1. Reporting Scenario # 5 September 18, 2005

2. Scenario # 5 Ms. Wright has malignant melanoma. Ms. Wright has malignant melanoma. Tumor obtained at resection was banked. Tumor obtained at resection was banked. Pt is enrolled on a IND vaccination trial using auto DC pulsed with an auto tumor cell lysate. Pt is enrolled on a IND vaccination trial using auto DC pulsed with an auto tumor cell lysate. Vaccine is delivered intradermally every 2 weeks x 4. Vaccine is delivered intradermally every 2 weeks x 4.

3. Scenario # 5 An apheresis product is used to prepare monocytes. An apheresis product is used to prepare monocytes. Cells are cultured with IL-4 & GM- CSF in a closed system. Cells are cultured with IL-4 & GM- CSF in a closed system. Day 6, iDC are tested (sterility, endotoxin & mycoplasma). Day 6, iDC are tested (sterility, endotoxin & mycoplasma). iDC = 60% CD86+HLA-DR+ & 32% Lymphs. iDC = 60% CD86+HLA-DR+ & 32% Lymphs. iDC Spec = 70% CD86+HLA-DR+ cells (iDC do not pass spec, but process continued) iDC Spec = 70% CD86+HLA-DR+ cells (iDC do not pass spec, but process continued)

4. Scenario # 5 iDC are matured using IL-1ß, TNF-α, IL-6 and auto tumor lysate. iDC are matured using IL-1ß, TNF-α, IL-6 and auto tumor lysate. Final product did not meet the spec of 70% CD86+HLA-DR+mDC. Final product did not meet the spec of 70% CD86+HLA-DR+mDC. All safety tests were within spec. All safety tests were within spec. The PI is notified and decides to deliver the vaccine. The PI is notified and decides to deliver the vaccine. The lab director releases the vaccine, but starts a deviation report. The lab director releases the vaccine, but starts a deviation report.

5. Scenario # 5 Was the PI correct in delivering the vaccine that did not meet spec? Was the PI correct in delivering the vaccine that did not meet spec? Non-FDA response: PI was correct, because this is not a safety issue. Non-FDA response: PI was correct, because this is not a safety issue. FDA response: FDA response: Deviation from release criteria or specifications (even non-safety criteria) should be discussed with the FDA prior to administration, if possible. Deviation from release criteria or specifications (even non-safety criteria) should be discussed with the FDA prior to administration, if possible. The sponsor should report the release of the product as a protocol deviation/violation. The sponsor should report the release of the product as a protocol deviation/violation. LESSON: BE CAREFUL HOW YOU WRITE YOUR PRODUCT SPECIFICATIONS OR RELEASE CRITERIA. YOU CAN WRITE THESE AS ACTION LIMITS OR TARGETS, BUT THE FDA CONSIDERS A SPECIFICATION AS SOMETHING THAT YOU MUST MEET, OR IT IS A DEVIATION. LESSON: BE CAREFUL HOW YOU WRITE YOUR PRODUCT SPECIFICATIONS OR RELEASE CRITERIA. YOU CAN WRITE THESE AS ACTION LIMITS OR TARGETS, BUT THE FDA CONSIDERS A SPECIFICATION AS SOMETHING THAT YOU MUST MEET, OR IT IS A DEVIATION.

6. Scenario # 5 Should this deviation be reported to the FDA? If so, how should it be reported? Should this deviation be reported to the FDA? If so, how should it be reported? Non-FDA response: Yes, in the IND annual report. Non-FDA response: Yes, in the IND annual report. FDA response: Major deviations need to be reported in an expedited fashion. FDA response: Major deviations need to be reported in an expedited fashion.

7. Scenario # 5 Can the laboratory ‘improve’ the procedure by removing lymphocytes without asking the FDA permission? Can the laboratory ‘improve’ the procedure by removing lymphocytes without asking the FDA permission? Attempts to “improve” the product should not be done unless the alternative manufacturing steps have been outlined in SOPs and IND. Attempts to “improve” the product should not be done unless the alternative manufacturing steps have been outlined in SOPs and IND.