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 agencys 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 FDAs 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 doesnt 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