Demonstrating 
Substantial Evidence of 
Effectiveness for  
Human Drug and 
Biological Products 
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DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 (CDER) Ei Thu Lwin, Office of New Drug 
Policy, 301-796-0728 or (CBER) Office of Communication, Outreach and Development, 800-
835-4709 or 240-402-8010, ocod@fda.hhs.gov.  
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Biologics Evaluation and Research (CBER) 
Center for Drug Evaluation and Research (CDER) 
 
December 2019 
Clinical/Medical 
   
Demonstrating 
Substantial Evidence of 
Effectiveness for  
Human Drug and 
Biological Products 
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 
 
and/or 
 
Office of Communication, Outreach and Development  
Center for Biologics Evaluation and Research 
 Food and Drug Administration 
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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 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Biologics Evaluation and Research (CBER) 
Center for Drug Evaluation and Research (CDER) 
 
 December 2019 
Clinical/Medical
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  STANDARD OF EFFECTIVENESS FOR DRUGS AND BIOLOGICS .................... 3 
A.  Statutory standard ......................................................................................................................... 3 
B.  Scientific basis for the statutory standard ................................................................................... 4 
III.  THE QUALITY OF CLINICAL EVIDENCE TO ESTABLISH EFFECTIVENESS
  ...........................................................................................................5 
A.  Trial designs ................................................................................................................................... 5 
B.  Trial endpoints ............................................................................................................................... 7 
C.  Statistical considerations ............................................................................................................... 8 
IV.  THE QUANTITY OF CLINICAL EVIDENCE TO ESTABLISH 
EFFECTIVENESS ............................................................................................................ 8 
A.  Meeting the substantial evidence standard based on two adequate and well-controlled     
clinical investigations ..................................................................................................................... 8 
1. Two adequate and well-controlled clinical investigations .............................................................. 8 
2.  One adequate and well-controlled large multicenter trial that can provide substantial evidence of         
effectiveness ..................................................................................................................................... 9 
B.  Meeting the substantial evidence standard based on one adequate and well-controlled 
clinical investigation plus confirmatory evidence ..................................................................... 10 
1. One adequate and well-controlled clinical investigation on a new indication for an approved 
drug, supported by existing adequate and well-controlled clinical investigation(s) that 
demonstrated the effectiveness of the drug for its other, closely related approved indication(s) .. 11 
2. One adequate and well-controlled clinical investigation supported by data that provide strong 
mechanistic support ....................................................................................................................... 11 
3. One adequate and well-controlled clinical investigation with compelling results, supported by 
additional data from the natural history of the disease ................................................................. 12 
4. One adequate and well-controlled clinical investigation of the new drug, supported by scientific 
knowledge about the effectiveness of other drugs in the same pharmacological class ................. 12 
C.  Meeting the substantial evidence standard for a new population or a different dose, 
regimen, or dosage form, based on reliance of FDAs previous finding of effectiveness of an 
approved drug when scientifically justified and legally permissible ....................................... 13 
V.     EXAMPLES OF CLINICAL CIRCUMSTANCES WHERE ADDITIONAL 
FLEXIBILITY MAY BE WARRANTED .................................................................... 14 
A.  When the disease is life-threatening or severely debilitating with an unmet medical need .. 14 
1. Trial design .................................................................................................................................... 15 
2. Trial endpoints ............................................................................................................................... 15 
3. Number of trials ............................................................................................................................. 16 
4. Statistical considerations ............................................................................................................... 16 
B.  When the disease is rare .............................................................................................................. 16 
1. Trial design .................................................................................................................................... 16 
2. Trial endpoints ............................................................................................................................... 17 
3. Number of trials ............................................................................................................................. 17 
4. Statistical considerations ............................................................................................................... 17 
C.  When conducting a human efficacy trial is not ethical or feasible .......................................... 18 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Demonstrating Substantial Evidence of Effectiveness for  
2  Human Drug and Biological Products 
3  Guidance for Industry 
4   
5   
6  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
7  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
8  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
9  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
10  for this guidance as listed on the title page.   
11   
12   
13   
14  I.  INTRODUCTION  
15   
16  This document is intended to provide guidance to applicants planning to file new drug 
17  applications (NDAs), biologics license applications (BLAs), or applications for supplemental 
18  indications on the evidence to be provided to demonstrate effectiveness.  This guidance 
19  complements and expands on the 1998 guidance entitled Providing Clinical Evidence of 
20  Effectiveness for Human Drug and Biological Products (the 1998 guidance)1.   
21   
22  The 1998 guidance was issued in response to the Food and Drug Administration Modernization 
23  Act of 1997 (FDAMA) (Pub. L. 105115), which stated that the substantial evidence 
24  requirement for effectiveness, which had generally been interpreted as calling for two adequate 
25  and well-controlled trials, could also be met by a single trial2 plus confirmatory evidence.  The 
26  1998 guidance, therefore, provided many examples of the types of evidence that could be 
27  considered confirmatory evidence, with a specific focus on adequate and well-controlled trials of 
28  the test agent in related populations or indications, as well as a number of illustrations of a single 
29  adequate and well-controlled trial supported by convincing evidence of the drugs mechanism of 
30  action in treating a disease or condition.   
31   
32  FDAMA thus introduced a specific new area of flexibility in the evidence needed to support 
33  effectiveness, but there are many other characteristics of the evidence supporting effectiveness 
34  that can vary (notably, trial designs, trial endpoints, statistical methodology), and evidence that 
35  varies in such ways potentially can provide substantial evidence of effectiveness but because of 
36  these characteristics may provide greater or lesser certainty.  These characteristics also deserve 
37  consideration and were not discussed in the 1998 guidance.  FDAs consideration of these 
38  various designs, endpoints, and analyses which can differ in the strength of evidence they 
                                                 
1 FDA updates guidances periodically.  To make sure you have the most recent version of a guidance, check the 
FDA webpage.  The guidances mentioned in this document are available on the guidance web page at 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs, and 
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics.     
2 In this guidance, the terms trial and clinical trial have the same meaning as the term clinical investigation as 
the latter is defined in FDA regulations (see, e.g., 21 CFR 312.3(b)). 
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
39  provide, reflects the Agencys longstanding flexibility when considering the types of data and 
40  evidence that can meet the substantial evidence requirement.  
41   
42  Although FDAs evidentiary standard for effectiveness has not changed since 1998, the 
43  evolution of drug development and science has led to changes in the types of drug development 
44  programs submitted to the Agency.  Specifically, there are more programs studying serious 
45  diseases lacking effective treatment, more programs in rare diseases, and more programs for 
46  therapies targeted at disease subsets.  There is a need for more Agency guidance on the 
47  flexibility in the amount and type of evidence needed to meet the substantial evidence standard 
48  in these circumstances.  The approaches discussed in this guidance can yield evidence that meets 
49  the statutory standard for substantial evidence and reflect the evolving landscape of drug 
50  development. 
51   
52  The substantial evidence of effectiveness standard in the statute (discussed in Section II) refers 
53  to both the quality and the quantity of the evidence.  It clearly provides that all clinical 
54  investigations supporting effectiveness should be of appropriate design and of high quality (i.e., 
55  adequate and well-controlled; discussed in Section III).  Sponsors often seek advice on what trial 
56  design will be considered acceptable in various development programs.  This guidance discusses, 
57  in part, what clinical trial designs are considered adequate and well-controlled, and under what 
58  circumstances it may be appropriate to use a given design (discussed in Section III.A). 
59   
60  The clinical endpoints studied are a critical aspect of evidence quality (discussed in Section 
61  III.B).  The Agency accepts clinical endpoints that reflect patient benefits (i.e., how patients feel, 
62  function, or survive) or validated surrogate endpoints3 (i.e., those that have been shown to 
63  predict a specific clinical benefit) as the basis for traditional approval.  In contrast to traditional 
64  approval, accelerated approval can be based on a demonstrated effect on a surrogate endpoint 
65  that is reasonably likely to predict a clinical benefit but where there are not sufficient data to 
66  show that it is a validated surrogate endpoint.  Effects on intermediate clinical endpoints4 can 
67  also be a basis for accelerated approval.  For drugs granted accelerated approval, FDA requires 
68  post-approval trials to verify the predicted clinical benefit. 
69   
70  This guidance also discusses the quantity of evidence needed in a given development program  
71  i.e., two adequate and well-controlled trials, one adequate and well-controlled trial plus 
72  confirmatory evidence, or reliance on a previous finding of effectiveness of an approved drug 
73  when scientifically justified and legally permissible (i.e., no new effectiveness or 
74  pharmacodynamic data would be needed) (discussed in the 1998 guidance and Section IV.A, 
75  IV.B, and IV.C, respectively).  It also expands upon the discussions included in the 1998 
76  guidance on the types of mechanistic and pharmacologic evidence and non-clinical evidence that 
77  can constitute confirmatory evidence.   
78   
                                                 
3 For more information on validated surrogate endpoints, see the BEST (Biomarkers, EndpointS, and other Tools) 
Resource available at:  https://www.ncbi.nlm.nih.gov/books/NBK453484/. 
4 An intermediate clinical endpoint is a clinical endpoint that can be measured earlier than irreversible morbidity or 
mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical 
benefit.  Section 506(c)(1)(A) of the Federal Food, Drug, and Cosmetic Act (FD&C Act). 
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Draft  Not for Implementation 
79  Although randomized superiority trials with a placebo- or active-control design generally 
80  provide the strongest evidence of effectiveness, this guidance discusses the circumstances under 
81  which trials not using a placebo control, superiority design, or randomization may be acceptable 
82  (discussed in Section V.A and V.B).  In addition, this guidance also discusses situations in which 
83  human efficacy trials are not ethical or feasible, and the animal rule may be applied (discussed in 
84  Section V.C). 
85   
86  The finding of substantial evidence of effectiveness is necessary but not sufficient for FDA 
87  approval.  The approval decision also requires a determination that the drug is safe for the 
88  intended use.  As all drugs have adverse effects, evaluating whether a drug is safe involves 
89  weighing whether the benefits of the drug outweigh its risks under the conditions of use defined 
90  in labeling.  Uncertainties regarding benefits and risks are considered when making an approval 
91  determination; a drug with greater risks may require a greater magnitude and certainty of benefit 
92  to support approval.  This benefit-risk analysis, as well as other determinations necessary for 
93  approval, is outside the scope of this guidance.   
94   
95  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
96  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
97  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
98  the word should in Agency guidances means that something is suggested or recommended, but 
99  not required.  
100   
101   
102  II.  STANDARD OF EFFECTIVENESS FOR DRUGS AND BIOLOGICS 
103   
104  A.  Statutory standard 
105   
106  In 1962, Congress required for the first time that drugs be shown to be effective as well as safe.  
107  A drugs effectiveness must be established by substantial evidence, which is defined as:  
108   
109  evidence consisting of adequate and well-controlled investigations, including 
110  clinical investigations, by experts qualified by scientific training and experience 
111  to evaluate the effectiveness of the drug involved, on the basis of which it could 
112  fairly and responsibly be concluded by such experts that the drug will have the 
113  effect it purports or is represented to have under the conditions of use prescribed, 
114  recommended, or suggested in the labeling or proposed labeling thereof.5   
115   
116  Under section 351 of the Public Health Service Act (PHS Act) (42 U.S.C. 262) licenses for 
117  biologics have been issued only upon a showing that the products are safe, pure, and potent.  
118  Potency has long been interpreted to include effectiveness (21 CFR 600.3(s)).  FDA has also 
119  generally considered substantial evidence of effectiveness to be necessary to support licensure  
120   
                                                 
5 The FD&C Act section 505(d) (21 U.S.C.  355(d)). 
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
121  of a biological product under section 351 of the PHS Act.6   
122   
123  FDA has interpreted the law as generally requiring at least two adequate and well-controlled 
124  clinical investigations,7 each convincing on its own, to establish effectiveness (discussed in 
125  Section IV.A.1).  Under specific circumstances, however, FDA has considered a large 
126  multicenter trial that has certain characteristics to satisfy the legal requirement for substantial 
127  evidence of effectiveness (discussed in Section II.C.3 of the 1998 guidance and Section IV.A.2).  
128  FDA may also rely on a previous finding of effectiveness of an approved drug when 
129  scientifically justified and legally permissible; in this case there is no need for additional 
130  adequate and well-controlled clinical efficacy trials (discussed in Section IV.C). 
131   
132  In addition to reliance on a single large multicenter trial or previous finding of effectiveness of 
133  an approved drug, there are other circumstances where substantial evidence of effectiveness can 
134  be provided outside of the setting of two adequate and well-controlled clinical investigations.  
135  Congress specifically provided for these in section 115(a) of FDAMA, which amended the 
136  statutory provision on substantial evidence of effectiveness, 21 U.S.C.  355(d), to add the 
137  following: 
138   
139  If [FDA] determines, based on relevant science, that data from one adequate and 
140  well-controlled clinical investigation and confirmatory evidence (obtained prior to 
141  or after such investigation) are sufficient to establish effectiveness, [FDA] may 
142  consider such data and evidence to constitute substantial evidence. 
143   
144  This modification explicitly recognized the potential for FDA to find that one adequate and well-
145  controlled clinical investigation with confirmatory evidence, including supportive data outside of 
146  a controlled trial, is sufficient to establish effectiveness (discussed in Section IV.B). 
147   
148  B.  Scientific basis for the statutory standard 
149   
150  To establish a drugs effectiveness, it is essential to distinguish the effect of the drug from other 
151  influences, such as spontaneous change in the course of the disease, placebo effect, or biased 
152  observation. 8  This is the basis for the statutory requirement that approval be based on adequate 
153  and well-controlled investigations, as well as the basis for FDAs regulations describing the 
154  characteristics of such investigations (i.e., design elements that are generally intended to 
155  minimize bias and permit a valid comparison with a control to provide a quantitative assessment 
156  of drug effect).   
157   
                                                 
6 In 1972, FDA initiated a review of the safety and effectiveness of all previously licensed biologics.  The Agency 
stated then that proof of effectiveness would, with limited exceptions, consist of controlled clinical investigations as 
defined in the provision for adequate and well-controlled studies for new drugs (21 CFR 314.126) (see former 21 
CFR 601.25(d)(2) (2015) (revoked as no longer necessary, 81 FR 7445 (Feb. 12, 2016))).  We note that, in section 
123(f)) of FDAMA, Congress also directed the agency to take measures to minimize differences in the review and 
approval of products required to have approved BLAs under section 351 of the PHS Act and products required to 
have approved NDAs under section 505(b)(1) of the FD&C Act. 
7 See FDA regulation regarding adequate and well-controlled studies at 21 CFR 314.126. 
8 21 CFR 314.126(a). 
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158  A second adequate and well-controlled investigation or confirmatory evidence provides 
159  substantiation of experimental results, which is a widely accepted scientific principle.  This 
160  approach is intended to minimize the possibility that other influences such as bias and chance 
161  findings could result in a false conclusion that a drug is effective when in fact it is not (false 
162  positive). 
163     
164   
165  III.   THE QUALITY OF CLINICAL EVIDENCE TO ESTABLISH EFFECTIVENESS   
166   
167  The quality of clinical evidence to establish effectiveness and the resulting level of certainty 
168  about the demonstration of substantial evidence is impacted by the selection of trial design and 
169  trial endpoint(s) as well as statistical considerations, as discussed below. 
170   
171  A.  Trial designs 
172   
173  Adequate and well-controlled clinical investigations provide the primary basis for determining 
174  whether there is substantial evidence to support the claims of effectiveness.9  FDA regulation at 
175  21 CFR 314.126(b) describes characteristics of an adequate and well-controlled clinical 
176  investigation, including choice of control, method of patient assignment to treatment (e.g., 
177  randomization), adequate measures to minimize bias (e.g., blinding), well-defined and reliable 
178  assessment of individuals response (i.e., efficacy endpoint), and adequate analysis of the clinical 
179  investigations results to assess the effects of the drug (i.e., statistical methods).  Although 
180  randomized double-blinded, concurrently controlled superiority trials are usually regarded as the 
181  most rigorous design, as discussed further below, five types of controls are described in section 
182  314.126:10 placebo concurrent control, dose-comparison concurrent control, no treatment 
183  concurrent control, active treatment concurrent control, and historical control (a type of external 
184  control).11  Of note, when the first version of the rule was published in 1970, historical controls 
185  and active treatment controls were included.12  Thus, from its earliest description of adequate and 
186  well-controlled trials, FDA included trial designs (as discussed below) that may be more difficult 
187  to interpret, which reflected FDAs recognition that different trial designs (including choice of 
188  control) may be appropriate in different disease settings. 
189   
190  Establishing superiority to a concurrent control group (whether an active agent, including a lower 
191  dose of the test drug, or placebo) generally provides strong evidence of effectiveness, because a 
192  superiority design does not depend on assumptions regarding the effectiveness of the control.  
                                                 
9 The FD&C Act section 505(d) (21 U.S.C.  355(d)); 21 CFR 314.126(a). 
10 See 50 FR 7452, 7487 (February 22, 1985). 
11 The regulation uses the term historical control, which is a subset of external control.  FDA also accepts other 
types of external controls.  An externally controlled trial compares a group of subjects receiving the test treatment 
with a group of patients external to the trial, rather than to an internal control group consisting of patients from the 
same trial population assigned to a different treatment.  The external control can be a group of patients, treated or 
untreated, at an earlier time (historical control) or a group, treated or untreated, during the same time period but in 
another setting.  An important subset of externally controlled trials are baseline controlled trials, where there is not 
a specific external control group but assurance, based on experience, that no change could occur (e.g., tumors are 
known not to shrink spontaneously or patients not given general anesthetic remain awake).  See International 
Conference on Harmonisation E10 guidance on Choice of Control Group and Related Issues in Clinical Trials (ICH 
E10).  This guidance uses the term external control, except when referring to section 314.126.  
12 See 35 FR 7250, 7251-7252 (May 8, 1970). 
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193  However, each of the trial designs has distinct considerations; for example, the lack of blinding 
194  when using a no treatment control could introduce bias, which may attenuate confidence in the 
195  trials results.  The dose-comparison design may support the effectiveness of the highest dose 
196  when a positive dose response is seen, but could leave uncertainty about whether lower tested 
197  doses were effective.   
198   
199  Although demonstrating that a new drug is superior to an active control provides strong evidence 
200  of effectiveness, a common goal of active controlled trials is to show non-inferiority (NI), i.e., 
201  that the new drug is not less effective than the active control by a specified amount, that amount 
202  being no larger than the effect the active control was expected (the effect is not measured) to 
203  have had in the NI trial based on the drugs past performance in trials.  Showing such non-
204  inferiority allows a conclusion that the new drug is effective.13  In general, with regard to 
205  establishing effectiveness, NI designs are credible and appropriate only in situations in which the 
206  active control has shown a consistent effect (generally compared with placebo) in prior 
207  superiority trials conducted in a patient population similar to the population in the clinical 
208  investigation being planned.  Unless a placebo group (or other treatment group where the intent 
209  is to demonstrate superiority of the test drug) is also included, these NI trials depend on the 
210  assumption, not confirmed in the trial, that the active control had its anticipated effect (which is 
211  the basis for the NI margin) in the trial.  As a result, the strength of evidence that may result from 
212  an NI trial can vary considerably depending on the specific disease setting and the choice of 
213  active control.  An NI trial that meets its objective (with respect to the pre-specified statistical 
214  testing plan) could mean either that both drugs were effective or, if neither control nor drug has 
215  its expected effect, that neither was effective in the trial.  Because interpretation of NI trials 
216  depends on assumptions not confirmed in the trial, this design is usually chosen when it would 
217  be unethical or infeasible to conduct one of the superiority designs discussed above (e.g., when 
218  withholding available therapy would not be clinically acceptable and the new drug is being 
219  studied as an alternative, rather than as an adjunct, to available therapy).    
220   
221  Externally controlled trials differ in several important ways from the other trial designs identified 
222  in 21 CFR 314.126.  Most notably, random assignment is not a feature of external control 
223  designs.  As a result, there may be differences in patient characteristics or concomitant 
224  treatments in the trial population compared to the external control population that lead to 
225  differences in outcomes that are unrelated to the investigational treatment.  In addition, the lack 
226  of blinding could introduce bias.  For these reasons, external control designs are usually reserved 
227  for specific circumstances, such as trials of diseases with high and predictable mortality or 
228  progressive morbidity (e.g., certain malignancies or certain rare diseases) and trials in which the 
229  effect of the drug is self-evident (e.g., general anesthetics).   
230   
231  Despite the limitations of externally controlled trials compared with concurrently controlled 
232  trials, strong support for effectiveness can emerge from externally controlled trials, especially 
233  when (1) the natural history of a disease is well defined, (2) the external control population is 
234  very similar to that of the treatment group, (3) concomitant treatments that affect the primary 
235  endpoint are not substantially different between the external control population and the trial 
236  population, and (4) the results provide compelling evidence of a change in the established 
237  progression of disease.  Such results could include partial or complete response in a disease 
                                                 
13 FDA guidance on Non-Inferiority Clinical Trials to Establish Effectiveness. 
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238  where spontaneous regression is not observed, or stabilization or improvement in function in a 
239  disease where progressive functional decline is well documented to occur over the duration of 
240  the treatment period in the trial.  Another example of where there is strong evidence of drug 
241  effectiveness is reversal of clinical signs and symptoms following a toxic exposure or overdose 
242  after administration of a drug antidote.  In all such circumstances, a detailed understanding of the 
243  full range of possible clinical outcomes, with a well-documented natural history of the disease in 
244  the absence of treatment, is essential to interpreting trial results and, therefore, drawing a 
245  conclusion about the effectiveness of the drug.  
246   
247  It is important to recognize that trial design alone does not determine whether evidence from the 
248  trial is sufficient to establish substantial evidence of effectiveness.  For example, compelling 
249  results may overcome challenges associated with less rigorous trial designs, such as those with 
250  an external control.  As discussed above, a small externally controlled trial with an outcome 
251  markedly superior to the well-established natural history of a disease may provide a compelling 
252  case for drug effectiveness.  Similarly, a successful active-controlled NI trial of a new 
253  antimicrobial drug or of a new anticoagulant to prevent stroke in patients with atrial fibrillation 
254  can provide strong evidence of effectiveness when it is well-established that the effect of the 
255  control antimicrobial or anticoagulant drug is large.   
256   
257  Poor execution can render a trial of any design to be not adequate or not well-controlled and, 
258  therefore, unable to provide substantial evidence of effectiveness.  Examples of this include (1) a 
259  randomized, double-blind, placebo-controlled trial where there is extensive drop-out of trial 
260  patients (with the potential for informative censoring), and (2) a randomized, double-blind, 
261  placebo-controlled trial in which unblinding is common due to an effect of the test drug, and 
262  where a modest treatment effect is found on a primary endpoint that is subject to bias when drug 
263  assignment is known (e.g., a physician global impression).  In these cases, the trials might not be 
264  considered adequate and well-controlled.  
265   
266  B.  Trial endpoints 
267   
268  One of the characteristics of an adequate and well-controlled clinical investigation is that the 
269  methods of assessment of subjects response are well-defined and reliable.14  Such a method of 
270  assessment can be a clinical endpoint15 or, where appropriate, a surrogate endpoint.16 
271   
                                                 
14 21 CFR 314.126(b)(6). 
15 An endpoint is a precisely defined variable intended to reflect an outcome of interest as a measure of drug effect 
that is prespecified (i.e., chosen before the data are analyzed) and statistically analyzed to address a particular 
research question.  A definition of clinical endpoint is provided in FDA guidance on Expedited Programs for 
Serious Conditions  Drugs and Biologics (FDA guidance on expedited programs).  A clinical endpoint can be used 
to support traditional approval. 
16 A definition of surrogate endpoint is provided in FDA guidance on expedited programs.  A surrogate endpoint 
that has been shown to predict a specific clinical benefit can be used to support traditional approval.  A surrogate 
endpoint that is reasonably likely to predict clinical benefit can be used to support accelerated approval.  Accelerated 
approval can also be based on an effect on a clinical endpoint that can be measured earlier than irreversible 
morbidity or mortality (IMM) and that is reasonably likely to predict an effect on IMM or other clinical benefit.  See 
FDA web page on Table of Surrogate Endpoints That Were the Basis of Drug Approval or Licensure, available at 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm613636.htm. 
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272  Although the statutory standard for effectiveness does not refer to particular endpoints or state a 
273  preference for clinical endpoints over surrogate endpoints, it is well established that the effect 
274  shown in the adequate and well-controlled clinical investigations, must be, in FDAs judgment, 
275  clinically meaningful.17 
276   
277  Many disease specific guidances have been issued by the Agency that can assist sponsors in 
278  identifying an appropriate trial endpoint.  In addition, discussion with appropriate review 
279  divisions early in clinical development can assist sponsors in identifying appropriate trial 
280  endpoints for a particular development program. 
281   
282  C.  Statistical considerations 
283   
284  The strength of evidence in each trial contributing to meeting the substantial evidence standard 
285  should be assessed by appropriate statistical methods.  The uncertainty about the findings from 
286  each trial should be sufficiently small and the findings should be unlikely to result from chance 
287  alone, as demonstrated by a statistically significant result or a high posterior probability of 
288  effectiveness.18  Statistical approaches should be specified in advance, to limit erroneous 
289  conclusions resulting from multiplicity. 
290   
291   
292  IV.  THE QUANTITY OF CLINICAL EVIDENCE TO ESTABLISH 
293  EFFECTIVENESS 
294   
295  A.  Meeting the substantial evidence standard based on two adequate and well-
296  controlled clinical investigations 
297   
298  1.  Two adequate and well-controlled clinical investigations 
299   
300  In many situations FDA requires two adequate and well-controlled trials to establish 
301  effectiveness.  This reflects the need for substantiation of experimental results, which has often 
302  been referred to as the need for replication of the finding.  Replication may not be the best term, 
303  however, as it may imply that precise repetition of the same experiment in other patients by other 
304  investigators is the only means to substantiate a conclusion.  Although two positive identically 
305  designed and conducted trials can provide substantial evidence of effectiveness, precise 
306  replication of a trial is only one of a number of possible means of obtaining substantiation of a 
307  clinical finding and, at times, can provide less persuasive evidence of benefit, as it could leave 
308  the conclusions of both trials vulnerable to any systematic biases inherent to the particular study 
309  design.   
310   
311  Two positive trials with differences in design and conduct may be more persuasive, as 
312  unrecognized design flaws or biases in study conduct will be less likely to impact the outcomes 
313  of both trials.  The consistency of results across two trials also greatly reduces the possibility that 
314  a biased, chance, site-specific, or fraudulent result will lead to an erroneous conclusion that a 
                                                 
17 See preamble to FDA final rule on accelerated approval (57 FR 58942, 58944 (December 11, 1992)). 
18 In a Bayesian framework the strength of evidence is assessed by the probability that the drug is effective given the 
data rather than by statistical significance. 
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315  drug is effective.  Such trials also may be more informative: for example, two positive trials 
316  using the same endpoint but with distinct study populations within the same proposed indication 
317  (e.g., one trial studying a new glucose-lowering drug in patients with type 2 diabetes receiving 
318  only diet and exercise therapy, and a second trial in patients with type 2 diabetes already on two 
319  or three oral antihyperglycemic agents) may provide evidence that is more generalizable to the 
320  population that will take the drug than two identical trials in a narrower population.  Similarly, 
321  two trials in the same disease using different but related clinical endpoints could support 
322  effectiveness and provide broader information about the drugs effect (e.g., one trial showing 
323  symptom improvement and a second trial showing improved survival in a more severely ill 
324  population). 
325   
326  2.         One adequate and well-controlled large multicenter trial that can provide 
327  substantial evidence of effectiveness 
328   
329  In general, substantiation of a drugs effectiveness obtained with two trials, especially with 
330  complementary design, as discussed above, will provide more convincing evidence of 
331  effectiveness than would a single trial.  In some circumstances, however, there may not be a 
332  meaningful difference between the strength of evidence provided by a single large multicenter 
333  adequate and well-controlled trial and that provided by two smaller adequate and well-controlled 
334  trials.  In such cases, the large multicenter trial can be considered, both scientifically and legally, 
335  to be, in effect, multiple trials and can be relied on to provide substantial evidence of 
336  effectiveness.  Large multicenter trials can include a broad range of subjects and investigation 
337  sites and have procedures in place to ensure trial quality (e.g., investigation site selection, 
338  monitoring, and auditing).  They generally are less vulnerable to certain biases such as selection 
339  or measurement bias, are often more generalizable to the intended population, and can often be 
340  evaluated for internal consistency across subgroups, centers, and multiple endpoints.  
341   
342  Reliance on a single large multicenter trial to establish effectiveness should generally be limited 
343  to situations in which the trial has demonstrated a clinically meaningful and statistically very 
344  persuasive effect on mortality, severe or irreversible morbidity, or prevention of a disease with 
345  potentially serious outcome, and with other characteristics described below, and confirmation of 
346  the result in a second trial would be impracticable or unethical.  For example, conducting a 
347  second trial after a strongly positive trial had demonstrated a decrease in post-infarction 
348  mortality, or prevention of pertussis would generally present significant ethical concerns.  
349  Repetition of positive trials showing only symptomatic benefit would generally not present the 
350  same ethical concerns. 
351   
352  In addition to the expectation that the single trial is large and multicenter, there should be no 
353  single trial site that is the main contributor to the observed effect, either by virtue of having a 
354  much bigger effect or many more patients than other sites; these characteristics help address 
355  concerns about bias and chance findings associated with a single trial.  As noted above it would 
356  also be expected that the effect size on the primary endpoint and the statistical analysis results 
357  are both persuasive. 
358   
359  Other characteristics, discussed below, also support the persuasiveness of a single trial in 
360  supporting the conclusion that there is substantial evidence of effectiveness.  Finding consistent, 
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361  and clinically meaningful effects on distinct prospectively specified endpoints (e.g., an effect on 
362  both myocardial infarction and stroke for a drug being studied for cardiovascular benefit) can 
363  provide further evidence that the results are not due to chance.  Moreover, an effect on a 
364  meaningful, objective endpoint, such as certain imaging endpoints, may complement a more 
365  subjective endpoint, such as a clinician- or patient-reported outcome.  In these cases, the internal 
366  consistency across endpoints not only reduces the possibility of a chance finding but also may 
367  further support the clinical utility of the results. 
368   
369  Frequently, large multicenter trials have relatively broad entry criteria and the trial populations 
370  may be diverse with regard to important covariates such as concomitant or prior therapy, disease 
371  stage, age, gender or race.  Analysis of the results of such trials for consistency across important 
372  patient subgroups can address concerns about generalizability of findings to various populations 
373  in a manner that may not be possible with smaller trials or trials with more narrow entry criteria. 
374   
375  Furthermore, there may be other characteristics of a large multicenter trial that increase 
376  confidence in its results.  For example, the multicenter trial may sometimes be appropriately 
377  analyzed as multiple trials within a single trial.  An example is a 4-arm (22 factorial) trial 
378  (placebo, drug A, drug B, and drug A + drug B) in which the effectiveness of drug A could be 
379  supported by two controlled comparisons if the combination of drug A + drug B is superior to 
380  drug B alone and drug A is superior to placebo. 
381   
382  Although a large multicenter trial with robust results can be persuasive, even a robust result can 
383  arise from bias.  For example, although two consistent findings within a single trial usually 
384  provide reassurance that a positive treatment effect is not due to chance, they do not protect 
385  against bias in trial conduct, biased analyses, or fraud.  Thus, close scrutiny of trial conduct, 
386  including, for example, completeness of follow-up, methods of analysis, imputation of missing 
387  data, evaluation of trial endpoints, is critical to evaluating such trials.  Findings from other trials 
388  that are not consistent with the findings of the single positive trial would need to be considered 
389  collectively, and could weaken the overall strength of evidence.   
390   
391  B.  Meeting the substantial evidence standard based on one adequate and well-
392  controlled clinical investigation plus confirmatory evidence 
393   
394  Under certain circumstances and consistent with FDAMA, FDA can conclude that one adequate 
395  and well-controlled clinical investigation plus confirmatory evidence is sufficient to establish 
396  effectiveness.  FDA will consider a number of factors when determining whether reliance on a 
397  single adequate and well-controlled clinical investigation plus confirmatory evidence is 
398  appropriate.  These factors may include the persuasiveness of the single trial; the robustness of 
399  the confirmatory evidence; the seriousness of the disease,19 particularly where there is an unmet 
400  medical need; the size of the patient population; and whether it is ethical and practicable to 
401  conduct more than one adequate and well-controlled clinical investigation.  Sponsors intending 
402  to establish substantial evidence of effectiveness using one adequate and well-controlled clinical 
                                                 
19 While seriousness of the disease is one of the factors that FDA considers, reliance on a single trial plus 
confirmatory evidence to establish effectiveness is not limited only to drugs for serious diseases, as the term is 
defined in 21 CFR 312.300(b)(1). 
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403  investigation plus confirmatory evidence should consult FDA in advance to discuss the 
404  appropriateness of such an approach for their development program. 
405    
406  Confirmatory evidence could include, for example, adequate and well-controlled clinical 
407  investigations in a related disease area, certain types of real world evidence20 such as extensive 
408  data on outcomes that provide further support for the lack of effect seen in the control group in 
409  the randomized trial, compelling mechanistic evidence in the setting of well-understood disease 
410  pathophysiology (e.g., pharmacodynamic data or compelling data from nonclinical testing), or 
411  well-documented natural history of the disease. 
412   
413  Below are examples of when a single adequate and well-controlled clinical investigation, 
414  together with confirmatory evidence, can establish effectiveness.  The strength of the single trial 
415  will affect the extent of confirmatory evidence required  for example, a trial showing 
416  compelling efficacy results (but not rising to the level that would be provided by a large 
417  multicenter trial, as discussed in Section IV.A.2) may require less confirmatory evidence.   
418   
419  1.  One adequate and well-controlled clinical investigation on a new indication for 
420  an approved drug, supported by existing adequate and well-controlled clinical 
421  investigation(s) that demonstrated the effectiveness of the drug for its other, 
422  closely related approved indication(s) 
423   
424  To establish effectiveness for a new indication of a product already approved by FDA  where 
425  the new indication is closely related to the other approved indication(s)  substantial evidence of 
426  effectiveness can be based on one adequate and well-controlled clinical investigation, generally a 
427  randomized concurrently controlled trial, of the new indication, supported by the confirmatory 
428  evidence provided by the existing adequate and well-controlled clinical investigation(s) that 
429  established effectiveness of the product for the related indication(s).  See Section II.C.2 of the 
430  1998 guidance for more details. 
431   
432  2.  One adequate and well-controlled clinical investigation supported by data that 
433  provide strong mechanistic support 
434   
435  A single adequate and well-controlled clinical investigation, generally a randomized 
436  concurrently controlled trial, together with earlier phase clinical results and/or testing that 
437  provide compelling mechanistic evidence in the setting of well-understood disease 
438  pathophysiology, may be sufficient to provide substantial evidence of effectiveness of a new 
439  drug or a new indication.  The mechanistic evidence would generally be obtained from clinical 
440  testing using a relevant and well understood pharmacodynamic endpoint not accepted by itself as 
441  an endpoint to establish evidence of effectiveness.  It also could be collected from other sources, 
442  such as animal studies (e.g., those using an established, relevant animal model to study the effect 
443  of the drug on a pharmacodynamic marker of known relevance to humans), or a combination of 
                                                 
20 Real world evidence is the clinical evidence regarding the usage, and potential benefits or risks, of a medical 
product derived from analysis of real world data.  Real world data are data relating to patient health status and/or the 
delivery of health care routinely collected from a variety of sources.  See FDA real world evidence web page, 
available at https://www.fda.gov/science-research/science-and-research-special-topics/real-world-evidence. 
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444  the two. 21  An example is enzyme replacement therapy, where a single adequate and well-
445  controlled clinical investigation that demonstrates the therapys efficacy is supported by 
446  evidence that the condition is caused by the enzyme deficiency and by earlier results that show 
447  the therapy increases enzyme activity to biologically active levels at the appropriate site and/or 
448  reduces disease-specific substrates.  Another example could be a trial of a drug which is a 
449  mineral or vitamin replacement that showed restoration of accepted normal concentrations, in 
450  concert with a prior large body of information showing the clinical consequences of deficiency 
451  states. 
452   
453  3.  One adequate and well-controlled clinical investigation with compelling results, 
454  supported by additional data from the natural history of the disease 
455   
456  In certain circumstances, FDA accepts one adequate and well-controlled clinical investigation 
457  that has generated compelling results as the basis to demonstrate effectiveness, when the single 
458  trial is supported by additional data from the natural history of the disease that reinforce the very 
459  persuasive finding.  For example, a single trial showing marked improvement in survival 
460  compared to a control group, either external to the trial or concurrent, could be supported by data 
461  from separate sources (e.g., a natural history study, case report forms, or registries) that 
462  demonstrate a very limited median survival time or other clinically highly important outcome 
463  without treatment.  In this case, the natural history data would represent confirmatory evidence. 
464   
465  4.  One adequate and well-controlled clinical investigation of the new drug, 
466  supported by scientific knowledge about the effectiveness of other drugs in the 
467  same pharmacological class 
468   
469  In certain circumstances, FDA accepts one adequate and well-controlled clinical investigation as 
470  the basis to demonstrate effectiveness, when the single trial is supported by confirmatory 
471  evidence of effectiveness from adequate and well-controlled trials of other drugs in the same 
472  pharmacological class.22  For example, the approval of two angiotensin II receptor blockers, 
473  losartan and irbesartan, for the treatment of diabetic nephropathy in patients with type 2 diabetes, 
474  hypertension, and abnormal kidney function, was based on effectiveness data from a single trial 
475  of each drug, supported by similarly favorable results from a single trial of the other drug.  In this 
                                                 
21 FDA supports 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 non-animal testing method they believe is suitable, 
adequate, validated, and feasible.  FDA will consider if such an alternative method could be assessed for 
equivalency to an animal test method. 
22 Reliance on data concerning a different drug raises legal issues that will need to be considered in each case.  If the 
applicant owns the data concerning the other drug, or has a right to refer to those data, such as a license, then the 
legal concerns are satisfied.  In the example of losartan and irbesartan cited in the text, the two applicants each 
agreed to permit the other to rely on their data.  If there is not such permission, for an NDA, the question will be 
raised whether the reliance makes the application a 505(b)(2) application.  If so, that may require compliance with 
patent certification requirements applicable to such applications and may mean that the submission or approval of 
the application will be affected by statutory exclusivity provisions.  For a BLA, in certain circumstances reliance on 
data not owned by the applicant, that is not in the public domain, and for which the applicant does not have a right of 
reference would raise additional legal considerations.   
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476  case, the two single trials supplied the needed confirmatory evidence for each other, as neither 
477  drug would have been approved for this indication based on the single trial alone.23 
478   
479  Whether this scenario applies to a particular development program depends on a number of 
480  factors, including but not limited to: (1) the strength of the evidence for effectiveness from the 
481  single trial; and (2) the relevance of the additional data derived from other drugs in the same 
482  class, including the similarity between the new drug and other drugs in the same class, 
483  particularly the pharmacologic activity or specificity of mechanism of action.24 
484   
485  C.  Meeting the substantial evidence standard for a new population or a 
486  different dose, regimen, or dosage form, based on reliance of FDAs previous 
487  finding of effectiveness of an approved drug when scientifically justified and 
488  legally permissible 
489   
490  When scientifically justified and legally permissible, FDA can rely on its previous finding of 
491  effectiveness of an approved drug to conclude that the drug will have the effect it purports or is 
492  represented to have,25 thus not requiring additional adequate and well-controlled clinical 
493  efficacy trials.  Ordinarily, this will be because other types of evidence provide a way to apply 
494  the known effectiveness to a new population or a different dose, regimen, or dosage form.  For 
495  example, the effectiveness of a drug for pediatric use can sometimes be based on FDAs previous 
496  finding of effectiveness of the drug in adults, together with scientific evidence that justifies such 
497  reliance.26  In this case, the scientific evidence may include, for example, evidence supporting a 
498  conclusion of similar disease course and pathophysiologic basis in adult and pediatric 
499  populations, and similar pharmacologic activity of the drug in adults and children (e.g., similar 
500  concentration-response relationships), as well as similar blood levels of the drug in adults and 
501  children.  The effectiveness of new dosage forms or dosing regimens may be demonstrated by 
502  the effectiveness trial(s) on the original dosage form or regimen, together with evidence that both 
503  the dosage forms or regimens have similar pharmacokinetic (PK) profiles.  In this case no new 
504  effectiveness or pharmacodynamic data would be needed, but sufficient safety data would still be 
505  needed.  See Section II.C.1. of the 1998 guidance for more details. 
506   
507   
                                                 
23 See Secondary Review Memo on losartan, May 3, 2002, available at 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/20386-S028_COZAAR_Medr1.pdf; see also the FDA-
approved labels for both products. 
24 A product development program under this scenario may result in a small safety database.  Sponsors should 
consult FDA guidance on Premarketing Risk Assessment, which notes that the appropriate size of a safety database 
depends on a number of factors specific to the product; two of them are particularly relevant to this scenario, i.e., the 
products novelty (i.e., whether it represents a new treatment or is similar to available treatment) and the availability 
of alternative therapies and the relative safety of those alternatives as compared to the new product.  For more 
details, see FDA guidance on Premarketing Risk Assessment. 
25 See the statutory definition of substantial evidence in section 505(d) of the FD&C Act. 
26 Section 505B(a)(2)(B)(i) of the FD&C Act (21 U.S.C.  355c(a)(2)(B)(i)). 
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508  V.     EXAMPLES OF CLINICAL CIRCUMSTANCES WHERE ADDITIONAL 
509  FLEXIBILITY MAY BE WARRANTED  
510   
511  The statutory standard of substantial evidence contains both a statement of what kind of 
512  evidence must exist (adequate and well-controlled investigations) and also an element of 
513  expert judgment.  Thus the standard requires that the investigations be such that it could fairly 
514  and responsibly be concluded by [qualified] experts that the drug will have the effect it purports 
515  or is represented to have,27 and permits approval on the basis of one trial and confirmatory 
516  evidence only If [FDA] determines, based on relevant science, that data . . . are sufficient to 
517  establish effectiveness.  For example, while FDA regulations outline five different types of 
518  studies that might be considered adequate and well-controlled,28 it has always been recognized 
519  that some designs (e.g., placebo concurrent control) provide more certainty than others (e.g., 
520  external controls).  FDA experts may fairly and responsibly rely on study designs that produce 
521  less certainty in some circumstances when a better design is not feasible or ethical.  This may be 
522  the case for life-threatening and severely debilitating diseases with an unmet medical need, for 
523  certain rare diseases, or potentially even for a more common disease where the availability of 
524  existing treatments makes certain design choices infeasible or unethical.  FDA would not, 
525  however, find it responsible to rely on such design choices in other situations in which, for 
526  example, the drug will be used for a less serious disease and greater certainty about benefits and 
527  risks is needed, or in cases where designs providing more certainty are possible.  In all cases, 
528  FDA must reach the conclusion that there is substantial evidence of effectiveness to approve a 
529  drug; however, the degree of certainty supporting such a conclusion may differ, depending on 
530  clinical circumstances (e.g., severity and rarity of the disease and unmet medical need). 
531   
532  This reflects the longstanding awareness that, in certain settings, a somewhat greater risk 
533  (compared to placebo-controlled or other randomized superiority trials) of false positive 
534  conclusions  and therefore less certainty about effectiveness  may be acceptable, when 
535  balanced against the risk of rejecting or delaying the marketing of an effective therapy, as 
536  described below for an unmet medical need.  The data supporting effectiveness could, despite the 
537  greater risk of error, support a conclusion that there is substantial evidence of effectiveness.  
538  Therefore, when selecting a trial design, a sponsor should consider the specific clinical 
539  circumstance, including the severity of the disease, unmet medical need (e.g., whether there is 
540  available therapy), the rarity of the disease, and whether it is feasible and ethical to conduct a 
541  randomized concurrently controlled superiority trial. 
542   
543  A.  When the disease is life-threatening or severely debilitating with an unmet 
544  medical need 
545   
546  As defined in 21 CFR 312, subpart E (21 CFR 312.81), the term life-threatening means 
547  diseases or conditions where the likelihood of death is high unless the course of the disease is 
548  interrupted, and diseases or conditions with potentially fatal outcomes, where the endpoint of 
549  clinical trial analysis is survival; the term severely debilitating means diseases or conditions 
                                                 
27 The law is clear that it is the FDA which must determine, after giving full consideration to all of the evidence 
that has been submitted, including expert opinions, if the studies meet the regulatory criteria and show 
effectiveness.  Warner-Lambert Co. v. Heckler, 787 F.2d 147, 154 (3rd Cir. 1986). 
28 21 CFR 314.126(b)(2). 
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550  that cause major irreversible morbidity.  An unmet medical need is a condition whose treatment 
551  or diagnosis is not addressed adequately by available therapy.29 
552   
553  Subpart E regulations promulgated in 198830 call for FDA to exercise its broad scientific 
554  judgment in applying the evidentiary approval standards to drugs for life-threatening and 
555  severely debilitating diseases, especially where there is no satisfactory alternative therapy.  In 
556  addition, the accelerated approval regulations built upon this recognition by acknowledging that 
557  reliance on a surrogate endpoint almost always introduces some uncertainty into the risk/benefit 
558  assessment, because clinical benefit is not measured directly and the quantitative relation of the 
559  effect on the surrogate to the clinical effect is rarely known.31  Together these regulations 
560  recognize the importance of facilitating the development of, and access to, safe and effective 
561  treatment options for life-threatening and severely debilitating diseases with unmet medical 
562  needs.  This approach has been reinforced by FDAs interactions with patients and their 
563  caregivers who describe their willingness to accept less certainty about effectiveness in return for 
564  earlier access to much needed medicines.  For example, for a life-threatening disease without any 
565  available treatment, FDA might accept the results of adequate and well-controlled investigations 
566  with less rigorous designs, such as a historically controlled study.  Below are considerations for 
567  drugs developed for life-threatening and severely debilitating diseases. 
568   
569  1.  Trial design 
570   
571  While a randomized placebo-controlled trial can provide more definitive evidence of a small 
572  treatment effect than any other kind of trial of the same size, there are instances when this design 
573  and other concurrently controlled superiority designs may not be feasible or ethical.  In such 
574  settings, other trial designs, such as non-inferiority trials or externally controlled trials can be 
575  acceptable if they provide substantial evidence of effectiveness (see discussion of noninferiority 
576  design and external control in Section III.A).  
577   
578  2.  Trial endpoints 
579   
580  As discussed in Section III.B, endpoint selection is an important consideration in clinical trial 
581  design.  The most straightforward and readily interpreted endpoints are those that directly 
582  measure clinical benefit or are validated surrogate endpoints shown to predict clinical benefit.  
583  Surrogate endpoints that are reasonably likely to predict clinical benefit can be relied on to 
584  establish effectiveness under the accelerated approval pathway.  Effects on intermediate clinical 
585  endpoints can also be a basis for accelerated approval.  Surrogate and intermediate clinical 
586  endpoints often can be assessed sooner than an endpoint that directly measures the clinical 
587  benefit or irreversible morbidity or mortality.  Note that for accelerated approval the evidentiary 
588  standard still applies  that is, there must be substantial evidence that the drug has a meaningful 
589  effect on the surrogate or intermediate clinical endpoint. 
                                                 
29 FDA guidance on expedited programs. 
30 21 CFR 312.80, subpart E; 21 CFR 314.105(c). 
31 The preamble to the final rule on accelerated approval also notes, when responding to a comment, that [a]lthough 
studies using surrogate endpoints may provide less assurance of clinical benefit than studies using clinical endpoints, 
FDA believes compliance with all of the elements of the accelerated approval program will not result in the 
marketing of large numbers of clinically ineffective drugs.  57 FR 58942, 58944 (December 11, 1992). 
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590  3.  Number of trials 
591   
592  Although two adequate and well-controlled clinical investigations remain the standard approach 
593  to generating substantial evidence of effectiveness in many disease settings, there are scenarios 
594  where the conduct of a second trial is not ethical or feasible.   
595   
596  For example, as discussed in section IV.A.2, when a large multicenter trial has demonstrated a 
597  clinically meaningful and statistically very persuasive effect on mortality, irreversible morbidity, 
598  or prevention of a disease with potentially serious outcome, a second trial would be 
599  impracticable or unethical.  In this case the single large multicenter trial would be considered 
600  sufficient to establish effectiveness. 
601   
602  4.  Statistical considerations 
603   
604  A typical criterion for concluding that a trial is positive (showed an effect) is a p value of < 0.05 
605  (two sided).  A lower p value, for example, would often be expected for reliance on a single trial.  
606  For a serious disease with no available therapy or a rare disease where sample size might be 
607  limited, as discussed further below, a somewhat higher p value  if prespecified and 
608  appropriately justified  might be acceptable. 
609   
610  B.  When the disease is rare 
611   
612  By statutory definition, a rare disease  including a genetically defined subset of a disease   
613  affects fewer than 200,000 people in the U.S.;32 but many rare diseases affect far fewer patients.  
614  A large number of rare diseases are pediatric diseases or have childhood onset.  In addition, 
615  many rare disorders are life-threatening or severely debilitating diseases with no approved 
616  treatments, leaving substantial unmet medical needs for patients.  Therefore, many of the 
617  considerations discussed above also apply to development programs for rare diseases.   
618   
619  FDA has a history of applying the philosophy underlying subpart E regulations to drugs for rare 
620  diseases.  FDA recognizes that certain aspects of drug development that are feasible for common 
621  diseases may not be feasible for rare diseases and that development challenges are often greater 
622  with increasing rarity of the disease.  The small population affected by a rare disease presents 
623  additional considerations that must be addressed and also calls for appropriate flexibility, 
624  discussed below. 
625   
626  1.  Trial design 
627   
628  Because of the small number of patients with a rare disease, the number of patients eligible for 
629  enrollment in a trial may be small.  In such situations, it is especially important to consider the 
630  advantages and disadvantages of various trial designs to achieve the objectives of establishing 
631  evidence of effectiveness as well as safety.  Randomized, placebo-controlled trials with equal 
632  allocation are generally the most efficient designs to assess effectiveness; however, depending on 
633  the circumstances, sponsors should consider alternatives such as unequal allocation in a 
634  randomized controlled trial (i.e., more patients receive the new drug than the control), which can 
                                                 
32 Section 526(a)(2) of the FD&C Act (21 U.S.C. 360bb(a)(2)). 
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635  provide increased safety experience and reduce the use of placebo, or a dose-comparison design 
636  (i.e., randomization to more than one dose, with or without placebo).  If the effect of the drug can 
637  be discerned relatively quickly after starting or discontinuing the drug, designs such as cross-
638  over trials, randomized withdrawal, or randomized delayed start should also be considered.  
639  Sometimes, as noted previously, a single-arm trial with an external control is an appropriate 
640  option.  The ability of these or other trial designs to generate substantial evidence of 
641  effectiveness is dependent on the specifics of each situation. 
642   
643  Sponsors of drugs intended for rare diseases should consider designing their first-in-human trial 
644  to be an adequate and well-controlled clinical investigation that has the potential, depending on 
645  the trial results, to provide part of the substantial evidence of effectiveness to support a 
646  marketing application.33 
647   
648  2.  Trial endpoints 
649   
650  Understanding of the pathophysiology of the underlying disease is important in planning clinical 
651  trials, including selection of endpoints.  For many rare diseases, well-characterized clinical 
652  efficacy endpoints appropriate for the disease may need to be developed.  In cases where 
653  utilizing clinical endpoints is not feasible because changes in symptoms and disease status occur 
654  too slowly to be measured in a clinical trial of reasonable duration, surrogate endpoints may be 
655  considered.  It will be particularly important to understand the pathophysiology and natural 
656  history of the disease to help identify potential surrogate endpoints. 
657   
658  3.  Number of trials 
659   
660  A second trial may be infeasible in certain rare disease settings where the limited patient 
661  populations preclude the conduct of a second trial.  A similar situation may also arise when a 
662  drug is developed to target, for example, a low-frequency, molecularly defined subset of a more 
663  common disease and it may not be possible to screen and enroll enough patients within a 
664  reasonable period of time to conduct the second trial.34  In these cases, the substantial evidence 
665  of effectiveness would typically be provided by a single trial plus confirmatory evidence. 
666   
667  4.  Statistical considerations 
668   
669  As noted above, treatments for rare diseases often are intended to address unmet medical needs, 
670  and the considerations of balancing the harmful consequences of false positive and false negative 
671  results will often apply.  In addition, the amount of evidence that can practically be acquired may 
672  be limited by the number of patients who can be recruited for trials.  FDA may interpret the 
673  substantial evidence standard flexibly considering the harmful consequences of false negative 
674  and false positive results and the amount of evidence that can practically be acquired.  Statistical 
675  approaches to evaluating treatments for rare diseases should consider the feasibility of trial 
                                                 
33 Draft guidance for industry Human Gene Therapy for Rare Diseases (July 2018).  When final, this guidance will 
represent the Agencys thinking on the topic is addresses. 
34 Guidance for industry Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease 
(October 2018). 
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676  design, sample size, and endpoints, using methods and thresholds for demonstrating substantial 
677  evidence that are appropriate to these settings.  
678   
679  C.  When conducting a human efficacy trial is not ethical or feasible 
680   
681  When it is not ethical or feasible to conduct clinical trials, FDA can allow the use of appropriate 
682  animal models to generate evidence to establish effectiveness for products intended to treat or 
683  prevent serious or life-threatening conditions caused by exposure to toxic biological, chemical,  
684  radiological, or nuclear substances.  FDAs regulation governing these trials is known as the 
685  Animal Rule.35 
                                                 
35 The Animal Rule applies to certain new drug products that have been studied for their safety and efficacy in 
ameliorating or preventing serious or life-threatening conditions caused by exposure to lethal or permanently 
disabling toxic biological, chemical, radiological, or nuclear substances. 21 CFR 314.600; see also 21 CFR 601.90 
(same restriction with respect to biological products). 
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