Rheumatoid Arthritis: 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Administrative draft guidance, not enacted legislation.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
Rheumatoid Arthritis:
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DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft
guidance.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 (CDER) Dr. Nikolay P. Nikolov at 301-796-
2300; (CBER) the Office of Communication, Outreach, and Development at 800-835-4709 or
301-827-1800; or (CDRH) Markham Luke at 301-796-5556.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
Center for Devices and Radiological Health (CDRH)
May 2013
Clinical/Medical
Revision 1
I:\8932dft.doc
05/13/13

Guidance for Industry
Rheumatoid Arthritis:
Developing Drug Products for
Treatment
Additional copies are available from:
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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
or
Office of Communication, Outreach, and Development, HFM-40
Center for Biologics Evaluation and Research, Food and Drug Administration
1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448
Tel: 800-835-4709 or 301-827-1800; E-mail: ocod@fda.hhs.gov
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm
or
Office of Communication, Education, and Radiation Programs
Division of Small Manufacturers, International, and Consumer Assistance, HFZ-220
Center for Devices and Radiological Health, Food and Drug Administration
1350 Piccard Drive, Rockville, MD 20850-4307
DSMICA E-mail: dsmica@cdrh.fda.gov; DSMICA Fax: 301-443-8818
(Tel) Manufacturers Assistance: 800-638-2041 or 301-443-6597
(Tel) International Staff: 301-827-3993
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/default.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
Center for Devices and Radiological Health (CDRH)
May 2013
Clinical/Medical
Revision 1

TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	CLINICAL DEVELOPMENT PROGRAM .................................................................. 2
A. 	Dose and Dosing Regimen Selection Considerations...................................................................2
B. 	Efficacy Considerations .................................................................................................................3
C. 	Safety Considerations.....................................................................................................................5
D. 	Drug-Device Combination Product Considerations....................................................................6
REFERENCES.............................................................................................................................. 8

Contains Nonbinding Recommendations
Draft — Not for Implementation
1 	Guidance for Industry1
2 	Rheumatoid Arthritis:
3 	Developing 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 	The purpose of this guidance is to outline the FDA’s current thinking on the principles of clinical
21 	development relevant to dose-selection and assessment of efficacy and safety to support the
22 	approval of drug products for the treatment of patients with rheumatoid arthritis (RA). It also
23 	addresses additional considerations for drug products developed as drug-device combination
24 	products. This guidance does not address nonclinical development, development of drug
25 	products for juvenile idiopathic arthritis, or development of biosimilar products.
26
27 	This guidance revises the guidance for industry Clinical Development Programs for Drugs,
28 	Devices, and Biological Products for the Treatment of Rheumatoid Arthritis (RA), published in
29 	February 1999.2 After it has been finalized, this guidance will replace the February 1999
30 	guidance and will reflect the current thinking of the FDA on RA drug product development. The
31 	FDA’s current thinking has been influenced by clinical development programs conducted for RA
32 	since the 1999 guidance published, and by changes in the standard of care for RA because of
33 	availability of many effective treatments. The revisions include:
34
35 	 	Dose(s) and dosing regimen(s) selection throughout the clinical development program
36
37 	 	Expectations for establishing efficacy in RA based on signs and symptoms and physical
38 	function domains
1 This guidance has been prepared by the Division of Pulmonary, Allergy, and Rheumatology Products in the Center
for Drug Evaluation and Research (CDER) in cooperation with the Center for Biologics Evaluation and Research
(CBER) and the Center for Devices and Radiological Health (CDRH) at the Food and Drug Administration.
2 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
39
40 	 	Use of efficacy endpoints such as clinical remission and prevention of structural damage
41 	progression
42
43 	 	Limiting the use of placebo
44
45 	 	Use of active comparator for safety and efficacy trials
46
47 	 	Principles of safety assessment
48
49 	 	Development of drug-device combination products
50
51 	This guidance does not discuss general issues of statistical analysis or clinical trial design. Those
52 	topics are addressed in the ICH guidances for industry E9 Statistical Principles for Clinical
53 	Trials and E10 Choice of Control Group and Related Issues in Clinical Trials, respectively.
54 	This guidance focuses on specific drug product development and trial design issues that are
55 	unique to the study of RA.
56
57 	FDA’s guidance documents, including this guidance, do not establish legally enforceable
58 	responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should
59 	be viewed only as recommendations, unless specific regulatory or statutory requirements are
60 	cited. The use of the word should in Agency guidances means that something is suggested or
61 	recommended, but not required.
62
63
64 	II. 	CLINICAL DEVELOPMENT PROGRAM
65
66 	A. 	Dose and Dosing Regimen Selection Considerations
67
68 	The selection of nominal dose(s) and dosing regimen(s) is a fundamental component of drug
69 	product development. The recommended dose(s) and dosing regimen(s) should be based on
70 	benefit-to-risk assessment and should be supported by all available data gathered throughout the
71 	development program. It is important to find the appropriate nominal dose and dosing regimen
72 	that produces efficacy with an acceptable long- and short-term safety profile. Many drug
73 	products intended to treat RA have the potential to cause serious dose-related adverse reactions,
74 	such as opportunistic infections and malignancy, which may not be apparent in short-term
75 	clinical trials (see section II.C. for further discussion of the clinical safety database). Dose-
76 	ranging exploration should begin early in the development program and often should continue
77 	throughout definitive efficacy and safety study(ies). Smaller early dose-ranging exploratory
78 	studies may not be adequate for selection of a single dose or a single dosing regimen.
79
80 	The following should be considered for the design of dose-ranging studies:
81
82 	 	Studying a wide range of doses and dosing regimens based on pharmacokinetic and
83 	relevant pharmacodynamic considerations.
84
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85 	 	Using endpoints sensitive to change to provide better discriminatory power for dose-
86
87
response assessment. A clinical endpoint such as the ACR20 response criteria may not
be optimal for this purpose,3 because it is a dichotomous endpoint, and using the
88
89
proportion of responders in a small group of patients could be unreliable. Endpoints such
as DAS28, 4 hybrid ACR response,5 and other continuous variables may be more sensitive
90 	to change and provide a more suitable alternative to ACR responder index. Supportive
91 	pharmacodynamic markers can be considered if scientifically justified.
92
93 	 	Timing of evaluation — assessing at the steep part of the dose-response curve for dose-
94 	response assessment. Endpoints should be evaluated at time points before the therapeutic
95 	plateau is likely (e.g., weeks 2 through 8) to better capture possible differences between
96 	doses. Later time points of evaluation (e.g., 12 weeks) may be informative in estimating
97 	clinical effect with chronic use.
98
99 	B. 	Efficacy Considerations
100
101 	To meet the regulatory standards for approval under section 505(d) of the Federal Food, Drug,
102 	and Cosmetic Act, sponsors must provide substantial evidence of efficacy in the enrolled patient
103 	population and demonstrate an acceptable risk-benefit profile for their drug product (21 U.S.C.
104 	355(d)). Studying more than one dose/dosing regimen or using an active comparator in
105 	definitive studies can facilitate the interpretation of efficacy and the overall risk-benefit
106 	evaluation. This section outlines the principles sponsors should follow to assess efficacy of drug
107 	products for the treatment of RA.
108
109 	1. 	Establishing efficacy in key RA domains. For marketing approval of drug products for
110 	the treatment of RA, sponsors should demonstrate substantial evidence of efficacy in the
111 	key RA domains: clinical response and physical function.
112
113 	 	Clinical response. ACR20 response criteria continues to be an accepted measure to
114 	demonstrate reduction in RA disease activity. In addition, higher levels of response,
115 	as measured by ACR50 and ACR70 response rates, and measures of low disease
116 	activity, such as DAS28 less than 2.6, can be used as supportive evidence of efficacy
117 	in the clinical response domain.
118
3 ACR20 (50, 70) response criteria — American College of Rheumatology response criteria is a dichotomous
composite endpoint indicating the proportion of patients with at least 20 (50, 70) percent improvement in the
number of tender and swollen joints, and in three out of the remaining five ACR core-set measures: patient pain,
patient global assessment of disease, physician global assessment of disease, physical functioning assessment
(Health Assessment Questionnaire-Disability Index (HAQ-DI)), and acute phase reactants.
4 DAS28 — Disease Activity Score 28 is a mathematically calculated, continuous, composite endpoint with
differential weighting given to each of the following components: tender joint count (28 joints), swollen joint count
(28 joints), acute phase reactant, and patient global assessment of arthritis.
5 Hybrid ACR response is a continuous score of the mean improvement in the core set measures combining the
ACR20, ACR50, and ACR70 response rates (American College of Rheumatology Committee to Reevaluate
Improvement Criteria 2007).
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Contains Nonbinding Recommendations
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119 	 	Physical function. Health Assessment Questionnaire-Disability Index (HAQ-DI) can
120 	be used to demonstrate improvement in physical function.6
121
122 	Data from 12-week placebo-controlled clinical trial(s) generally would be acceptable to
123 	provide evidence of efficacy in clinical response and physical function domains.
124
125 	2. 	Other domains. As noted in item 1 above, for marketing approval in RA, the
126 	foundational demonstration of efficacy should include clinical response and physical
127 	function using measures such as ACR20 response rates and HAQ-DI, respectively.
128 	Demonstration of efficacy in other domains that are important to patients and health care
129 	providers can provide further characterization of the efficacy of the drug product and its
130 	utility in clinical practice. Other domains can include:
131
132 	 	Prevention of structural damage progression. Reduction in radiographic evidence of
133 	structural damage progression is an important predictor of long-term benefits in
134 	delaying or preventing the progression to disability related to RA. Radiographic data
135 	using validated scoring methods have been used to demonstrate efficacy in this
136 	domain. However, demonstration of prevention of structural damage progression on
137 	radiographs has become increasingly difficult for several reasons:
138
139 	 	Use of placebo as a control in long-term trials (usually 6 months or longer for
140 	trials done in the past to demonstrate effect on radiographic outcomes) is no
141 	longer feasible (see item 3 below)
142
143 	 	The extent of progression in the placebo group is low during these short-term
144 	trials, and thus the observed treatment effect size of the investigational drug
145 	product is small and difficult to detect
146
147 	 	Limitations of the current analysis methods
148
149 	Therefore, sponsors should consider alternative study designs (e.g., active comparator
150 	studies), applying different measures (e.g., proportions of patients with radiographic
151 	progression), and alternative analytical methods when assessing radiographic benefit.
152 	Other imaging modalities, such as magnetic resonance imaging and ultrasonography,
153 	may allow for demonstration of benefit on structural damage progression in
154 	controlled studies that may be shorter than studies using radiographic data. However,
155 	these modalities have not been validated as outcome measures in RA to date.
156
157 	 	Clinical remission. Remission is an important goal of RA treatment. The American
158 	College of Rheumatology/European League Against Rheumatism (ACR/EULAR)
159 	Provisional Definition of Remission criteria may be acceptable for use in RA clinical
160 	development programs (ACR/EULAR 2011). Patients who achieve remission should
161 	be followed to provide some information on the durability of the remission response.
6 HAQ-DI assesses the degree of difficulty a patient has experienced during the past week in eight domains of daily
living activities: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and other activities.
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Contains Nonbinding Recommendations
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162
163 	 	Other aspects of RA. Other outcome measures may be informative as additional
164 	endpoints in RA clinical development programs. Sponsors should provide supportive
165 	evidence on the development of the selected measure. Sponsors also should provide
166 	the justification for use of a given measure, which should include importance, clinical
167 	relevance, and nonredundancy of the proposed outcome with other measures.
168
169 	3. 	Use of placebo. Assessment of efficacy in some domains may require long-term
170 	controlled clinical trial data. However, the availability of effective RA therapies and the
171 	shifting paradigm in the treatment of both early and established RA with a focus on early
172 	control of disease activity (Singh 2012) have provided a rationale for limiting the
173 	exposure of patients to placebo or ineffective therapies for a prolonged period of time
174 	(i.e., beyond 12 weeks) (American College of Rheumatology 2011). Therefore, studies
175 	longer than 12 weeks should include an active comparator as the control or provisions for
176 	escape to rescue treatment for patients with active disease.
177
178 	C. 	Safety Considerations
179
180 	The size of the safety database for drugs and biologic products should meet the minimum
181 	recommendations outlined in the ICH guidance for industry E1A The Extent of Population
182 	Exposure to Assess Clinical Safety: For Drugs Intended for Long-term Treatment of Non-Life-
183 	Threatening Conditions. However, drug products developed for RA may have potentially
184 	serious adverse effects that may cause concern. Unfortunately, the duration of trials that would
185 	support demonstration of efficacy may not be sufficient for an adequate safety assessment
186 	because the short duration of a placebo-controlled period (i.e., 12 weeks) would limit the amount
187 	of controlled safety data. Therefore, to better characterize the long-term safety profile of the
188 	investigational drug product and uncommon adverse events and events with longer latency
189 	periods, such as opportunistic infection and malignancy, we may request a premarket safety
190 	database of larger size and longer duration than recommended in ICH E1A for new molecular
191 	entities intended for the chronic treatment of RA.
192
193 	This request will likely include at least 1 year of controlled safety data for a new molecular entity
194 	with an active comparator arm to facilitate interpretation of these data. Safety data for a shorter
195 	duration may be considered if the drug product is not a new molecular entity. Reasonable
196 	comparator arms can include use of multiple doses of the investigational drug product or
197 	standard-of-care treatment in definitive clinical trials. Inclusion of more than one dose of
198 	investigational drug product can provide important dose-response information with regard to
199 	efficacy and safety. For safety issues of interest, sponsors should consider an independent
200 	adjudication process. The need for and details of specific monitoring may change as new data
201 	emerge. Sponsors are encouraged to discuss their plans for specific safety monitoring with the
202 	FDA during the early stages of drug product development.
203
204 	The approach to the analyses of safety data should take into account the complexity of the study
205 	design (e.g., crossover by response or escape provision, or crossover by design). In addition, the
206 	approach to the analyses of integrated safety data should take into account (possible) differing
207 	patient populations and/or differing study designs from multiple studies.
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208
209 	D. 	Drug-Device Combination Product Considerations
210
211 	Therapies developed for the treatment of RA include drug products that may require parenteral
212 	administration and the use of an accessory delivery unit (e.g., an autoinjector). In these cases,
213 	the manufacturer of the drug product should ensure that the accessory delivery unit is approved
214 	or cleared for marketing through the device regulatory process (e.g., 510(k) process or premarket
215 	approval) by the Center for Devices and Radiological Health. If the accessory delivery unit is
216 	not already approved or cleared for marketing, then it should be approved or cleared at least
217 	concurrently with the drug product approval.
218
219 	When the characteristics of the drug product and the delivery device are such that they meet the
220 	definition of a combination product under 21 CFR 3.2(e), the center with primary jurisdiction for
221 	premarket review and regulation for the combination product will be determined based on the
222 	procedure set forth in 21 CFR 3.4. For example, if the primary mode of action of the
223 	combination product is that of the drug product, the entire combination product is assigned to the
224 	Center for Drug Evaluation and Research. For such combination products, we generally need
225 	only one marketing application (e.g., a new drug application/biologics license application).
226 	Sponsors are encouraged to contact the Office of Combination Products with general questions
227 	regarding drug product jurisdiction and regulatory pathway for their drug-device combination
228 	products.
229
230 	Generally, each drug-device combination product should have a complete chemistry,
231 	manufacturing, and controls database; device design and development; and a substantially
232 	complete clinical development program to support efficacy and safety of the entire combination
233 	product. We anticipate that the to-be-marketed drug-device combination product will be used in
234 	the pivotal studies supporting the efficacy and safety of the combination product for marketing
235 	approval. For information on drug-device injector development, see the draft guidance for
236
237
industry and FDA staff Technical Considerations for Pen, Jet, and Related Injectors Intended for
Use with Drugs and Biological Products.7 This guidance includes information on issues such as
238 	root-cause analyses of device malfunction that may lead to potential improvements to the device
239
240
itself. Likewise, current good manufacturing practice requirements for combination products are
provided in 21 CFR part 4, subpart A. 8
241
242 	For the development of the RA drug delivery system, sponsors should take into consideration the
243 	characteristics of the intended user population and use environment. For products intended for
244 	self-administration by an RA patient, the device should be durable, and the dexterity and visual
245 	acuity required to use the device should be within the capability of RA patients. Human factor
246 	studies to assess use-related hazards should be conducted early in development, ideally before
247 	the conduct of key dose-ranging, safety, and efficacy studies. For further considerations on
7 When final, this guidance will represent the FDA’s current thinking on this topic. For the most recent version of a
guidance, check the FDA Drugs guidance Web page at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
8 See https://www.federalregister.gov/articles/2013/01/22/2013-01068/current-good-manufacturing-practice-
requirements-for-combination-products.
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248 	human factor studies, see the draft guidance for industry and FDA staff Applying Human Factors
249 	and Usability Engineering to Optimize Medical Device Design.9
250
251 	Ongoing evaluation of device performance should be incorporated into the pivotal studies for the
252 	combination product. For example, the evaluation should include asking patients to report
253 	devices they perceive to be broken or malfunctioning and to return any such device for
254 	evaluation and identification of the problem. Device use and performance also can be evaluated
255 	through directed questions defined in the protocols. In addition, a small number of devices (e.g.,
256 	100) that are apparently functioning normally should be collected after use and evaluated by in
257 	vitro performance testing to ensure device robustness.
258
259 	Although use of the to-be-marketed formulation and drug-device combination product
260 	throughout development is optimal, we acknowledge that changes to the drug product delivery
261 	system may occur. Changes in the formulation, excipients, or device components may affect the
262 	drug product delivery characteristics and clinical performance of the drug-device combination
263 	product. The extent of clinical data needed to support such changes depends on the nature of the
264 	change and the development stage. For example, a transition from a prefilled syringe to an
265 	autoinjector delivery system involves the following, at a minimum: (1) human factor studies to
266 	evaluate potential use-related risks of the modified combination product; (2) a pharmacokinetic
267 	bridging study that demonstrates similar delivery of the drug product to the same biospace across
268 	a range of body weights; and (3) real-life patient handling experience to assess device
269 	performance as discussed above. Depending on the extent of the proposed changes, additional
270 	clinical data may be needed to support efficacy and safety, including immunogenicity.
271
272 	Sponsors are encouraged to discuss these types of issues and appropriate marketing applications
273 	with the FDA as early in development as feasible.
274
9 When final, this guidance will represent the FDA’s current thinking on this topic. For the most recent version of
this guidance, check the FDA Device guidance Web page at
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm198577.htm. (When
final, this guidance will supersede the guidance for industry and FDA premarket and design control reviewers
Medical Device Use-Safety: Incorporating Human Factors Engineering into Risk Management. For the most
recent version of this guidance, check the FDA Device guidance Web page at
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm070271.htm.)
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275 	REFERENCES
276
277 	Literary
278
279 	ACR/EULAR, 2011, Provisional Definition of Remission in Rheumatoid Arthritis for Clinical
280 	Trials, Arthritis Rheum., Mar;63(3):573-86.
281
282 	American College of Rheumatology, 2011, Clinical Trial Priorities and Design Conference (July
283 	22-23, 2010), Arthritis Rheum., Aug;63(8):2151-6.
284
285 	American College of Rheumatology Committee to Reevaluate Improvement Criteria, 2007, A
286 	Proposed Revision to the ACR20: The Hybrid Measure of American College of Rheumatology
287 	Response, Arthritis Rheum., Mar 15;57(2):193-202.
288
289 	Singh, JA, 2012, Update of the 2008 American College of Rheumatology Recommendations for
290 	the Use of Disease-Modifying Antirheumatic Drugs and Biologic Agents in the Treatment of
291 	Rheumatoid Arthritis, Arthritis Care Res., May;64(5):625-39.
292
293 	Guidances
294
295 	Draft guidance for industry and FDA staff Applying Human Factors and Usability Engineering
296 	to Optimize Medical Device Design
297
298 	Draft guidance for industry and FDA staff Technical Considerations for Pen, Jet, and Related
299 	Injectors Intended for Use with Drugs and Biological Products
300
301 	Guidance for industry and FDA premarket and design control reviewers Medical Device Use-
302 	Safety: Incorporating Human Factors Engineering into Risk Management
303
304 	ICH guidance for industry E1A The Extent of Population Exposure to Assess Clinical Safety:
305 	For Drugs Intended for Long-term Treatment of Non-Life-Threatening Conditions
306
8