Osteoarthritis:  Structural 
Endpoints for the Development 
of Drugs, Devices, and Biological 
Products for Treatment 
Guidance for Industry 
 
 
 
DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit electronic comments to https://www.regulations.gov.  Submit written 
comments to the Dockets Management Staff (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) Nikolay Nikolov at 301-796-5281, 
(CBER) the Office of Communication, Outreach, and Development at 800-835-4709 or 240-402-
8010, or (CDRH) Sahar Dawisha at 301-796-6182 or the Division of Hematology and 
Immunology Devices at 301-796-5480.  
 
 
 
 
 
 
 
 
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) 
 
August 2018 
Clinical/Medical 
15437dftcln.doc 
07/18/18   
Osteoarthritis:  Structural 
Endpoints for the Development of 
Drugs, Devices, and Biological 
Products for Treatment 
Guidance for Industry 
 
 
Additional copies are available from: 
 
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Center for Drug Evaluation and Research 
Food and Drug Administration 
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Silver Spring, MD  20993-0002  
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https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
and/or 
 
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Food and Drug Administration 
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and/or 
 
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Email: CDRH-Guidance@fda.hhs.gov 
https://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) 
 
August 2018 
Clinical/Medical 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION AND BACKGROUND .................................................................... 1 
II.  CONSIDERATIONS FOR DEVELOPMENT .............................................................. 2 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Osteoarthritis:  Structural Endpoints for the Development of  
2  Drugs, Devices, and Biological Products for Treatment 
3  Guidance for Industry1 
4   
5   
6   
7   
8  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
9  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
10  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
11  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
12  for this guidance as listed on the title page. 
13   
14   
15   
16   
17  I.  INTRODUCTION AND BACKGROUND 
18   
19  The purpose of his guidance is to assist sponsors who are developing drugs, devices, or 
20  biological products (medical products) to treat the underlying pathophysiology and structural 
21  progression of osteoarthritis (OA).2   
22   
23  Approvals for OA to date have been based on patient-reported outcome measures that assess pain 
24  and function.  However, treatments that inhibit structural damage or target the underlying 
25  pathophysiology associated with OA remain elusive and represent an unmet medical need.  This 
26  draft guidance is intended to serve as a focus for continued discussions among FDA, sponsors of 
27  medical products, the academic community, and the public regarding the assessment of structural 
28  endpoints.  This guidance does not address improvement of symptoms of OA, such as pain or 
29  functional impairment.  FDA recognizes the importance of these outcomes, which will be 
30  addressed in future guidance.3   
31   
32  This guidance does not contain discussion of the general issues of statistical analysis or clinical 
33  trial design.  For drugs and biological products, those topics are addressed in the ICH guidances 
                                                 
1 This guidance has been prepared by the Division of Pulmonary, Allergy, and Rheumatology in the Center for Drug 
Evaluation and Research in cooperation with the Center for Biologics Evaluation and Research and the Center for 
Devices and Radiological Health at the Food and Drug Administration.  
 
2 For the purposes of this guidance, all references to drugs include both human drugs and therapeutic biological 
products unless otherwise specified. 
 
3 The previous draft guidance for industry Clinical Development Programs for Drugs, Devices, and Biological 
Products Intended for the Treatment of Osteoarthritis (OA), published July 15, 1999, has been withdrawn. 
 
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
34  for industry E9 Statistical Principles for Clinical Trials and E10 Choice of Control Group and 
35  Related Issues in Clinical Trials, respectively.4  
36   
37  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
38  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
39  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
40  the word should in Agency guidances means that something is suggested or recommended, but 
41  not required.  
42   
43   
44  II.  CONSIDERATIONS FOR DEVELOPMENT 
45   
46  Sponsors should consider the following regarding structural endpoints for developing medical 
47  products for the treatment of OA: 
48   
49    FDA recognizes that OA can be a serious disease with an unmet medical need for 
50  therapies that modify the underlying pathophysiology of the disease and potentially 
51  change its natural course to prevent long-term disability.  However, there are several 
52  ongoing issues with developing such products, including the multifactorial and complex 
53  etiopathogenesis of the disease, the well-recognized discordance between structural 
54  changes and signs/symptoms/function, the lack of standard definitions of disease 
55  progression, and, correspondingly, the absence of endpoints to reliably assess the ability 
56  of a product to alter OA disease progression.  
57   
58    Because of the complex and variable pathologic changes through which OA impairs 
59  function and leads to long-term disability and/or joint replacement, at this time it is 
60  unclear what magnitude of change in structural endpoints would translate to a clinically 
61  meaningful benefit to patients (i.e., reliably predict both reduced pain and increased 
62  function or prolonged time to end-stage disease).  Thus, no structural endpoints have 
63  been used for traditional or accelerated approval in OA to date.   
64   
65    To accept structural endpoints as valid outcome measures for accelerated approval, there 
66  should be substantial confidence, either based on empirical evidence from randomized, 
67  controlled comparisons from clinical trials and/or based on a comprehensive 
68  understanding of the disease process and product mechanism of action, that an effect on 
69  the candidate structural endpoint will reliably predict an effect on the clinical outcomes 
70  of interest.5  The ultimate goal of treatments related to inhibition of structural damage or 
71  targeting the underlying pathophysiology associated with OA is to avoid or significantly 
72  delay the complications of joint failure and the need for joint replacement, and also to 
73  reduce the deterioration of function and worsening of pain.   
74   
                                                 
4 We update guidances periodically.  For the most recent version of a guidance, check the FDA guidance web page 
at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm. 
 
5 Fleming TR and Powers JH, 2012, Biomarkers and Surrogate Endpoints in Clinical Trials, Statistics in Medicine, 
31.25: 29732984. 
2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
75  At this time, the ability of treatment effects on common measures of structural progression to 
76  reliably predict treatment effects on direct measures of how patients function and feel, has not 
77  been established.  Therefore, FDA welcomes efforts to address the above considerations and is 
78  open to work with all stakeholders on such programs.  
3