Welcome and Introduction

1. Welcome and Introduction Lee S. Simon, MD Division Director Analgesic, Anti-inflammatory and Ophthalmologic Drug Products ODEV/CDER

2. Arthritis Advisory Committee • Meeting to discuss a Concept Paper developed by multiple groups within the agency to determine the basis for a guidance for the development of therapies in Systemic Lupus Erythematosus • Claims • Trial Designs • Application of possible accelerated approval

3. Guidance • What is a guidance document? • 21 CFR 10.115 (Code of Federal Regulations) • Guidance documents are those prepared for FDA staff, applicants/sponsors, and the public that describe the agency’s interpretation of, or policy on a regulatory issue • Guidance documents include: the design, production, labeling, promotion, manufacturing, and testing of regulated products; the processing, content, and evaluation and or approval of submissions; and inspection and enforcement policies

4. Guidance • Guidance documents do not establish legally enforceable rights or responsibilities; They do not legally bind the public or FDA • You may choose to use an approach other than the one set forth in the document. • However, the alternative approach must comply with relevant statutes and regulations. FDA is willing to discuss alternative approaches to ensure that they comply with these requirements. • Although there is no legal binding, it is important to note that such a document represents current thinking of the FDA regarding these issues. • If the FDA departs from these guidance documents, they do so only with appropriate justification and supervisory concurrence.

5. Guidance • What are the FDA’s procedures for development and issuance of such a document: • Before a working draft is developed, FDA can seek or accept early input from individuals or groups outside the agency. This can be done through participation in or holding public meetings and/or workshops. • After draft is developed • Publish notice in Federal Register • Post draft on internet and make hard copy available • Invite comment • Hold further public meetings such an advisory committee meeting to discuss the document • Once decided and “finalized” again notice is posted in the Federal Register and the document is placed on internet and made available as hard copy.

6. Approved Drugs/Biologics for the Treatment of SLE • Hydroxychloroquine (chronic discoid and systemic) • Glucocorticoids • Low dose acetylsalicylic acid

7. Not-Approved Drugs/Biologics Used “Off Label” in the Treatment of SLE • Cyclophosphamide either oral or IV • Mycophenolate mofetil • Methotrexate • Many NSAIDs/COX-2 selective inhibitors • Azathioprine • Other immune modulators

8. Issues in SLE Clinical Studies Unique characteristics of studies in SLE: • Heterogeneity of disease and patients • Morbidity, mortality spontaneously (?) improved last three decades • Lack of clear outcome measures/ “fixed” damage • Length of time to observe desired response • Lack of clear guidance • Disease course difficult to predict a priori • Typically observed “flares” and remissions • Multiple organ system involvement • Progression variable, recurrences hard to predict

9. Issues to Consider in the Development of Outcomes for Clinical Trials in SLE • These will be reviewed but one issue should be highlighted • Disease activity indices • reliability and validity, • usual levels in active disease, • and responsiveness to treatment defined in corroborating prospective studies

10. Clinical Trials for Regulatory Approval Address issues regarding the effects of a systemic inflammatory disease on the whole person • Disease activity • Response to therapy • Amount of damage prevented which would have been caused by disease vs. fixed damage not able to evidence improvement but may be an important observation if not worsening • Damage caused by the treatment Address issues regarding individual organ involvement • Disease activity • Response to therapy • Amount of damage prevented which would have been caused by disease • Damage caused by the treatment Address issues regarding improvement in target area, but no worsening elsewhere

11. Surrogates vs. Biomarkers While surrogate endpoints are candidate criteria for drug approval, a broader term, biomarker, or even early marker is commonly applied. The latter do not have the same regulatory implication. Surrogates may be bio-markers, but not all bio-markers are surrogates.

12. Conclusions • In the scenario of a complex disease it is important to be creative in trial design: clinical endpoints unclear • Important to remember that determining safety requires a robust data set • We will support the study of therapeutic effects regarding the state of the disease as well as specific organ involvement; yet the overall state of disease doesn’t worsen • Given the heterogeneity of the disease might consider the development of a responder index • Early and active dialogue with members of the agency is strongly recommended

13. Agenda • State of the Art • Potential claims • The potential for accelerated approvals and application of early/bio-markers • Trial designs • In between each major topic we will entertain discussion from the floor at the discretion of the chair, when announced please approach microphone, identify self and declare any conflicts of interest