1. CLAIMS STRUCTURE FOR SLE Jeffrey Siegel, M.D. Arthritis Advisory Committee September 29, 2003

2. Clinical Development in SLE No new products approved for SLE in recent years Guidance on what would represent adequate evidence of efficacy may facilitate drug development Ideally, guidance should recognize a broad range of potential benefits therapeutic products could achieve in SLE

3. Formulating Claims Structure In guidance, desirable to include wide range of potential clinical benefits Challenges: – SLE has varied manifestations – Waxing & waning disease activity – Paucity of randomized clinical trial data to characterize clinical benefits of many currently used agents

4. Potential Claims Improves disease activity in a specific organ Reduction in signs & symptoms – Based on trial showing improvement in disease activity index (DAI) compared to control – If improvement concerns non-internal organ system manifestations, may be better described as “improvement in constitutional aspects” Prevention of lupus flares Complete response / Remission Improvement in health related-quality of life

5. Organ-Specific Disease Activity Evidence: Study enrolling patients with active disease in a specific organ system – E.g. renal, hematologic, pulmonary, CNS – Could also include > 1 organ system with stratification Successful trial would demonstrate better control of disease in involved organ system compared to control

6. Outcome Measures for Organ- Specific Disease In many cases, outcome measures not yet well defined for organ-specific manifestations – Presents challenge for design of clinical trials Portions of DAIs assessing specific organs could be explored for suitability as outcome measure The definition of success could be restricted to remission or could allow partial responses in control of disease activity to also be recognized as a benefit

7. Lupus Nephritis Specific example of disease-specific manifestation of SLE Has represented major cause of morbidity and mortality: – Modern management associated with improved outcomes than earlier eras – Current treatment modalities nonetheless with considerable toxicity

8. Possible Outcome Measures for Lupus Nephritis Survival, ESRD represent clear clinical benefit but may occur too infrequently to serve as sensitive indicators of treatment effect Doubling of serum creatinine reported to predict progression to ESRD in certain populations Smaller increases in serum creatinine, e.g. 50% Sustained attainment of renal remission using accepted criteria for urinary sediment, GFR, proteinuria

9. Reduction in Signs & Symptoms Reflect benefit in signs of disease activity and associated symptoms: – Considerable internal agency discussion about relative merits of “signs & symptoms” claim vs. “improvement in constitutional symptoms” Clinical trial would assess overall control of disease activity using a DAI: – E.g. SLEDAI, SLAM, BILAG Since DAI’s measure a wide range of disease manifestations, defining the clinical benefits demonstrated in a successful trial may be complex

10. Example: Trial #1 Study enrolls patients with active SLE, stratified for type of internal organ involvement At end of trial, scores on DAI statistically significantly reduced compared to control – % of subjects with renal, pulmonary, CNS, hematologic manifestations each about 25%; all show improvement with study drug Conclude efficacy on variety of major internal organ manifestations of SLE

11. Example: Trial #2 Study enrolls patients with active SLE, not stratified for type of organ involvement At end of trial, scores on DAI stastistically significantly reduced compared to control – % of subjects with renal, pulmonary, CNS, hematologic manifestations only ~10%; no clear evidence of improvement with study drug – Improvement on DAI attributable to arthritis, skin, fatigue Conclude there is a drug effect but no clear evidence of efficacy on internal organ manifestations

12. Signs & Symptoms Claim To attain a signs & symptoms claim, a product would need to show benefits in control of the common and serious manifestations of SLE Therefore a trial demonstrating efficacy would need to: – Enroll subjects with disease affecting major target organs in SLE – Demonstrate that efficacy is general and not restricted to specific organ systems

13. Reduction in Constitutional Symptoms Some products may demonstrate effect on DAIs without affecting disease activity in major internal organs by affecting “constitutional” aspects of disease – E.g. effects on arthritis, rash, fever, fatigue, serositis Perhaps reduction in constitutional aspects of disease should be recognized as a distinct claim?

14. Constitutional Symptoms Claim Improvement in constitutional symptoms may represent a clinical benefit of products that do not affect internal organ system manifestations Challenge: – Currently no validated instruments for assessing constitutional symptoms

15. Prevention of Lupus Flares Demonstration of efficacy in preventing lupus flares would be established in trials of adequate length showing 1 or more of: – Reduced frequency of flares – Increased time to flare – Reduced severity Validated definition of flare essential

16. Claim of Prevention of Lupus Flares Efficacy in prevention of flares could be seen as similar to control of disease activity However, some products may be effective in preventing flares but ineffective in treating acute disease: – E.g. high dose corticosteroids may treat acute disease but are too toxic to use long-term to prevent flares – Other products may be better tolerated long-term and could have utility in preventing flares (e.g. Esdaile et al, NEJM, 1991) Suggests prevention of lupus flares may represent a distinct benefit in some circumstances

17. Complete Clinical Response / Remission Defined by analogy with similar claim for RA as prolonged absence of disease activity Clinical trial evidence: – Absence of disease activity for 6 consecutive months – 12 month trial with DAI score achieving zero – For complete response, outcome would be achieved while receiving other lupus-directed therapies – For remission, outcome achieved on no other lupus therapy Claim could pertain to one specific organ or for treatment of lupus generally, depending on patient population studied

18. Some Caveats Proposed claims structure allows for approval of products affecting targeted organ systems Product must show overall favorable risk / benefit ratio – E.g. no worsening of other aspects of SLE to counterbalance benefits; acceptable adverse event profile Of necessity, regardless of claim sought, clinical trials should assess all relevant domains: disease activity, irreversible damage, health related- quality of life

19. Health Related-Quality of Life (HRQL) OMERACT recognized HRQL as a key domain in assessment of SLE Recognizing claim of improvement in HRQL under consideration – Product would previously be shown to reduce disease activity – Evidence should include validated HRQL measure, patient global assessment Assessment of HRQL outcomes should include same statistical rigor as other endpoints

20. Conclusion Proposed claims structure would recognize variety of potential clinical benefits Challenge is: – Designing clinical trials that clearly demonstrate which patients would benefit from the therapeutic product and the benefits they would attain – Describing benefits seen in studies in a useful and accurate manner for patients and clinicians Clinical trials should assess effects on all domains of disease to fully characterize risk/benefit