1. Evaluating A Systemic Therapy Psoriasis 1.Efficacy 2.Safety 3.Labeling

2. What patients want!!! Effective –Clear or nearly clear is what patients want Keeps on working –Patients do not wish to constantly use therapy when the disease returns treatment should work at least as well. Convenient- limited trips to MD –Not messy –Does not require much time

3. What patients want cont’d. Safe –Does not make patient uncomfortable (or worse) while being used –Safe long term / repeated use does not preclude or interact with other treatments

4. Psoriasis –Psoriasis is a chronic disease (average duration about 50 years!!! –Extent and impact vary greatly among patients and in the affected individual over time.

5. Questions for today –Does it work? –Does it keep working? –Is it safe? –Do its potential benefits outweigh its risks?

6. Does it work? In what types of patients has efficacy been demonstrated? How well/often does it work? –(statistically significant is not enough) What are factors associated with success/failure? – ( Do available data help select patients for when the drug is most effective?)

7. Does it keep working? Psoriasis is a chronic disease. If a treatment has risks, its utility depends on –Low incidence of rebound –Length of remission –Efficacy (by patient criteria)

8. Is it safe? Short time and long term safety with use repeated must be assessed Concerns for this class: 1.Infection 2.Cancer – especially lymphoma and SCC 3.Immunologically mediated diseases (LE, MS, etc). 4.Immunologic reaction to the drug (I.e. antibodies) May decrease efficacy May be a health risk

9. Is it safe cont’d Do we have sufficient and robust data? Is it likely PMS will provide timely and Robust date? (I.e can we rely on Phase IV commitments?)

10. Do its benefits outweigh its risks? Short term perspective insufficient. A long term view is needed Do available data allow us to recommend approval? What labeling will put the drug in proper perspective given when we know?

11. PASI This meeting is not about the PASI ( or what percentage improvement represents significant clinical improvement.) The PASI is a flawed scale. We could (and have) spent many hours extolling its virtues and condemning its shortcomings.

12. Past Comments about the PASI at Advisory Committee Meetings Dr. Joseph McGuire: “I think no one is satisfied with the clinical fidelity of PASI….” Dr. Robert Stern “ Lets pass on the PASI” –(not a compliment to the PASI) Dr. Mark Lebwohl –“ Now I entirely agree with Dr. Stern, we have to pass on the PASI……..

13. The Literature Dr. Michael Bigby ( JAAD, 1996) –“ The major problem with indices ( PASI) is that they confound area of involvement with extent of disease.” –“Until better scales are developed trials with the simplest and most objective outcome variables are best.” ( Bigby, JAAD, 1996)

14. A Proposal Acknowledging the limitations of the evaluation metrics utilized in the studies we will review today, let us agree to utilize the agreed upon two primary end points today. 1.PASI 75% improvement 2.Clear or almost clear And try not to complicate the discussion of this product with debate about how to measure psoriasis.

15. Current Labeling (Indication) of Systemic Therapies for Psoriasis.

16. Caution: Methoxsalen is a potent drug. 1.Photochemotherapy (Methoxsalen with long wave UVA radiation) is indicated for the symptomatic control of severe, recalcitrant disabling psoriasis not adequately responsive to other forms of therapy and when the diagnosis has been supported by biopsy.

17. Soriatane Soriatane is indicated for the treatment of severe psoriasis. – Because of significant adverse effects associated with its use, Soriatane should be prescribed only by physicians knowledgeable in the systemic use of retinoids. –Methotrexate is indicated in the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy, but only when the diagnosis has been established, as a biopsy and/or after dermatologic consultation.

18. Neoral –Psoriasis: Neoral is indicated for the treatment of adult, nonimmunocompromised patients with severe (I.e extensive and/or disabling) recalcitrant, plaque psoriasis who have failed to respond to at least one systemic therapy.

19. Amevive Amevive is indicated for the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy.

20. Today’s Task Answers FDA’s questions. Judge if benefits outweigh Risk Suggest Additional Data Needs for Judging Long Term Role