Alcoholism: 

Developing Drugs for 

Treatment 

Guidance for Industry 

 
 
 
 
 
DRAFT GUIDANCE
 
 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance. Submit electronic comments to http://www.regulations.gov.  Submit written 
comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, rm. 1061, Rockville, MD  20852. All comments should be identified with 
the docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document contact Rachel Skeete at 301-796-2280.  
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER)
  
 
February 2015 

Clinical/Medical 
 
15003dft.doc  
 
02/09/15   
Alcoholism: 

Developing Drugs for 

Treatment 

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 
  
Tel: 855-543-3784 or 301-796-3400;  Fax: 301-431-6353; Email:  druginfo@fda.hhs.gov  

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER)
  
 
February 2015 

Clinical/Medical 
 
   
TABLE OF CONTENTS 
 
 
I.   INTRODUCTION............................................................................................................. 1
  
II.   DEVELOPMENT PROGRAM ....................................................................................... 2
  
A.   General Considerations .................................................................................................................3
  
1.  Early Phase Clinical Development Considerations .........................................................................3
  
2.  Drug Development Population .........................................................................................................3
  
3.  Efficacy Considerations ...................................................................................................................4
  
4.  Safety Considerations.......................................................................................................................4
  
B.   Specific Efficacy Trial Considerations .........................................................................................4
  
1.  Trial Design......................................................................................................................................4
  
2.  Trial Population ...............................................................................................................................5
  
3.  Entry Criteria ...................................................................................................................................6
  
4.  Special Populations  ..........................................................................................................................6
  
5.  Choice of Comparators ....................................................................................................................6
  
6.  Efficacy Endpoints ............................................................................................................................7
  
7.  Endpoint Adjudication ......................................................................................................................7 
 
REFERENCES.............................................................................................................................. 9 
 
APPENDIX 1: TERMINOLOGY RELATED TO PROBLEM ALCOHOL USE .............. 10 
 
APPENDIX 2: SOURCES PROVIDING SUPPORT FOR NO HEAVY DRINKING 

AS A VALID SURROGATE FOR CLINICAL BENEFIT .................................................... 11 
 
 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation  
Alcoholism:  Developing Drugs for Treatment 
1 
1 
Guidance for Industry  
2 
3   
4   
5   
6   
7  This draft guidance, when finalized, will represent the Food and Drug Administrations (FDAs) current 
8  thinking on this topic.  It does not create or confer any rights for or  on any  person and does not operate to 
9  bind FDA or the public.  You can use an alternative approach if the approach satisfies the requirements of 
10  the applicable statutes and regulations. If  you want to discuss an alternative approach, contact the FDA 
11  staff responsible for implementing this guidance.  If you cannot identify the appropriate FDA staff, call 
12  the appropriate number listed on the title page of this guidance.  
13   
14   
15   
16   
17  I.  INTRODUCTION  
18   
19  The purpose of this guidance is to assist sponsors in the clinical development of drugs for the 
20  treatment of alcoholism.2  There are many different terms, definitions, and diagnostic criteria that 
21  have been used to describe this condition.  However, in this guidance, we use the term  
22  alcoholism to describe patients with alcohol use problems that would make them candidates for 
23  treatment with medication.  As the World Health Organization (WHO) notes,3 alcoholism is a 
24  term of long-standing use and is generally taken to refer to chronic continual drinking or 
25  periodic consumption of alcohol which is characterized by impaired control over drinking, 
26  frequent episodes of intoxication, and preoccupation with alcohol and the use of alcohol despite 
27  adverse consequences. Further discussion of terminology can be found in Appendix 1.   
28   
29  We are issuing this guidance to better communicate our current thinking on the appropriate 
30  endpoints for clinical trials of drugs to treat alcoholism, and to apprise sponsors of possible 
31  alternatives to abstinence-based endpoints, which have often been considered an unattainable 
32  threshold in the clinical trial setting, and which may be considered a hindrance to clinical 
33  development for drugs to treat alcoholism.  This guidance provides supporting information for 
34  the endpoints as appropriate measures of clinical benefit.  This draft guidance is intended to 
35  serve as a focus for continued discussions among the Division of Anesthesia, Analgesia, and 
                                                 
1 This  guidance has been  prepared by the Division of  Anesthesia, Analgesia, and Addiction Products in the Center 
for Drug Evaluation and Research (CDER) at the Food and Drug Administration.   
 
2 For the purposes of this guidance, all references to drugs  include both human  drugs and therapeutic biological 
products  unless otherwise specified.  
 
3 http://www.who.int/substance_abuse/terminology/who_lexicon/en/ (accessed 2/1/14) 
 
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36  Addiction Products (DAAAP), pharmaceutical sponsors, the academic community, and the 
37  public.4    
38   
39  This guidance does not contain discussion of the general issues of statistical analysis or clinical 
40  trial design. Those topics are addressed in the ICH guidances for industry E9  Statistical 
41  Principles for Clinical Trials and E10 Choice of Control Group and Related Issues in Clinical 
42  Trials, respectively.5  
43   
44  FDAs guidance documents, including this guidance, do not establish legally enforceable 
45  responsibilities. Instead, guidances describe the Agencys current thinking on a topic and should 
46  be viewed only as recommendations, unless specific regulatory or statutory requirements are 
47  cited. The use of the word should in Agency guidances means that something is suggested or 
48  recommended, but not required. 
49   
50   
51  II.  DEVELOPMENT PROGRAM 
52   
53  In all diagnostic schemes, alcoholism is identified by behavior  continued self-administration 
54  of alcohol despite physical and psychosocial consequences.  Alcoholism is understood to be a 
55  chronic, relapsing disorder that may require long-term and even lifelong treatment.  The aim of 
56  treatment is often expressed as an effort to modify drinking behavior, but the actual desired 
57  effect is improvement in physical and psychosocial consequences.  Therefore, drinking behavior 
58  (particularly that snapshot of behavior that can be observed during the brief window of a clinical 
59  trial) is considered a surrogate endpoint, not a direct measure of how the patient feels or 
60  functions. Trials intended to show direct effects on physical or psychosocial consequences of 
61  drug use would need to be long and large, and may be impractical.  As such, sponsors do not 
62  need to demonstrate a direct effect on the physical and psychosocial consequences of alcoholism  
63  in alcoholism clinical trials, but they should show modifications in drinking behavior ascribed to 
64  a particular treatment that are likely to translate to improvement in the physical and psychosocial 
65  consequences. 
66   
67  Because drinking behavior is considered a surrogate endpoint, sponsors should document a 
68  pattern of behavior that can be reasonably predictive of clinical benefit (e.g., improvement in the 
69  way the patient feels or functions). Patients who attain and sustain complete abstinence from  
70  alcohol may be assumed to accrue clinical benefit.  Thus, trials showing a difference in the 
71  proportion of patients who attain and sustain complete abstinence may support an indication of 
72  treatment of alcoholism.  We believe analyses of existing data also support the use of another 
73  valid surrogate endpoint defined by a pattern of reduced drinking, described as no heavy drinking 
74  days.  Heavy drinking days are defined by the National Institute on Alcohol Abuse and 
75  Alcoholism (NIAAA) as days when the patient consumes more than four standard drinks (men) 
                                                 
4 In addition to consulting  guidances, sponsors are encouraged to contact the division to  discuss specific issues that 
arise during the development of drugs to treat alcoholism.   
 
5  We  update  guidances periodically.  To make sure you  have the most recent version of a guidance, check the FDA  
Drugs guidance Web page  at  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
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76  or more than three standard drinks (women).  Standard drinks are defined in the United States as 
77  containing 14 grams of alcohol, such as would be found in a standard shot of hard liquor, a 12-
78  ounce bottle of beer, or a 5-ounce glass of wine. An analysis of the proportion of patients who 
79  attain and sustain a pattern of drinking that never exceeds the heavy drinking definitions may be 
80  appropriate. 
81   
82  We anticipate this pattern to be attained within a reasonable, behaviorally, and 
83  pharmacologically justified grace period, and that it be sustained for at least 6 months of 
84  treatment.  We do not necessarily expect that efficacy will be sustained after the drug is 
85  withdrawn if the drug is intended to be administered chronically.  
86   
87  DAAAPs current recommendation is for trials of 6 months duration, with a primary endpoint of 
88  the proportion of patients who do not have any heavy drinking days during the observation 
89  period (percent no heavy drinking days). Background explanations to support the validity of this 
90  endpoint as a surrogate for clinical benefit may be found in Appendix 2. 
91   
92  A.  General Considerations 
93   
94  1.  Early Phase Clinical Development Considerations   
95   
96  As part of their early phase clinical development program, sponsors should consider drug-
97  alcohol interactions and may need to conduct formal drug-alcohol interaction trials.  When 
98  designing the early phase clinical development program, sponsors should also be aware of, and 
99  give consideration to, the possibility that patients with chronic alcoholism or with hepatic 
100  impairment might have different pharmacokinetic/pharmacodynamic profiles from the general 
101  population. 
102   
103  2.  Drug Development Population  
104   
105  In general, the target population for this indication should be adults who are seeking treatment 
106  for alcoholism. Early phase trials in which alcohol is administered generally should be 
107  conducted in nontreatment-seeking individuals, although there may be some circumstances under 
108  which administration of alcohol to treatment-seeking individuals may be justified.  
109   
110  To fulfill the requirements of the Pediatric Research Equity Act (PREA),6 studies in adolescents 
111  (12 through 16 years old) may be required.  Sponsors should assess the size of the treatment-
112  seeking population to determine whether studies in this population may be practicably 
113  conducted. A waiver will be considered based on this assessment. 
114   
                                                 
6  PREA, originally enacted on December 3, 2003 (Public Law 108-155), codified many of the elements of the 
pediatric rule, and established requirements for studies of certain drugs and biological  products used in  pediatric 
patients.  PREA (section 505B of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C.  355c),  reauthorized by the 
Food and  Drug Administration  Amendments Act of 2007, as Title IV, on September 27, 2007  (21 U.S.C. 355c), and  
made permanent in  2012  with the passage of the Food and Drug Administration Safety and Innovation Act (Public  
Law 112-144), requires pediatric studies for  certain  drugs and biological products.  
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115  3.   Efficacy Considerations   
116   
117  Generally, two adequate and well-controlled trials will be needed to support an efficacy claim for 
118  this indication. 
119   
120  4.  Safety Considerations  
121   
122  The safety database should be sufficiently sized, from both the standpoint of sample size and 
123  length of observation, to assess the safety of a drug intended for the treatment of a chronic 
124  disease. 
125   
126  The size of the safety database depends on a number of factors, including whether the drug is a 
127  new molecular entity (NME) or a reformulation of a known drug substance, the nature of the 
128  safety findings from the clinical trials, and the nonclinical data for the drug under development.  
129  For the safety evaluation of an NME intended for treatment of alcoholism, we recommend 
130  sponsors refer to the ICH guidance for industry E1A The Extent of Population Exposure to 
131  Assess Clinical Safety: For Drugs Intended for Long-Term Treatment of Non-Life-Threatening 
132  Conditions for drugs intended for long-term treatment of non-life-threatening conditions and to 
133  the guidance for industry Premarketing Risk Assessment.  These guidances make 
134  recommendations on the minimum size of the database.  A safety database larger than 
135  recommended in these guidances may be warranted for a number of reasons (many of which are 
136  discussed in these guidances), including safety signals emerging as more clinical data become  
137  available.  
138   
139  For reformulations of drugs with existing alcoholism indications, the size of the safety database 
140  should reflect the differences from existing formulations of the drug and the gap in safety data 
141  expected from these differences. In general, in the case of reformulated drugs, the amount of 
142  safety data that should be collected to support safe use depends on differences in 
143  pharmacokinetics and route of administration.  To determine an appropriate number of patients 
144  for the safety database for a drug previously approved for an alcoholism indication, or other 
145  indication, sponsors should consider the extent of differences between the previous patient 
146  population studied and the alcoholism population under evaluation, and whether the differences 
147  alter the risk for adverse reactions.  
148   
149  B.  Specific Efficacy Trial Considerations 
150   
151  1.  Trial Design 
152   
153  Alcoholism clinical trials should be designed as randomized, placebo-controlled, superiority 
154  trials with a minimum duration of 6 months and a primary endpoint based on the response rate.  
155  Responders can be defined either as patients who do not drink at all during the observation 
156  period, or as patients who do not have any heavy drinking days during the observation period.  A 
157  responder analysis is recommended because calculations of group mean values such as percent 
158  days abstinent or percent of heavy drinking days across a treatment group are difficult to 
159  interpret with respect to the clinical benefit for individual patients.  Responder analyses illustrate 
160  the clinically important effect of a treatment in an individualized fashion, and facilitate risk-
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161  benefit comparisons. Responder analyses also may reveal the effect of a drug that has a 
162  clinically important effect in a small subset of patients.  
163   
164  The primary endpoint and responder definition were chosen based on unpublished analyses 
165  commissioned by NIAAA of longitudinal data from both clinical trial settings and observational 
166  settings. Patients who never exceeded the heavy drinking limits had minimal alcohol-related 
167  consequences and were much less likely to have relapsed at follow-up.  
168   
169  Abstinence also can be used as a responder definition for the primary endpoint.  
170   
171  The recommended trial duration is based on data indicating that drinking patterns over shorter 
172  durations of time, such as 12 weeks, may not be stable or representative of future experience 
173  (Zweben and Cisler 2003) and may be too brief to predict ongoing treatment response.  It is 
174  acknowledged that many other chronic diseases are studied in trials of only 3 months (12 
175  weeks) duration using direct measures of clinical benefit.  However, the problems associated 
176  with alcoholism are not readily reversible with cessation of drinking or with the avoidance of 
177  heavy drinking. Sustained adherence to the target change in drinking behavior, an indirect  
178  measure, is needed to accrue clinical benefit.   
179   
180  It is also understood that periods of abstinence are quite common among alcohol-dependent 
181  individuals: in one survey (Schuckit, Tipp, et al. 1997), periods of abstinence lasting at least 3 
182  months were reported by 62.3 percent. This could make it hard to show a treatment effect in a 
183  brief alcoholism treatment trial.   
184   
185  Some might suggest that trials of 1 years duration would be more appropriate.  In the alcoholism  
186  field, the duration of abstinence considered to represent a stable condition, or sustained 
187  remission, is often set at 12 months.7  Once well-established, abstinence from alcohol appears, 
188  for many patients, to be a stable pattern, sustained over several years of follow-up (Dawson, 
189  Goldstein, et al. 2007). However, based on data indicating that abstinence at 6 months has been 
190  shown to be a predictor of abstinence at 5-year follow-up (Weisner, Ray, et al. 2003), and in the 
191  interest of practicality, we recommend trials with a minimum of 6 months on-treatment 
192  observation. 
193   
194  Neither abstinence nor no heavy drinking responder definitions need any additional data to 
195  support the pattern of drinking behavior as a valid surrogate for clinical benefit.  
196   
197  Sponsors can choose other definitions of treatment responders, but would need to submit data 
198  that demonstrate the target drinking pattern they select is a valid surrogate for clinical benefit.  
199   
200  2.  Trial Population  
201   
202  The trial population should be patients with alcoholism who require pharmacologic treatment.  
203  The Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria are commonly used to 
204  define addiction populations. However, the latest version of the DSM (DSM-V) subsumes all 
                                                 
7 Diagnostic and Statistical Manual  of Mental Disorders, 2000, Fourth Edition, Text Revision (DSM-IV-TR), 
American Psychiatric Publishing, Inc.  
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205  problematic use of alcohol under the term  alcohol use disorders  (AUD). The blanket designation 
206  of AUD introduces ambiguity with respect to defining a trial population for alcoholism clinical 
207  trials, because patients with mild or early alcohol use problems would be included if all patients 
208  with DSM-V AUD were enrolled.  Therefore, sponsors should create eligibility criteria adequate 
209  to define a population of patients with a degree of AUD severity that may benefit from 
210  pharmacologic treatment.  The DSM diagnostic criteria for AUD can be used as a foundation, 
211  augmented by other key factors that would identify that set of patients with AUD for whom  
212  pharmacologic treatment would be appropriate.  These might include a requirement that 
213  particular DSM-V diagnostic criteria are met, or that other features are present, such as a 
214  subjective loss of control over drinking. 
215   
216  It is important to highlight that patients with mild degrees of AUD are likely to benefit from  
217  nonpharmacologic interventions and are therefore not the target population for drugs to treat 
218  alcoholism.  This means both that the risk-benefit calculation is different for these patients than 
219  for those who are in need of pharmacologic treatment, and that they may have a high rate of 
220  placebo response that can complicate the demonstration of efficacy in clinical trials.  Thus, we 
221  recommend that patients whose problems fall into  the category of mild alcohol use disorder, 
222  some patients who would meet criteria for moderate alcohol use disorder, or those who are 
223  perceived to have a problem of abuse but not addiction, are not generally the ideal population for 
224  study. 
225   
226  3.  Entry Criteria  
227   
228  Patients should have a history of episodes of heavy drinking in the period before screening that 
229  would permit detection of a change in drinking behavior in this regard as a result of 
230  pharmacotherapy.  Patients with a history suggestive of clinically significant withdrawal 
231  symptoms can be enrolled, but the protocol should include procedures to monitor for withdrawal 
232  and to provide necessary treatment.  
233   
234  The decision to enroll patients who are drinking at baseline or patients who have ceased drinking 
235  at the time of enrollment should be based on the presumed mechanism of action of the drug.  
236  Some drugs may be hypothesized to be effective in helping patients to stop drinking by blocking 
237  the effects of alcohol (i.e., via extinction of the behavior).  Other drugs might be useful in 
238  reducing the risk of relapse once drinking has ceased.  
239   
240  4.  Special Populations 
241   
242  Patients with a range of comorbid conditions typically seen in patients with alcoholism, 
243  including hepatic impairment, should be enrolled in clinical trials.  
244   
245  5.  Choice of Comparators  
246   
247  Sponsors should use placebo comparators.  An active comparator also can be included in the 
248  trial. Claims of comparative superiority, however, involve specific planning in trial design to 
249  demonstrate that there is a clinically meaningful benefit of the drug in question over the 
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250  comparator.  The comparator drug should be used in an effective dose and in an appropriate 
251  population to support a comparative claim.  
252   
253  6.  Efficacy Endpoints  
254   
255  Trials should measure the proportion of patients in each treatment group who attain, and sustain 
256  over the observation period, a target drinking pattern that is considered a valid surrogate for 
257  clinical benefit. The following two options can be used as target drinking patterns and do not 
258  need any additional data to support the pattern as  a valid surrogate for clinical benefit.  Sponsors 
259  should discuss other options with the division.  
260   
261  (1)  Abstinence.  As noted above, trials that use complete abstinence as the target drinking 
262  pattern can be used. 
263   
264  (2)  No Heavy Drinking. Trials that use no heavy drinking as the target drinking pattern can 
265  be used. This is based on several lines of evidence that provide support for this pattern as 
266  a valid surrogate for clinical benefit. Several of these lines of support are from  
267  unpublished analyses, but there are also published studies that confirm these analyses.  
268  Support for this endpoint is summarized in Appendix 2. 
269   
270  7.  Endpoint Adjudication 
271   
272  Information about patients drinking can be collected using the Time-Line Follow-Back Method 
273  (TLFB) (Sobell, Maisto, et al. 1979). Briefly, the TLFB is a calendar-assisted retrospective 
274  reconstruction of how many drinks were consumed per day.  Initially, the TLFB was developed 
275  to be administered by a research assistant, but other techniques including computer-based 
276  administration have also been developed.  The retrospective window is as long as 3 months.  It is 
277  generally understood that the TLFB data are not a precise reflection of a patients drinking, but 
278  the TLFB has been widely accepted as providing a reasonable estimate that is sensitive to 
279  change. 
280   
281  Note that if sponsors are interested in documenting only abstinence versus any drinking, or 
282  adherence to nonheavy limits versus any violation of heavy drinking limits, it may not be 
283  necessary to use the TLFB method of reconstruction of drinking day by day.  Other methods may 
284  be sufficient for obtaining the information necessary to adjudicate the patient as a responder or 
285  nonresponder. For example, the Alcohol Research Group/National Alcohol Research Centers 
286  2009  2010 National Alcohol Survey8 used the following question: Think of all kinds of 
287  alcoholic beverages combined, that is, any combination of bottles or cans of beer, glasses of 
288  wine, drinks containing liquor of any kind, or coolers, flavored malt beverages or pre-made 
289  cocktails. In this question, 1 drink is equal to a 12 ounce bottle or can of beer or cooler, a five 
290  ounce glass of wine, or a 1 shot of liquor (1.5 ounces).  During the last 12 months, what is the 
291  largest number of drinks you had on any single day?. 
292   
293  Either self-report method should be supplemented by some type of biological verification.  
294  Currently, there are no ideal biomarkers of drinking that can be used to reliably capture any 
                                                 
8 http://www.arg.org/downloads/arg/N12%20FINAL%20Landline%20Questionnaire.pdf (accessed 4/25/14) 
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295  instance of drinking or of heavy drinking, but some attempt to collect biological data may have 
296  the effect of increasing the veracity of self-report.  Additionally, patients who are acutely 
297  intoxicated cannot give reliable retrospective accounts.  Therefore, at a minimum, a breath 
298  alcohol measurement at each visit should be incorporated.  
299   
300  It is recommended that the data on alcohol use be collected by staff who are not providing 
301  counseling. This is intended to reduce the likelihood that patients will conceal drinking to avoid 
302  disappointing the therapist. 
303   
304  If sponsors are interested in documenting only whether patients are responders or nonresponders, 
305  it is not necessary to accurately reconstruct the amount consumed on each day of the trial, and 
306  therefore there are methods to ensure that missing data should be relatively rare.  A patient who 
307  has already had a heavy drinking day during the efficacy ascertainment period is already 
308  adjudicated even if lost to follow-up. If a patient who met the responder definition up to the 
309  point of dropping out can be located by telephone, he or she can be asked What is the largest 
310  number of drinks you had on any one occasion since the last time we saw you?  If the patient  
311  indicates that he or she has had at least one heavy drinking day, the outcome for that patient is 
312  adjudicated and is not considered missing.  Patients who self-report ongoing adherence to the no 
313  heavy drinking limits may present a challenge because of the lack of biological verification or 
314  other sources of confirmation of self-report; these patients might be included as either responders 
315  or nonresponders in different sensitivity analyses.  Only patients who met the responder 
316  definition up to the point of loss to follow-up and cannot be located should be considered truly 
317  unadjudicated. Careful attention to obtaining contact information at the time of trial enrollment 
318  can limit the number of patients for whom outcome data are truly missing.  
319   
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320  REFERENCES  
321   
322  Dawson, DA, RB Goldstein, and BF Grant, 2007, Rates and Correlates of Relapse Among 
323  Individuals in Remission From DSM-IV Alcohol Dependence: A 3-Year Follow-Up, Alcohol 
324  Clin Exp. Res., 31, 2036-2045. 
325   
326  Delucchi, KL and C Weisner, 2010, Transitioning Into and Out of Problem Drinking Across 
327  Seven Years, J Stud. Alcohol Drugs, 71, 210-218. 
328   
329  Greenfield, TK, 2000, Ways of Measuring Drinking Patterns and the Difference They Make:  
330  Experience with Graduated Frequencies, J Subst. Abuse, 12, 33-49. 
331   
332  Sanchez-Craig, M, DA Wilkinson, and R Davila, 1995, Empirically Based Guidelines for 
333  Moderate Drinking:  1-Year Results From Three Studies With Problem Drinkers, Am. J Public 
334  Health, 85, 823-828. 
335   
336  Schuckit, MA, JE Tipp, TL Smith, and KK Bucholz, 1997, Periods of Abstinence Following the 
337  Onset of Alcohol Dependence in 1,853 Men and Women, J Stud. Alcohol, 58, 581-589. 
338   
339  Sobell, LC, SA Maisto, MB Sobell, and AM Cooper, 1979, Reliability of Alcohol Abusers Self-
340  Reports of Drinking Behavior, Behav. Res. Ther., 17, 157-160. 
341   
342  Weisner, C, GT Ray, JR Mertens, DD Satre, and C Moore, 2003, Short-Term Alcohol and Drug 
343  Treatment Outcomes Predict Long-Term Outcome, Drug Alcohol Depend., 71, 281-294. 
344   
345  Zweben, A and RA Cisler, 2003, Clinical and Methodological Utility of a Composite Outcome 
346  Measure for Alcohol Treatment Research, Alcohol Clin Exp. Res., 27, 1680-1685. 
347   
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348  APPENDIX 1:  TERMINOLOGY RELATED TO PROBLEM ALCOHOL USE 
349   
350  The WHO notes that alcoholism may be considered to be synonymous with alcohol addiction, 
351  but does not endorse the use of either term.  Addiction, per the WHO, is Repeated use of a 
352  psychoactive substance or substances, to the extent that the user (referred to as an addict) is 
353  periodically or chronically intoxicated, shows a compulsion to take the preferred substance (or 
354  substances), has great difficulty in voluntarily ceasing or modifying substance use, and exhibits 
355  determination to obtain psychoactive substances by almost any means.  Typically, tolerance is 
356  prominent and a withdrawal syndrome frequently occurs when substance use is interrupted.9  
357   
358  More recently, the term  alcohol dependence was substituted for both alcoholism and alcohol 
359  addiction in diagnostic criteria by both the WHO and the American Psychiatric Association 
360  (APA), because of concerns that the word addiction carried an unwanted stigma, and in turn, 
361  could be a barrier to seeking treatment.  However, this created ambiguity, because the term  
362  dependence came to have dual meanings connoting both a physical neuroadaptation (sometimes 
363  called physical dependence) and the notion of addiction. 
364   
365  Another term, alcohol abuse has been applied when individuals use alcohol to the point of 
366  experiencing problems caused by drinking, but do not manifest features of alcoholism.  Notably, 
367  there have been concerns voiced that the term  abuse also carries a stigma that would prevent 
368  individuals from self-identifying or seeking treatment and suggestions have been made to 
369  abandon this term as well, replacing it with misuse.  For FDA purposes, the terms addiction, 
370  dependence, abuse, and misuse are distinct from  one another, but we acknowledge that they may 
371  be used inconsistently, and sometimes interchangeably.  We have retained the historical term, 
372  alcoholism, in this guidance because of ambiguity and ongoing evolution in the use of other 
373  terms. 
374   
375  In the most recent version of the APAs DSM, a new diagnostic approach subsuming all 
376  problematic use of alcohol under the term AUD has been put forth.  This construct eliminates the 
377  distinction between alcohol abuse and alcohol dependence (the latter term being essentially 
378  synonymous with alcohol addiction or alcoholism), and creates a diagnosis for individuals with 
379  problems mild enough that they are merely markers for future problems related to drinking.  This 
380  facilitates early identification and intervention, but it also creates a problematic level of 
381  heterogeneity in the group of people who meet criteria for the diagnosis of AUD.  
382   
                                                 
9 http://www.who.int/substance_abuse/terminology/who_lexicon/en 
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383  APPENDIX 2:  SOURCES PROVIDING SUPPORT FOR NO HEAVY DRINKING  
384  AS A VALID SURROGATE FOR CLINICAL BENEFIT 
385   
386  This Appendix summarizes select sources of information that provide support for the distinctive 
387  pattern of drinking reduction, referred to as no heavy drinking days in this guidance, as a valid 
388  surrogate for clinical benefit. 
389   
390  Project MATCH 
391   
392  The first unpublished analysis, commissioned by the Treatment Research Branch at NIAAA, 
393  explored the dataset from Project MATCH, a trial comparing 3 different behavioral 
394  (nonpharmacologic) treatments delivered over 12 weeks in 1,726 patients with diagnoses of 
395  alcohol abuse or dependence who had been actively drinking in the 3 months before trial entry.  
396  Assessments were conducted every 3 months, capturing both alcohol consumption and various 
397  measures of drinking-related consequences, and patient function or dysfunction.  The analysis 
398  examined the relationship of problems and functioning to various measures of drinking.10  The 
399  investigator found a high degree of variability using continuous measures of drinking such as 
400  percent days abstinent or drinks per day, but that a consumption quantity cut-off was related 
401  strongly to an array of consequences and functioning variables.  The conclusion was that the best 
402  single predictor of nonconsequential drinking was never exceeding the daily heavy drinking 
403  limits.  The recommendations based on this analysis were that the target pattern of drinking 
404  should be defined as being abstinent or never exceeding three drinks on a single occasion 
405  (women) or four drinks on a single occasion (men).  In the sample analyzed, 22 percent of 
406  patients met this definition over the full 12-month post-treatment follow-up. 
407   
408  If a target drinking pattern based on percent days abstinent was of interest, the analysis suggested 
409  that similar functional outcomes would require a pattern of 92 percent days abstinent.  Because 
410  of high degrees of fluctuations in consumption and status across time, the analysis also suggested 
411  that longer follow-up periods (6 to 12 months) were needed to provide insight into more 
412  sustained status.  
413   
414  National Alcohol Surveys 
415   
416  The second NIAAA-commissioned analysis used data from the 1995 and 2000 National Alcohol 
417  Surveys, which collected information on alcohol consumption using a graduated frequencies 
418  measure (Greenfield 2000), alcohol dependence criteria, and information about alcohol-related 
419  social consequences. Participants included 7,447 current drinkers, but the analysis focused on 
420  the subset of 820 respondents who either reported having had prior treatment for alcohol 
421  problems or endorsed a concern about their drinking, to better approximate the target population 
422  for alcoholism treatment drugs.  
423   
424  The investigator concluded that treated or concerned drinkers who restrict intake to low volume 
425  (averaging fewer than 2 drinks per week) and whose quantities in a day never exceeded 
                                                 
10 The analysis of the Project MATCH data was conducted  by Dr. Ron A. Cisler. 
 
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426  3 (women)/4(men) carry low risk of 12-month dependence or abuse (less than 5 percent).11   
427  Those drinking 4 plus/5 plus even on occasion have significantly higher risks (10 to 20 percent) 
428  of meeting criteria for AUD.  The report noted that If [treated or concerned] individuals drink at 
429  all, the only somewhat safe level appears to be drinking less than 2 drinks/week on average and 
430  never exceeding 4 drinks for a man or 3 drinks in a day for a woman.  
431   
432  National Epidemiologic Survey on Alcohol and Related Conditions 
433   
434  Findings from two waves of data from the National Epidemiologic Survey on Alcohol and 
435  Related Conditions were published by Deborah Dawson and colleagues (Dawson, Goldstein, et 
436  al. 2007). Wave 1, collected in 2001 to 2002, identified 4,422 individuals who had met criteria 
437  for alcohol dependence before the past year.  Of these:  
438   
439     25.0 percent were still classified as dependent in the past year 
440   
441     27.3 percent were classified as being in partial remission 
442   
443     11.8 percent were asymptomatic risk drinkers who demonstrated a pattern of drinking 
444  that put them at risk of relapse  
445   
446     17.7 percent were low-risk drinkers (no heavy drinking days) 
447   
448     18.2 percent were abstainers 
449   
450  The last 3 categories comprise 2,109 individuals in full remission from alcohol dependence. 
451   
452  At Wave 2, collected 2004 to 2005, 1,772 of those 2,109 individuals were re-interviewed.  
453  Recurrence of AUD symptoms occurred in 51 percent of asymptomatic risk drinkers (any heavy 
454  drinking days); 27.2 percent of low-risk drinkers (no heavy drinking days); and 7.3 percent of 
455  abstainers. The adjusted odds ratios of recurrence of AUD symptoms compared to abstainers 
456  was 14.6 for asymptomatic risk drinkers and 5.8 for low-risk drinkers.  
457   
458  The proportion of individuals who had been in remission at Wave 1 who met criteria for alcohol 
459  dependence at Wave 2 was 10.2 percent for asymptomatic risk drinkers (any heavy drinking 
460  days); 4 percent for low-risk drinkers (no heavy drinking days); and 2.9 percent for abstainers.  
461  The adjusted odds ratios of recurrence of dependence,  relative to abstainers, was 7.0 for risk 
462  drinkers and 3.0 for low-risk drinkers. Thus, compared to abstinence, no heavy drinking days 
463  does still represent three times the risk of relapse to dependence compared to abstinence and 
464  nearly six times the risk of relapse to AUD symptoms.  However, drinking patterns including any 
465  heavy drinking days seem to carry 7 times the risk of relapse to dependence compared to 
466  abstinence and nearly 15 times the risk of relapse to AUD symptoms compared to abstinence.  
467  Those who engaged in risk drinking (equals heavy drinking days) even fewer than 1 time per 
468  month at Wave 1 were significantly more likely to meet criteria for dependence at Wave 2 than 
                                                 
11 The analysis  of National  Alcohol Survey  data was conducted by Dr. Thomas Greenfield. 
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469  those who did not, and there was no association between frequency of risk drinking and the 
470  adjusted prospective risks of chronic medical conditions other than liver disease. 
471   
472  Weisner 
473   
474  Delucchi and Weisner (Delucchi and Weisner 2010) examined transitions into and out of 
475  problem drinking across 7 years in a longitudinal study of 1,350 problem drinkers sampled from  
476  one countys general population (general population sample) and individuals entering the 
477  countys public and private chemical dependency programs (treatment sample).  Problem  
478  drinking was defined as 2 or more of the following in the previous 12 months:  (1) 5 plus drinks 
479  per day at least once a month for men or 3 plus drinks in a day weekly for women; (2) 1 or more 
480  alcohol-related social consequences (from a list of 8); and (3) 1 or more alcohol dependence 
481  symptoms (from a list of 9).  Follow-up interviews were conducted 1, 3, 5, and 7 years after 
482  baseline. The extent to which problem drinkers transition into and out of problem drinking was 
483  examined using Markov modeling. 
484   
485  The authors reported that a latent Markov model with heterogeneous transitions and five patterns 
486  fit the data, and the estimated transition probabilities are displayed in the following figure found 
487  in the article.   
488   
489  
490  Source: Delucchi  and Weisner, 2010, p. 215.    
491   
492  The authors demonstrated that individuals transitioning into a status of nonproblem drinker are 
493  likely to remain in that status over time.  Conversely, if individuals maintain a problem drinker 
494  status over time, it becomes increasingly difficult to transition out of that status.   
495   
496  Sanchez-Craig  
497   
498  Data from three independent trials involving two distinct populations of problem drinkers were 
499  pooled with the intent of refining guidelines on moderate drinking for heavy drinkers (Sanchez-
500  Craig, Wilkinson, et al. 1995).  The trial patients were 235 individuals who participated in 3 
501  trials of secondary prevention of alcohol problems and were interviewed at the 12-month follow-
502  up period. Patients were classified as problem-free (reporting no alcohol-related problems in the 
503  past 6 or 9 months) or problem (reporting 1 or more problems).  In the problem-free group, the 
504  average number of drinks per day and the upper limit of the confidence interval were less than 
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505  four. For the group reporting a problem, the mean quantity per day drinking was 5.5.  The 
506  authors also conducted an analysis grouping patients at 12-month follow-up into 4 categories 
507  based on both the amount of drinks consumed per day and the frequency of drinking in a week.  
508  The authors concluded that the two groups above the cutoff on quantity of drinks per day (i.e., 
509  five or more for men and four or more for women) had similar prevalence of all problem types 
510  and higher prevalence, while the two groups below this cutoff experienced a low likelihood of 
511  problems.  This is an additional source of support that was already available at the time that 
512  NIAAA had commissioned the formerly described analyses.  
513   
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