Reporting Scenario # 5Reporting Scenario # 5

September 18, 2005September 18, 2005

Scenario # 5Scenario # 5 Ms. Wright has malignant Ms. Wright has malignant

melanoma.melanoma. Tumor obtained at resection Tumor obtained at resection

was banked.was banked. Pt is enrolled on a IND Pt is enrolled on a IND

vaccination trial using auto DC vaccination trial using auto DC pulsed with an auto tumor cell pulsed with an auto tumor cell lysate.lysate.

Vaccine is delivered Vaccine is delivered intradermally every 2 weeks x 4.intradermally every 2 weeks x 4.

Scenario # 5Scenario # 5 An apheresis product is used to An apheresis product is used to

prepare monocytes.prepare monocytes. Cells are cultured with IL-4 & GM-Cells are cultured with IL-4 & GM-

CSF in a closed system.CSF in a closed system. Day 6, iDC are tested (sterility, Day 6, iDC are tested (sterility,

endotoxin & mycoplasma).endotoxin & mycoplasma). iDC = 60% CD86+HLA-DR+ & 32% iDC = 60% CD86+HLA-DR+ & 32%

Lymphs.Lymphs. iDC Spec = 70% CD86+HLA-DR+ iDC Spec = 70% CD86+HLA-DR+

cells cells (iDC do not pass spec, but (iDC do not pass spec, but process continued)process continued)

Scenario # 5Scenario # 5 iDC are matured using IL-1iDC are matured using IL-1ßß, TNF-, TNF-αα, ,

IL-6 and auto tumor lysate.IL-6 and auto tumor lysate. Final product did not meet the Final product did not meet the

spec of 70% CD86+HLA-DR+mDCspec 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 The PI is notified and decides to

deliver the vaccine.deliver the vaccine. The lab director releases the The lab director releases the

vaccine, but starts a deviation report.vaccine, but starts a deviation report.

Scenario # 5Scenario # 5

Was the PI correct in delivering the vaccine that did Was the PI correct in delivering the vaccine that did not meet spec?not meet spec?

Non-FDA response: PI was correct, because this is Non-FDA response: PI was correct, because this is not a safety issue.not a safety issue.

FDA response:FDA response: Deviation from release criteria or specifications (even Deviation from release criteria or specifications (even

non-safety criteria) should be discussed with the FDA non-safety criteria) should be discussed with the FDA prior to administration, if possible.prior to administration, if possible.

The sponsor should report the release of the product The sponsor should report the release of the product as a protocol deviation/violation.as a protocol deviation/violation.

LESSON: BE CAREFUL HOW YOU WRITE YOUR LESSON: BE CAREFUL HOW YOU WRITE YOUR PRODUCT SPECIFICATIONS OR RELEASE PRODUCT SPECIFICATIONS OR RELEASE CRITERIA. YOU CAN WRITE THESE AS ACTION CRITERIA. YOU CAN WRITE THESE AS ACTION LIMITS OR TARGETS, BUT THE FDA LIMITS OR TARGETS, BUT THE FDA CONSIDERS A SPECIFICATION AS SOMETHING CONSIDERS A SPECIFICATION AS SOMETHING THAT YOU MUST MEET, OR IT IS A DEVIATION.THAT YOU MUST MEET, OR IT IS A DEVIATION.

Scenario # 5Scenario # 5

Should this deviation be Should this deviation be reported to the FDA? If so, how reported to the FDA? If so, how should it be reported?should it be reported?

Non-FDA response: Yes, in the Non-FDA response: Yes, in the IND annual report. IND annual report.

FDA response: Major deviations FDA response: Major deviations need to be reported in an need to be reported in an expedited fashion.expedited fashion.

Scenario # 5Scenario # 5

Can the laboratory ‘improve’ the Can the laboratory ‘improve’ the procedure by removing procedure by removing lymphocytes without asking the lymphocytes without asking the FDA permission?FDA permission?

Attempts to “improve” the Attempts to “improve” the product should not be done product should not be done unless the alternative unless the alternative manufacturing steps have been manufacturing steps have been outlined in SOPs and IND.outlined in SOPs and IND.