Welcome and Introduction

Lee S. Simon, MDDivision Director

Analgesic, Anti-inflammatory and Ophthalmologic Drug Products

ODEV/CDER

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

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

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.

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.

Approved Drugs/Biologics for the Treatment of SLE

• Hydroxychloroquine (chronic discoid and systemic)

• Glucocorticoids

• Low dose acetylsalicylic acid

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

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

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

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

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.

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

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