Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: Developing Drug Products for Treatment

Administrative draft guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

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DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft
guidance.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 Industry1
2 	Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: Developing
3 	Drug Products for Treatment
4
5
6
7
8 	This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) 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 FDA’s 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 	FDA’s guidance documents, including this guidance, do not establish legally enforceable
44 	responsibilities. Instead, guidances describe the Agency’s 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
2
4 The Voice of the Patient, A Series of Reports From the U.S. Food and Drug Administration’s (FDA’s) 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)

Contains Nonbinding Recommendations
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
100
Drug development in CFS/ME should focus on measures of clinically relevant effects in a
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
115
designation, breakthrough therapy designation, accelerated approval, and priority review, see the
draft guidance for industry Expedited Programs for Serious Conditions—Drugs 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 FDA’s current thinking on this topic.
3

Contains Nonbinding Recommendations
Draft — Not for Implementation
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
124
and Cosmetic Act, sponsors must provide substantial evidence of efficacy in the enrolled patient
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

Contains Nonbinding Recommendations
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
168
 	Establishing efficacy in key CFS/ME domains. To support efficacy of drug products
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
174
the effect through assessments of fatigue, subjectively measured). The selected
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.
5

Contains Nonbinding Recommendations
Draft — Not for Implementation
204 	‒ 	Improving health-related quality of life. Health-related quality of life (HRQL) is a
205 	multidomain concept that represents the patient’s 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 patient’s 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 patient’s 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
Draft — Not for Implementation
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
265
safety data may be needed depending on the safety profile observed for the drug product and the
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.
7

Contains Nonbinding Recommendations
Draft — Not for Implementation
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

Contains Nonbinding Recommendations
Draft — Not for Implementation
297 	REFERENCES
298
299 	Guidances
300
301 	Draft guidance for industry Expedited Programs for Serious Conditions—Drugs 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 Administration’s
314 	(FDA’s) 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