Guidance for Industry 

Chronic Fatigue Syndrome/ 

Myalgic Encephalomyelitis: 

Developing Drug Products for 

Treatment 

 
 
 
DRAFT GUIDANCE
 
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 Dr. Janet W. Maynard at 301-796-2300.  
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER)
  
 
March 2014 

Clinical/Medical 

 
16617dft.doc  
 
03/06/14   
Guidance for Industry 

Chronic Fatigue Syndrome/ 

Myalgic Encephalomyelitis: 

Developing Drug Products for 

Treatment 

 
 
 
Additional copies are available from: 

 
Office of Communications, Division  of Drug Information 

Center for Drug Evaluation  and Research 

Food and  Drug Administration 
 
10903 New Hampshire Ave., Bldg. 51, rm. 2201 

Silver Spring, MD   20993-0002 

Tel:  301-796-3400; Fax: 301-847-8714; E-mail:  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)
  
 
March 2014 

Clinical/Medical 

 
   
TABLE OF CONTENTS 
 
 
I.   INTRODUCTION............................................................................................................. 1
  
II.   BACKGROUND ............................................................................................................... 2
  
III.   DEVELOPMENT PROGRAM ....................................................................................... 3
  
A.   General Considerations .................................................................................................................3
  
1.  Drug Development Population .........................................................................................................3
  
2.  Unmet Medical Need ........................................................................................................................3
  
3.  Efficacy Considerations ...................................................................................................................4
  
B.   Specific Efficacy Trial Considerations .........................................................................................4
  
1.  Trial Design......................................................................................................................................4
  
2.  Efficacy Endpoints ............................................................................................................................5
  
3.  Trial Duration ..................................................................................................................................6
  
4.  Number of Trials ..............................................................................................................................6
  
5.  Concomitant Treatments ..................................................................................................................6
  
C.   Safety Considerations.....................................................................................................................7
  
D.   Other Considerations .....................................................................................................................7
  
1.  Combination Drug Products ............................................................................................................7 
 
2.  Drug-Device Combination Product Considerations ........................................................................7 
 
REFERENCES.............................................................................................................................. 9
  
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation  
1 
Guidance for Industry  
1 
Chronic Fatigue Syndrome/Myalgic Encephalomyelitis:  Developing 
2 
Drug Products for Treatment 
3 
4   
5   
6   
7   
8  This draft guidance, when finalized, will represent the Food and Drug Administrations (FDAs) current 
9  thinking on this topic.  It does not create or confer any rights for or  on any  person and does not operate to 
10  bind FDA or the public.  You can use an alternative approach if the approach satisfies the requirements of 
11  the applicable statutes and regulations. If  you want to discuss an alternative approach, contact the FDA 
12  staff responsible for implementing this guidance.  If you cannot identify the appropriate FDA staff, call 
13  the appropriate number listed on the title page of this guidance.  
14   
15   
16   
17   
18  I.  INTRODUCTION  
19   
20  This guidance is intended to assist sponsors in the development of drug products for the 
21  treatment of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME).2  This guidance 
22  focuses on specific drug development and trial design issues that are unique to the study of 
23  CFS/ME and on the FDAs current thinking on how effective treatments can be developed for 
24  CFS/ME. The points discussed in this guidance may not be applicable to all drug products.  The 
25  FDA encourages sponsors to design clinical programs that fit their particular needs and to 
26  discuss their planned approach with the Division of Pulmonary, Allergy, and Rheumatology 
27  Products. 
28   
29  This guidance does not contain discussion of the general issues of statistical analysis, clinical 
30  trial design, or patient-reported outcome (PRO) instruments.  Those topics are addressed in the 
31  ICH guidances for industry E9  Statistical Principles for Clinical Trials and E10 Choice of 
32  Control Group and Related Issues in Clinical Trials and the guidance for industry Patient-
33  Reported Outcome Measures: Use in Medical Product Development to Support Labeling 
34  Claims, respectively.3  This guidance does not address nomenclature considerations or 
35  nonclinical development.  
36   
                                                 
1 This  guidance has been  prepared by the Division of Pulmonary, Allergy, and Rheumatology Products in  the Center  
for Drug Evaluation and Research (CDER) at the Food and Drug Administration.   
 
2 In this guidance, the term  drug product includes all types of therapeutic agents, such as small and large molecule 
drugs, and therapeutic  biological products, regulated within  CDER.  
 
3  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.  
1 
 Contains Nonbinding Recommendations 
Draft  Not for Implementation  
37  For this guidance, the terms CFS, ME, and CFS/ME are used interchangeably.  The term  
38  CFS/ME is used in the singular to refer to a disease or set of diseases.  The term CFS/ME is 
39  intended to be inclusive and does not infer the cause of different symptom complexes.  
40  Currently, the FDA does not recognize a particular definition or name as appropriate for use in 
41  clinical trials of drug products for CFS/ME. 
42   
43  FDAs guidance documents, including this guidance, do not establish legally enforceable 
44  responsibilities. Instead, guidances describe the Agencys current thinking on a topic and should 
45  be viewed only as recommendations, unless specific regulatory or statutory requirements are 
46  cited. The use of the word should in Agency guidances means that something is suggested or 
47  recommended, but not required. 
48   
49   
50  II.  BACKGROUND 
51   
52  CFS/ME is a complex disease that can be debilitating.  The exact cause or causes of CFS/ME are 
53  unknown. Symptoms affect several body systems and may include severe fatigue or exhaustion, 
54  unrefreshing sleep, weakness, muscle and joint pain, impaired memory or mental concentration, 
55  tender lymph nodes, sore throat, headaches, and sleep dysfunction.  Many patients experience 
56  post-exertional malaise, which may occur without warning and upon even minimal physical or 
57  cognitive exertion, and is associated with acute exacerbation of these symptoms.  The nature and 
58  severity of symptoms vary from person to person, and diagnosis is challenging because there are 
59  no specific tests for the disease.  Post-exertional malaise and cognitive impairment are symptoms  
60  that can be particularly severe and disabling.4    
61   
62  According to the Centers for Disease Control and Prevention (CDC), between one and four 
63  million people in the United States are afflicted with CFS.5  Although CFS/ME is most common 
64  in 40- to 60-year-old women, CFS/ME affects both sexes and all racial, age, and socioeconomic 
65  groups. The disease may occur with a sudden onset, such as following an infection, or may 
66  occur with a gradual onset. Some patients improve spontaneously; however, many patients 
67  experience a prolonged course of illness with either periods of remission and exacerbation or 
68  steady decline. 
69    
70  CFS/ME affects patients ability to function in daily activities of work, school, household 
71  management, and personal care.  Many patients with CFS/ME are bedbound some or all of the 
72  time and experience loss of careers, decreased quality of family life, social isolation, and feelings 
73  of hopelessness. 
74   
                                                 
4 The Voice of the Patient, A Series of Reports From the U.S. Food and Drug  Administrations (FDAs) Patient-
Focused Drug  Development Initiative, Chronic Fatigue Syndrome and Myalgic Encephalomyelitis 
(http://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM368806.pdf). 
 
5 Recognition and Management of Chronic Fatigue Syndrome:  A Resource Guide for Health Care Professionals 
(http://www.cdc.gov/cfs/hcp.html)  
2 
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Draft  Not for Implementation  
75  CFS/ME is a serious disease and there are no approved therapies indicated to treat CFS/ME.  The 
76  lack of approved therapies indicated for the treatment of CFS/ME represents a public health 
77  concern. 
78   
79   
80  III.   DEVELOPMENT PROGRAM 
81   
82  A.  General Considerations  
83   
84  1.  Drug Development Population 
85   
86  A number of different clinical diagnostic criteria are in use for CFS/ME, including the 1988 
87  CDC criteria (Holmes, Kaplan, et al. 1988), the Fukuda Criteria (1994 Case Definition; Fukuda, 
88  Straus, et al. 1994), the International Criteria (Carruthers, van der Sande, et al. 2011), and the 
89  Canadian consensus criteria (Carruthers, Jain, et al. 2003).  Currently, there is no single case 
90  definition or set of criteria that is uniformly recognized as the standard for diagnosing patients 
91  with the disease.  At this time, the FDA does not recognize any particular disease definition, 
92  nomenclature, or diagnostic criteria for CFS/ME as the most appropriate for use in clinical trials 
93  of new drug products. Consequently, any case definition or criteria for CFS/ME can be used to 
94  define the patient population. Sponsors should provide justification for the chosen case 
95  definition or criteria and should provide sufficient details of the enrollment criteria (21 CFR 
96  314.126). Regardless of the case definition or criteria used, the clinical trial should exclude 
97  patients with potentially confounding diagnoses, including, but not limited to, congestive heart 
98  failure, malignancy, and chronic hepatitis, that cause fatigue and similar symptom complexes.  
99  Drug development in CFS/ME should focus on measures of clinically relevant effects in a 
100  defined patient population.6    
101   
102  Sponsors should define whether the targeted patient population reflects the general CFS/ME 
103  population or a subset, such as patients with CFS/ME and postural orthostatic tachycardia 
104  syndrome (POTS).  Generally, it is helpful to define the specific indicated population early in the 
105  clinical development program.  Ultimately, the targeted patient population used in the definitive 
106  clinical trials should be reflected in labeling.   
107   
108  2.  Unmet Medical Need 
109   
110  CFS/ME is a serious disease and there is unmet medical need in the treatment of CFS/ME.  
111  There are FDA programs intended to help ensure that therapies for serious conditions are 
112  approved and available to patients as soon as it can be concluded that the benefits of a therapy 
113  outweigh its risks. For information regarding expedited programs, including fast track 
114  designation, breakthrough therapy designation, accelerated approval, and priority review, see the 
115  draft guidance for industry Expedited Programs for Serious ConditionsDrugs and Biologics.7    
116  This guidance includes information regarding FDA programs intended to facilitate and expedite 
                                                 
6 See the ICH guidance for industry  E8  General Considerations for Clinical Trials. 
 
7  When final, this guidance will represent the FDAs current  thinking on this topic.  
3 
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117  development and review of drugs to address unmet medical need in the treatment of serious or 
118  life-threatening conditions.   
119   
120  3.  Efficacy Considerations   
121   
122  To meet the regulatory standards for approval under section 505(d) of the Federal Food, Drug, 
123  and Cosmetic Act, sponsors must provide substantial evidence of efficacy in the enrolled patient  
124  population and demonstrate an acceptable risk-benefit profile for their drug product.8  This 
125  section outlines the principles of assessing efficacy of drug products for the treatment of 
126  CFS/ME. 
127   
128  The efficacy endpoints selected for evaluation of drug products for the treatment of CFS/ME 
129  should include patient-reported symptoms using well-defined and reliable PRO instruments.  
130  These patient-reported symptoms can include any scientifically supported and logical 
131  combination of symptoms that are common in CFS/ME.  Additionally, sponsors should consider 
132  using objective measures.  Several potential efficacy endpoints that may be suitable for use in 
133  clinical trials of drug products for CFS/ME are mentioned in the following sections; however, 
134  sponsors are encouraged to also propose other clinically meaningful endpoints that may better 
135  assess the efficacy of their drug products.  As with all adequate and well-controlled clinical 
136  investigations, the protocol for the study and the report of results should explain the variables 
137  measured, the methods of observation, and criteria used to assess response (21 CFR 
138  314.126(b)(6)). 
139   
140  For most drug products, phase 3 trials that use a single primary efficacy endpoint with supportive 
141  secondary efficacy endpoints should be adequate to establish efficacy, provided the efficacy 
142  findings are robust and clinically meaningful.  The wording of the indication statement should 
143  reflect the effect assessed by the primary efficacy endpoint used. 
144   
145  The FDA understands that there is an emerging body of research focused on understanding a 
146  range of laboratory abnormalities and biomarkers in CFS/ME.  Although biomarkers can be 
147  considered as exploratory endpoints, the primary endpoints used to demonstrate efficacy should 
148  reflect the claimed clinical benefit related to how a patient feels or functions.   
149   
150  B.  Specific Efficacy Trial Considerations  
151   
152  1.  Trial Design 
153   
154  The nature and design of the definitive trials depends on the type of drug product that is being 
155  studied and the clinical benefit to be demonstrated.  In general, trials should be placebo-
156  controlled, double-blinded, randomized, and parallel-group in design.  The use of a placebo 
157  control should not preclude usual care treatments in patients randomized to placebo (see section 
158  III.B.5., Concomitant Treatments).  The appropriateness of a placebo control may change in the 
159  future when approved drug products become available such that use of placebo control raises 
160  ethical issues (i.e., if a drug product is approved for treatment of patients with CFS/ME).   
161   
                                                 
8  21 U.S.C. 355(d) 
4 
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Draft  Not for Implementation  
162  2.  Efficacy Endpoints  
163   
164  This section outlines the principles sponsors should follow to assess efficacy of drug products for 
165  the treatment of CFS/ME.  
166   
167     Establishing efficacy in key CFS/ME domains. To support efficacy of drug products 
168  for the treatment of CFS/ME, sponsors should demonstrate substantial evidence9 of 
169  efficacy in the key CFS/ME domain:  symptoms.   
170   
171    Symptoms. The primary efficacy endpoint should reflect the claimed clinical benefit 
172  (e.g., a drug product intended to reduce fatigue associated with CFS/ME should show 
173  the effect through assessments of fatigue, subjectively measured).  The selected 
174  primary efficacy endpoint should be clinically meaningful.10    
175   
176    Methods for symptom assessments.  The FDA is not aware of existing PRO 
177  instruments or set of instruments optimal for measurement of fatigue or other 
178  symptoms of CFS/ME.  The division will consider the use of symptom  
179  assessments that have been developed and evaluated in other conditions or novel 
180  instruments.  These alternatives should be discussed with the division early in 
181  drug development.    
182   
183     Other domains.  Other domains that are important to patients can provide further 
184  characterization of the efficacy of the drug product and its utility in clinical practice.  
185  Other domains can include the following:  
186   
187    Exercise capacity and post-exertional malaise. CFS/ME can be associated with both 
188  reduced exercise capacity and post-exertional malaise.  It is important to consider that  
189  post-exertional malaise and exercise capacity represent two different potential 
190  treatment benefits, and a drug product may act on both, or it may act on one, but not 
191  the other. The efficacy endpoints should reflect the claimed clinical benefit (e.g., a 
192  drug product intended to decrease post-exertional malaise should show the effect 
193  through objective assessments of exercise capacity and PROs). 
194   
195    Methods for exercise capacity and post-exertional malaise assessment.   
196  Assessment of exercise capacity by treadmill or cycle ergometry or PROs 
197  intended to measure post-exertional symptoms can be used to assess efficacy of a 
198  drug product. Although the FDA is not aware of existing PRO instruments for 
199  post-exertional malaise, the division will consider the use of existing or newly 
200  developed measures for this use.  These assessment tools should be considered in 
201  the context of the desired trial population, because some assessment tools would 
202  not be appropriate for patients with large degrees of functional impairment.   
203   
                                                 
9  21 U.S.C. 355(d) 
 
10  See ICH E8. 
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204    Improving health-related quality of life. Health-related quality of life (HRQL) is a 
205  multidomain concept that represents the patients general perception of the effect of 
206  illness and treatment on physical, psychological, and social aspects of life.  
207  Improvement in HRQL is an important aspect of CFS/ME treatment.   
208   
209    Methods for assessing HRQL. The FDA is not aware of existing HRQL 
210  instruments that are designed to systematically assess different aspects of the 
211  effect of CFS/ME on a patients life.  However, the division will consider the use 
212  of HRQL instruments that have been developed in other populations or novel 
213  instruments for the purposes of assessment of efficacy in CFS/ME.  The FDA 
214  often suggests that specific domains of health status and HRQL that are most 
215  relevant to the disease of interest (e.g., disease-related symptoms or disease-
216  related effect on physical functioning or cognitive functioning) be specified as 
217  primary or secondary endpoints to assess treatment benefit in clinical trials, while 
218  broader measures of overall HRQL be used as exploratory outcome measures in 
219  clinical trials.   
220   
221  For example, CFS/ME impairs the degree to which patients can perform  
222  successfully tasks and roles required for everyday living (e.g., patients ability to 
223  function in daily activities of work, school, household management, and personal 
224  care). Direct evidence of treatment benefit can be supported by demonstration of 
225  the effect of treatment on the patients performance of activities of value in his or 
226  her daily life. The choice of the specific assessment tool depends on the context 
227  of the targeted trial population. 
228   
229  3.  Trial Duration  
230   
231  The duration of controlled clinical trials may be influenced by data from earlier trials, so this 
232  should be discussed with the FDA during protocol development.  In general, sponsors should use 
233  data from 24-week placebo-controlled clinical trial(s) to provide evidence of efficacy in 
234  symptom relief domains.  Assessment of efficacy in some other domains may need long-term  
235  controlled clinical trial data. Longer durations of treatment may be needed to adequately assess 
236  safety. 
237   
238  4.  Number of Trials  
239   
240  Generally, support from two definitive trials should establish efficacy for a drug product being 
241  developed to provide symptom  relief for CFS/ME.  The trials should provide independent 
242  substantiation of the evidence of efficacy, but need not be identical in design.   
243   
244  5.  Concomitant Treatments  
245   
246  In general, patients enrolled in the trial should be permitted to use concomitant treatments as 
247  needed to manage disease symptoms.  An appropriate analysis plan should be defined in the 
248  protocol to account for possible imbalance of concomitant treatment use between treatment 
249  groups. For some treatments, consideration should be given in the design, conduct, and 
6 
 Contains Nonbinding Recommendations 
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250  interpretation of the trial to the need for any medications for acute symptoms (e.g., analgesics for 
251  pain exacerbations). 
252   
253  C.  Safety Considerations 
254   
255  Treatment of CFS/ME is usually prolonged; therefore, sponsors should collect long-term safety 
256  data. The size of the safety database should be consistent with the recommendations outlined in 
257  the ICH guidance for industry E1A The Extent of Population Exposure to Assess Clinical Safety:  
258  For Drugs Intended for Long-Term Treatment of Non-Life-Threatening Conditions.  
259  Consideration should be given to whether the drug  is designed for intermittent or continuous use.  
260  Consideration also should be given to other concomitant drugs that CFS/ME patients are likely to 
261  take. In cases where efficacy trials are substantially less than 1 year, or if the drug product is to 
262  be chronically administered, separate long-term safety trials should be conducted with 
263  consideration of including a control arm to facilitate interpretation of these data.  Additional 
264  safety data may be needed depending on the safety profile observed for the drug product and the 
265  specific situation.11  Sponsors are encouraged to discuss their plans for specific safety monitoring 
266  with the FDA during the early stages of drug product development.   
267   
268  D.  Other Considerations 
269   
270  1.  Combination Drug Products 
271   
272  Given the complexity of CFS/ME, it is possible that a single drug may not possess all necessary 
273  pharmacological activity to result in a desired therapeutic effect.  Therefore, a new drug product 
274  can be a combination of two or more individual drugs.  Two or more drugs may be combined in 
275  a single dosage form when each component makes a contribution to the claimed effect and the 
276  dosing of each component is such that the combination is safe and effective for a significant 
277  patient population requiring such concurrent therapy (21 CFR 300.50, Fixed-combination 
278  prescription drugs for humans).  A reasonable way to support the efficacy of a combination drug 
279  product would be to compare the combination drug product to each of its constituents in the 
280  same placebo-controlled clinical trial to demonstrate that the combination drug product provides 
281  clinical benefit that is superior to each of its constituents (see section III.B.1., Trial Design).  
282   
283  2.  Drug-Device Combination Product Considerations 
284   
285  Therapies developed for the treatment of CFS/ME can include drug products that require 
286  parenteral administration and the use of an accessory delivery unit (e.g., an injector device).  In 
287  these cases, the manufacturer of the drug product should ensure that the accessory delivery unit 
288  is approved or cleared for marketing through the device regulatory process (e.g., 510(k) process 
289  or premarket approval) by the Center for Devices and Radiological Health.  If the accessory 
290  delivery unit is not already approved or cleared for marketing, then it should be approved or 
291  cleared at least concurrently with the drug product approval.  Generally, each drug-device 
292  combination product should have a complete chemistry, manufacturing, and controls database; 
293  device design and development; and a substantially complete clinical development program to 
294  support efficacy and safety of the entire combination product.  Sponsors are encouraged to 
                                                 
11  See ICH E1A.  
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295  contact the Office of Combination Products and the division early in the development stage to 
296  seek guidance for their drug-device combination product. 
8 
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297  REFERENCES  
298   
299  Guidances 
300   
301  Draft guidance for industry Expedited Programs for Serious ConditionsDrugs and Biologics  
302   
303  Guidance for industry Patient-Reported Outcome Measures:  Use in Medical Product 
304  Development to Support Labeling Claims  
305   
306  ICH guidance for industry E1A The Extent of Population Exposure to Assess Clinical Safety:  
307  For Drugs Intended for Long-Term Treatment of Non-Life-Threatening Conditions  
308   
309  ICH guidance for industry E8  General Considerations for Clinical Trials   
310   
311  Other 
312   
313  The Voice of the Patient, A Series of Reports From the U.S. Food and Drug Administrations 
314  (FDAs) Patient-Focused Drug Development Initiative, Chronic Fatigue Syndrome and Myalgic 
315  Encephalomyelitis 
316  (http://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM368806.p 
317  df) 
318   
319  Recognition and Management of Chronic Fatigue  Syndrome:  A Resource Guide for Health Care 
320  Professionals (http://www.cdc.gov/cfs/hcp.html) 
321   
322  Literary 
323   
324  Carruthers BM, Jain AK, De Meirleir KL, et al., 2003, Myalgic Encephalomyelitis/Chronic 
325  Fatigue Syndrome:  Clinical Working Case Definition, Diagnostic and Treatment Protocols, J 
326  CFS, 11:7-116. 
327   
328  Carruthers BM, van der Sande MI, DeMairleir KL, et al., 2011, Myalgic Encephalomyelitis:  
329  International Consensus Criteria, J Intern Med, 270:327-38.  
330   
331  Fukuda K, Straus S, Hickie I, et al., 1994, The Chronic Fatigue Syndrome:  A Comprehensive 
332  Approach to its Definition and Study, Ann Inter Med, 121:953-9.  
333   
334  Holmes GP, Kaplan JE, Gantz NM, et al., 1988, Chronic Fatigue Syndrome:  A Working Case 
335  Definition, Ann Intern Med, 108:387-89. 
336   
9