attributable to the pharmacological action of the drug than to chance. 
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278  potassium, phosphate), and in vitro or in vivo data convincingly demonstrate the ability 
279  of the drug to bind a meaningful percentage of the substrate 
280   
281    When the therapy is an antimicrobial drug, proposed for use in combination with a novel 
282  inhibitor of a bacterial-resistance mechanism (e.g., beta-lactam antibacterial drug with a 
283  novel beta-lactamase inhibitor), and in vitro and animal data demonstrate increased 
284  activity of the combination compared with the antimicrobial alone against organisms 
285  resistant to the antimicrobial alone 
286   
287  C.  Evidence from a Relevant Animal Model 
288   
289  Animal data (e.g., proof-of-concept data, pharmacological studies, toxicology studies) are used 
290  in drug development for a number of purposes, including to help characterize a therapys 
291  pharmacodynamic effects (which may be done either in healthy animals or in animal models of 
292  disease, as appropriate); provide evidence of efficacy in an animal model of disease, using an 
293  endpoint that is intended to reflect or translate to a similar outcome in humans with disease; or 
294  profile drug toxicity.12  Typically, results of studies conducted in an animal model of disease are 
295  intended to support progressing a drug candidate forward from preclinical to clinical 
296  development, rather than to support a finding of substantial evidence.  Infrequently, however, 
297  sponsors can use data from an established animal model of disease as confirmatory evidence of 
298  effectiveness; in such cases, sponsors should discuss in advance these planned nonclinical 
299  studies with the appropriate FDA review division.   
300   
301  Whether data from an established animal model of disease would be suitable as confirmatory 
302  evidence depends on several factors, including similarity of pathophysiology and manifestations 
303  of the disease in the animal model and in humans, elucidation of the drugs mechanism of action 
304  with evidence of similar pharmacology and pharmacodynamics in the animal model and humans 
305  with disease, and evidence that the results of efficacy studies conducted in the animal model 
306  reasonably support clinical benefits and outcomes in humans with disease (e.g., if the disease in 
307  humans leads to renal failure and the drug is intended to preserve renal function, showing that 
308  the animal model of disease also is characterized by renal failure and the drug reduces 
309  progression of renal failure when tested in the animal model).  Although animal models are 
310  useful in the preclinical stages of drug development, only a few such models may accurately 
311  predict human responses quantitatively or even qualitatively.  Only models that have proved to 
312  be translational (i.e., prior drugs with the same intended clinical effect have been shown to have 
313  this effect observed in the animal model, with similar exposure-response) are likely to be 
314  considered as confirmatory evidence. 
315   
316  Examples of when animal data may be appropriate for use as confirmatory evidence include the 
317  following:  
318   
 
12 FDA supports the principles of the 3Rs (reduce/refine/replace) for animal use in testing when feasible.  FDA 
encourages sponsors to consult with review divisions when considering a nonanimal testing method believed to be 
suitable, adequate, validated, and feasible.  FDA will consider if the alternative method could be assessed for 
equivalency to an animal test method. 
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319    When the drug is an antimicrobial agent, and there is a well-established model of 
320  infection for a relevant infectious disease, and use of the therapy in the animal model 
321  demonstrates antimicrobial activity 
322   
323    When the product is a preventive vaccine, and there is a well-established model of 
324  infection for a relevant infectious disease, and use of the vaccine in the animal model 
325  demonstrates prevention of disease 
326   
327   
328  Using animal model data as confirmatory evidence of effectiveness in the setting of one adequate 
329  and well-controlled clinical investigation is distinct from the approval pathway established in 
330  FDA regulations collectively known as the animal rule,13, although some of the considerations 
331  that are relevant to approval under the animal rule (e.g., the need for a well-understood 
332  underlying pathophysiology, the predictiveness of the animal model, and the relatedness of the 
333  animal efficacy to the desired benefit in humans)14 may also be relevant where results of studies 
334  conducted in an animal model are used as confirmatory evidence of effectiveness.   
335   
336  D.  Evidence from Other Members of the Same Pharmacological Class 
337   
338  In certain circumstances, FDA has accepted one adequate and well-controlled clinical 
339  investigation as the basis to demonstrate effectiveness, when the single trial is supported by 
340  confirmatory evidence of effectiveness from adequate and well-controlled trials of other drugs in 
341  the same pharmacological class approved for the same indication.15  The ability to use 
342  information about drugs in a pharmacological class as confirmatory evidence generally depends 
343  on all of the following:  
344   
345    The mechanism of action of the new drug, which should be the same as that of approved 
346  members of the class.  
347   
348    The extent to which similar endpoints were measured across the class, and the 
349  homogeneity of each drugs effect on clinical outcomes.  Relevant considerations 
350  generally include whether the new drug has similar effects on the same endpoints 
351  assessed for approved drugs, or whether the new drug demonstrates positive effects on 
352  some endpoints and no effect or adverse effects on others. 
353   
354    The consistency and predictability of the measured effect among drug class members. 
355   
 
13 21 CFR part 314, subpart I (drugs) and 21 CFR part 601, subpart H (biological products).  The animal rule only 
applies when it is not ethical or feasible to conduct clinical studies.  In such situations FDA can allow the use of 
adequate and well-controlled efficacy studies in appropriate animal models to generate evidence to establish 
effectiveness of products intended to treat or prevent serious or life-threatening conditions caused by exposure to 
lethal or permanently disabling toxic biological, chemical, radiological, or nuclear substances. 
 
14 See 21 CFR 314.610(a).  
 
15 See footnote 6. 
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356    The number of drugs approved in the class.  Although it is not possible to assign a 
357  threshold number, the greater the number of approved drugs in a class that demonstrate 
358  the same general effects, the greater the confidence is likely to be that these effects are 
359  related to a common pharmacological effect. 
360   
361  E.  Natural History Evidence 
362   
363  In certain circumstances, natural history data can provide confirmatory evidence to substantiate 
364  the results of a single adequate and well-controlled investigation.  Such an approach can be 
365  useful when there is uncertainty about whether the outcomes observed in the control group 
366  accurately reflect those that would have been expected in the absence of the intervention.  
367  Natural history data being used as confirmatory evidence should be distinct from any data used 
368  as a control for the single adequate and well-controlled clinical investigation. 
369   
370  Examples of when natural history data may be appropriate for use as confirmatory evidence 
371  include the following:  
372   
373    A novel drug to treat patients with an acquired blood enzyme deficiency, where patients 
374  had high levels of the abnormal blood protein at baseline with deficient oxygen-carrying 
375  capacity.  In the double-blind, placebo-controlled crossover design clinical trial, each 
376  participant served as his or her own control, with demonstration of nonmeasurable 
377  abnormal blood protein levels and improvement in oxygenation after drug administration 
378  but not after administration of placebo, and complete resolution of this disorder.  The 
379  evidence from the one adequate and well-controlled clinical investigation could be 
380  supported by confirmatory evidence, from natural history data, which demonstrates 
381  failure of this disorder to spontaneously resolve with subsequent high morbidity and 
382  mortality. 
383   
384    A drug for a progressive disease, for which the adequate and well-controlled clinical 
385  investigation demonstrates stability of a clinically important outcome in the experimental 
386  group compared with deterioration in the control group, and for which natural history 
387  data are available to confirm the amount of deterioration in the control group is an 
388  expected outcome for the period of observation.   
389   
390  F.  Real-World Data/Evidence 
391   
392  Pursuant to section 3022 of the 21st Century Cures Act16 FDA developed a program to evaluate 
393  the potential use of real-world evidence to help support the approval of a new indication for a 
394  drug already approved under section 505(c) of the FD&C Act or to help support or satisfy post-
395  approval study requirements.17 
 
16 Public Law 114255, signed December 13, 2016. 
 
17 This real-world evidence program also covers biological products licensed under the Public Health Service Act.  
See Framework for FDAs Real-World Evidence Program, available at 
https://www.fda.gov/media/120060/download. 
 
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396   
397  For the purposes of this guidance, FDA defines real world data (RWD) and real-world evidence 
398  (RWE)18 as follows:  
399   
400    RWD are data relating to patient health status or the delivery of health care routinely 
401  collected from a variety of sources (e.g., electronic health records, medical claims data, 
402  registries). 
403   
404    RWE is the clinical evidence about the usage and potential benefits or risks of a drug 
405  derived from analysis of real-world data. 
406   
407  As noted above, confirmatory evidence can come from one or a variety of sources, including 
408  RWD sources.  Whether an RWD source may be appropriate to develop RWE that serves as 
409  confirmatory evidence depends on several factors, including but not limited to the reliability and 
410  relevance of the RWD source and, when relevant, the quality of the study design and the use of 
411  appropriate prespecified statistical methods and analyses.19  FDA recommends that sponsors 
412  discuss with the relevant review divisions any plans to use RWE as confirmatory evidence in a 
413  drug development program.   
414   
415  G.  Evidence from Expanded Access Use of an Investigational Drug 
416   
417  Expanded access generally refers to the use of an investigational drug when the primary purpose 
418  is to diagnose, monitor, or treat a patients or group of patients disease or condition rather than 
419  to obtain the kind of information about the drug that is generally derived from clinical trials.20  It 
420  may also refer to use of an approved drug where availability is limited by a risk evaluation and 
421  mitigation strategy (REMS) for diagnostic, monitoring, or treatment purposes, by patients who 
422  cannot obtain the drug under the REMS.21 Expanded access may be permitted where the patient 
423  or patients have a serious or immediately life-threatening diseases or conditions where there is no 
424  comparable or satisfactory alternative therapy available; where the potential patient benefit 
425  justifies the potential risks of treatment; and where the requested use will not interfere with the 
 
18 See the draft guidance for industry Real-World Data: Assessing Electronic Health Records and Medical Claims 
Data to Support Regulatory Decision-Making for Drug and Biological Products (September 2021).  When final, this 
guidance will represent the FDAs current thinking on this topic. 
 
19 See the draft guidances for industry Real-World Data: Assessing Electronic Health Records and Medical Claims 
Data to Support Regulatory Decision-Making for Drug and Biological Products, Considerations for the Use of 
Real-World Data and Real-World Evidence to Support Regulatory Decision-Making for Drug and Biological 
Products (December 2021), Real-World Data:  Assessing Registries to Support Regulatory Decision-Making for 
Drug and Biological Products (November 2021), and Data Standards for Drug and Biological Product Submissions 
Containing Real-World Data (October 2021).  When final, these guidances will represent the FDAs current 
thinking on these topics.  Also refer to FDAs Real-World Evidence web page, available at 
https://www.fda.gov/science-research/science-and-research-special-topics/real-world-evidence. 
 
20 21 CFR 312.300(a); see also the guidance for industry Expanded Access to Investigational Drugs for Treatment 
Use: Questions and Answers (June 2016). 
 
21 Id. 
 
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426  initiation, conduct, or completion of clinical investigations that could support marketing approval 
427  of the expanded access use or otherwise compromise the potential development of the therapy 
428  for the expanded access.22  Under FDA regulations, expanded access may be authorized if the 
429  relevant criteria are met for an individual patient, under either emergency or nonemergency 
430  conditions, or for a group of patients.23 
431   
432  Although the purpose of expanded access is not primarily for research, if the patient outcome 
433  information collected under expanded access use of the drug is of sufficient quantity and quality 
434  to be highly persuasive, the information may be considered for use as confirmatory evidence.  
435  Typically, however, only limited and inconsistent information is available from expanded access 
436  (e.g., source documents are often lacking, diagnostic criteria and stage of disease may vary, 
437  monitoring and outcome assessments vary across patients, among other limitations), and such 
438  information provides an incomplete picture of the course of events, which may make the 
439  information unfit for use as confirmatory evidence.   
440   
441  The following scenario is an example of how patient outcome information collected under 
442  expanded access could be used as confirmatory evidence: 
443   
444    A new drug application for an antidote to treat overdose of a chemotherapy drug, where 
445  the application included patient outcome information from a large number of single 
446  patient emergency investigational new drug applications for which the sponsor collected 
447  detailed medical records, and the documented clinical results were markedly improved 
448  compared with the expected serious outcome in the absence of treatment.  Such 
449  information could then potentially serve as confirmatory evidence supporting the results 
450  of one adequate and well-controlled clinical investigation. 
451   
452   
453  IV.  PROCESS CONSIDERATIONS 
454   
455  As discussed above, FDA recommends that sponsors discuss early with the review divisions any 
456  plans to use one adequate and well-controlled clinical investigation and confirmatory evidence to 
457  establish substantial evidence of effectiveness.  During these discussions, sponsors should do the 
458  following: 
459   
460    Provide a strong scientific rationale to support the use of a single clinical investigation 
461  and confirmatory evidence for their specific drug development program, taking into 
462  account the considerations outlined in section III of this document. 
463   
464    Describe the anticipated design of one adequate and well-controlled clinical investigation 
465  that the confirmatory evidence is intended to support. 
466   
 
22 See 21 CFR 312.305(a). 
 
23 See 21 CFR 312.310; 312.315, and 312.320.   
 
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467    Discuss the confirmatory evidence they intend to use to demonstrate, in conjunction with 
468  one adequate and well-controlled clinical investigation, substantial evidence of 
469  effectiveness.  Sponsors should describe the type (i.e., data source) and quantity of 
470  confirmatory evidence that will be included in their application.   
471   
472  Sponsors should continue to meet with the Agency throughout product development, particularly 
473  if changes to the clinical investigation or confirmatory evidence are contemplated. 
474   
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