29 4.4 EARLY WITHDRAWAL OF SUBJECTS .............................................................................. 30 4.4.1 WHEN AND HOW TO WITHDRAW SUBJECTS ............................................................... 30 4.4.2 DATA COLLECTION AND FOLLOW -UP FOR WITHDRAWN SUBJECTS ............................ 30 5 STUDY DRUG .....................................................................................................................31 5.1 DESCRIPTION ................................................................................................................. 31 5.2 PACKAGING ................................................................................................................... 31 5.3 RECEIVING , STORAGE , DISPENSING AND RETURN .......................................................... 32 5.3.1 RECEIPT OF DRUG SUPPLIES ....................................................................................... 32 5.3.2 STORAGE .................................................................................................................... 32 5.3.3 DISPENSING OF STUDY DRUG ..................................................................................... 32 5.3.4 PRECAUTIONS WITH INVESTIGATIONAL MEDICINAL PRODUCT ................................... 33 5.3.5 PREPARATION OF INVESTIGATIONAL PRODUCT .......................................................... 33 5.3.6 RETURN OR DESTRUCTION OF STUDY DRUG .............................................................. 34 5.4 USE OF CELLECTRA ELECTROPORATION DEVICE ..................................................... 35 5.4.1 INVESTIGATIONAL DEVICE ACCOUNTABILITY ............................................................ 35 6 STUDY PROCEDURES AND TREATMENTS ...............................................................35 6.1 COHORT I ....................................................................................................................... 35 6.1.1 PRE TREATMENT EVALUATION (SCREENING ; DONE WITHIN 28 DAYS OF FIRST DOSE)35 6.1.2 VISIT FOR IMMUNOTHERAPY (PRE AND POST SURGERY : EVERY 3 WEEKS ± 3 DAYS ).. 36 6.1.3 SURGERY .................................................................................................................... 37 6.1.4 POST SURGERY 2 WEEK FOLLOW UP (± 7 DAYS ) .......................................................... 37 6.1.5 INSPECTION VISIT 4 WEEKS POST-SURGERY (±7 DAYS ) ............................................. 37 6.1.6 2 WEEK FOLLOW UP POST LAST DOSE OF IMMUNOTHERAPY (±3 DAYS) ................... 37 6.1.7 LONG TERM FOLLOW UP (EVERY 3 MON THS ±7 DAYS FOR 6 MONTHS )/END OF STUDY VISIT 38 6.2 COHORT II ..................................................................................................................... 38 6.2.1 PRE-TREATMENT EVALUATION (SCREENING ; WITHIN 28 DAYS OF FIRST DOSE ) .......... 38 6.2.2 VISIT FOR IMMUNOTHERAPY (4 DOSES EVERY 3 WEEKS ±3 DAYS ) ............................ 39 6.2.3 2 WEEK FOLLOW UP POST LAST DOSE OF IMMUNOTHERAPY (± 3 DAYS ) ................... 39 6.2.4 LONG TERM FOLLOW UP (EVERY 3 MONTHS ± 7 DAYS FOR 6 MONTHS )/END OF STUDY VISIT 39 6.3 TIMING AND EVALUATION ............................................................................................. 40 6.3.1 INFORMED CONSENT .................................................................................................. 40 6.3.2 ASSIGNMENT OF SUBJECT NUMBERS .......................................................................... 40 6.3.3 MEDICAL HISTORY /EXISTING EVENTS /ILLNESSES ..................................................... 40 6.3.4 SAFETY ASSESSMENTS ............................................................................................... 40 6.4 OPTIONAL COLLECTION O F LEFTOVER TUMOR TISSUE SAMPLE ..................................... 42 6.5 HLA TESTING ................................................................................................................ 42 6.6 INJECTION OF INO-3112 FOLLOWED BY ELECTROPORATION ......................................... 42 6.6.1 MANAGEMENT OF ANXIETY AND PAIN DUE TO EP PROCEDURE .................................. 43 6.6.2 ASSESSMENT OF INJECTION SITE REACTIONS ............................................................. 43 7 STATISTICAL PLAN .........................................................................................................44 7.1 SAMPLE SIZE DETERMINATION ...................................................................................... 44 5 Date: 8 April, 2016 v 2.1 INO-3112 UPCC # 39313 / HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol 7.2 STATISTICAL METHODS ................................................................................................. 44 7.3 SUBJECT POPULATION (S) FOR ANALYSIS ....................................................................... 44 8 SAFETY AND ADVERSE EVENTS .................................................................................44 8.1 DEFINITIONS .................................................................................................................. 44 8.1.1 UNANTICIPATED PROBLEMS INVOLVING RISK TO SUBJECTS OR OTHERS ................... 44 8.1.2 ADVERSE EVENT ........................................................................................................ 45 8.1.3 SERIOUS ADVERSE EVENT .......................................................................................... 45 8.1.4 ADVERSE EVENT REPORTING PERIOD ........................................................................ 46 8.1.5 CAUSAL RELATIONSHIP OF CLINICAL MATERIAL TO ADVERSE EVENTS .................... 47 8.1.6 PREEXISTING CONDITION ........................................................................................... 48 8.1.7 GENERAL PHYSICAL EXAMINATION FINDINGS ........................................................... 48 8.1.8 POST-STUDY REPORTING REQUIREMENTS .................................................................. 48 8.1.9 ABNORMAL LABORATORY VALUES ........................................................................... 48 8.1.10 HOSPITALIZATION , PROLONGED HOSPITALIZATION OR SURGERY .............................. 49 8.2 RECORDING OF ADVERSE EVENTS ................................................................................. 49 8.3 REPORTING OF SERIOUS ADVE RSE EVENTS AND UNANTICIPATED PROBLEMS ............... 50 8.3.1 EVENTS REQUIRING EXPEDITED REPORTING .............................................................. 50 8.3.2 STOPPING RULES (CRITERIA FOR PAUSIN G OF STUDY ) ............................................... 51 8.3.3 INVESTIGATOR REPORTIN G: INOVIO PHARMACEUTICALS , INC. ................................... 51 8.3.4 INVESTIGATOR REPORTING : THE PENN IRB ............................................................... 52 8.3.5 OTHER REPORTABLE EVENTS : .................................................................................... 53 8.4 REPORTABLE EVENTS .................................................................................................... 53 8.5 REPORTING OF DEVICE RELATED COMPLAINTS ............................................................. 54 9 DATA HANDLING AND RE CORD KEEPING ..............................................................54 9.1 CONFIDENTIALITY ......................................................................................................... 54 9.2 SOURCE DOCUMENTS .................................................................................................... 54 9.3 CASE REPORT FORMS .................................................................................................... 54 9.4 RECORDS RETENTION .................................................................................................... 54 10 STUDY MONITORING, AUDITING, AND INSPECTING ..........................................55 10.1 STUDY MONITORING ...................................................................................................... 55 10.2 MEDICAL MONITOR ....................................................................................................... 55 10.3 AUDITING AND INSPECTING ........................................................................................... 55 11 ETHICAL CONSIDERATIONS ........................................................................................56 12 STUDY FINANCES .............................................................................................................56 12.1 FUNDING SOURCE ..........................................................................................................