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DRAFT GUIDANCE
 
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 

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Tel:  301-796-3400; Fax: 301-847-8714; E-mail:  druginfo@fda.hhs.gov 

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or 

 
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Tel: 800-835-4709 or 301-827-1800;  E-mail: ocod@fda.hhs.gov 
 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm 

 
or 

 
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Division of  Small Manufacturers, International, and Consumer Assistance, HFZ-220 

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(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 Industry  
1 
Rheumatoid Arthritis:   

2 
Developing 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  The purpose of this guidance is to outline the FDAs 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  FDAs 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  FDAs guidance documents, including this guidance, do not establish legally enforceable 
58  responsibilities. Instead, guidances describe the Agencys 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   
2 
 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
85     Using endpoints sensitive to change to provide better discriminatory power for dose-
86  response assessment.  A clinical endpoint such as the ACR20 response criteria may not 
87  be optimal for this purpose,3 because it is a dichotomous endpoint, and using the 
88  proportion of responders in a small group of patients could be unreliable.  Endpoints such 
89  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).  
3 
 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
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. 
4 
 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
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. 
5 
 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
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  industry and FDA staff Technical Considerations for Pen, Jet, and Related Injectors Intended for 
237  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  itself. Likewise, current good manufacturing practice requirements for combination products are 
240  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 FDAs 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. 
6 
 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
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 FDAs 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.) 
7 
 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
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