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16.2 institutional review boards and

The protocol and consent form will be reviewed and approved by the IRB/IEC of each participating center and Halozyme prior to study initiation. Serious adverse experiences regardless of causality will be reported to the IRB/IEC in accordance with the standard operating procedures and policies of the IRB/IEC, and the Investigator will keep the IRB/IEC informed as to the progress of the study. The Investigator will obtain assurance of IRB/IEC compliance with regulations. Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, protocol amendments, Investigator's Brochure, consent forms, information concerning patient recruitment, payment or compensation procedures, or other pertinent information) will be submitted to the IRB/IEC. The IRB/IECs written unconditional approval of the study protocol and the informed consent form will be in the possession of the Investigator before the study is initiated. The IRB/IECs unconditional approval statement will be transmitted by the Investigator to Halozyme Therapeutics prior to the shipment of study supplies to the site. This approval must refer to the study by exact protocol title and number and should identify the documents reviewed and the date of review. Protocol and/or informed consent modifications or changes may not be initiated without prior written IRB/IEC approval except when necessary to eliminate immediate hazards to the patients or when the change(s) involves only logistical or administrative aspects of the study. Such modifications will be submitted to the IRB/IEC and written verification that the modification was submitted and subsequently approved should be obtained. The IRB/IEC must be informed of revisions to other documents originally submitted for review; serious and/or unexpected adverse experiences occurring during the study in accordance with the standard operating procedures and policies of the IRB; new information that may affect adversely the safety of the patients of the conduct of the study; an annual update and/or request for re-approval; and when the study has been completed.
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16.3 informed consent form

Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH GCP, US Code of Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance Portability and Accountability Act (HIPAA, if applicable), and local regulations. The Investigator will prepare the informed consent form, assent and HIPAA authorization prior to submission to the IRB/IEC. The consent form generated by the Investigator must be acceptable to the Sponsor and be approved by the IRB/IEC. The written consent document will embody the elements of informed consent as described in the International Conference on Harmonisation and will also comply with local regulations. The Investigator will send an IRB/IEC-approved copy of the Informed Consent Form to the Sponsor (or designee) for the study file. A properly executed, written, informed consent will be obtained from each subject prior to entering the subject into the trial. Information should be given in both oral and written form and subjects (or their legal representatives) must be given ample opportunity to inquire about details of the study. If appropriate and required by the local IRB/IEC, assent from the subject will also be obtained. If a subject is unable to sign the informed consent form (ICF) and the HIPAA authorization, a legal representative may sign for the subject. A copy of the signed consent form (and assent) will be given to the subject or legal representative of the subject and the original will be maintained with the subject's records.
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16.4 regulatory documentation

Prior to implementing this protocol at UCSF HDFCCC, the protocol, informed consent form, HIPAA authorization and any other information pertaining to participants must be approved by the UCSF IRB. Prior to implementing this protocol at the participating sites, approval for the UCSF IRB approved protocol must be obtained from the participating site's IRB.  
The following documents must be provided to UCSF HDFCCC before the participating site can be initiated and begin enrolling participants:  
Participating Site IRB approval(s) for the protocol, appendices, informed consent form and HIPAA authorization Participating Site IRB approved consent form Participating Site IRB membership list Participating Site IRB's Federal Wide Assurance number and OHRP Registration number Curriculum vitae and medical license for each investigator and consenting professional Documentation of Human Subject Research Certification training for investigators and key staff members at the Participating Site Participating site laboratory certifications and normals Upon receipt of the required documents, UCSF HDFCCC will formally contact the site and grant permission to proceed with enrollment.
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16.5 coordinating center documentation of

It is the responsibility of the Study Chair to maintain adequate files documenting the distribution of study documents as well as their receipt (when possible). The HDFCCC recommends that the Study Chair maintain a correspondence file and log for each segment of distribution (e.g., FDA, drug manufacturer, participating sites, etc.). Correspondence file: should contain copies (paper or electronic) of all protocol versions, cover letters, amendment outlines (summary of changes), etc., along with distribution documentation and (when available) documentation of receipt. Correspondence log: should be a brief list of all documents distributed including the date sent, recipient(s), and (if available) a tracking number and date received. At a minimum, the Study Chair must keep documentation of when and to whom the protocol, its updates and safety information are distributed.
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16.6 publications

The preparation and submittal for publication of manuscripts containing the study results shall be in accordance with a process determined by mutual written agreement among the Halozyme and participating institutions. The publication or presentation of any study results shall comply with all applicable privacy laws, including, but not limited to, the Health Insurance Portability and Accountability Act of 1996.
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16.7 investigator responsibilities

By signing the Agreement of Investigator form, the Investigator agrees to:  
1. Conduct the study in accordance with the protocol and only make changes after notifying the Sponsor (or designee), except when to protect the safety, rights or welfare of subjects.  
2. Personally conduct or supervise the study (or investigation). 3. Ensure that the requirements relating to obtaining informed consent and IRB review and approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56.  
4. Report to the Sponsor or designee any AEs that occur in the course of the study, in accordance with §21 CFR 312.64.  
5. Ensure that all associates, colleagues and employees assisting in the conduct of the study are informed about their obligations in meeting the above commitments.  
6. Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to make those records available for inspection with the Sponsor (or designee).  
7. Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be responsible for initial and continuing review and approval of the clinical study.  
8. Promptly report to the IRB, , (or designee) all changes in the research activity and all unanticipated problems involving risks to subjects or others (to include amendments and IND safety reports).
9. Seek IRB approval before any changes are made in the research study, except when necessary to eliminate hazards to the patients/subjects.  
10. Comply with all other requirements regarding the obligations of clinical investigators and all other pertinent requirements listed in § 21 CFR part 312.
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17 recommended dosing of enoxaparin

Enoxaparin will be administered to all subjects to minimize the risk of thromboembolic events
(TE) events. Enoxaparin will be administered subcutaneously (SC) at a dose of 1 mg/kg/day.  
Rounding of the dose may be done per Institution policy and when using prefilled syringes supplied Refer to Table 8 for examples of rounding based on the expected enoxaparin dose. If the rounded dose is greater than 20% of the expected dose based on weight, the Sponsor should be consulted.  
| Enoxaparin Expected Dose   | Rounded Enoxaparin Dose   | Syringes Dispensed   |
|----------------------------|---------------------------|----------------------|
| (mg)                       | (mg)                      |                      |
| 50-69                      | 60                        | 60 mg x1             |
| 70-89                      | 80                        | 80 mg x1             |
| 90-109                     | 100                       | 100 mg x 1           |
| 110-134                    | 120                       | 120 mg x 1           |
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18 references

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17. Jenkins, R.H., et al., *Myofibroblastic differentiation leads to hyaluronan accumulation* through reduced hyaluronan turnover. J Biol Chem, 2004. 279(40): p. 41453-60.  
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19. Von Hoff, D.D., et al., Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol, 2011. 29(34): p. 454854.  
20. Desai, N., et al., Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clin Cancer Res, 2006. 12(4): p. 1317-24.  
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27. Cuenod, C.A., et al., *Tumor angiogenesis: pathophysiology and implications for contrastenhanced MRI and CT assessment.* Abdom Imaging, 2006. 31(2): p. 188-93.  
28. Bali, M.A., et al., *Tumoral and nontumoral pancreas: correlation between quantitative* dynamic contrast-enhanced MR imaging and histopathologic parameters. Radiology, 2011. 261(2): p. 456-66.  
29. Wang, Y., et al., Diffusion-weighted MR imaging of solid and cystic lesions of the pancreas. Radiographics, 2011. 31(3): p. E47-64.  
30. Infante, J.R., Ramanathan, R.K., Borad, M.J., Rosen, L.S., Korn, R., Dychter, S.S.,
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32. Callery, M.P., et al., *Pretreatment assessment of resectable and borderline resectable* pancreatic cancer: expert consensus statement. Ann Surg Oncol, 2009. 16(7): p. 172733.  
33. Bruno, O., et al., Utility of CT in the diagnosis of pancreatic fistula after pancreaticoduodenectomy in patients with soft pancreas. AJR Am J Roentgenol, 2009.  
193(3): p. W175-80.  
34. Machado, N.O., Pancreatic fistula after pancreatectomy: definitions, risk factors, preventive measures, and management-review. Int J Surg Oncol, 2012. **2012**: p.  
602478.  
35. Varadhachary, G.R., et al., Borderline resectable pancreatic cancer: definitions, management, and role of preoperative therapy. Ann Surg Oncol, 2006. 13(8): p. 103546.  
36. Kim, S.S., et al., Preoperative FOLFIRINOX for borderline resectable pancreatic cancer:
Is radiation necessary in the modern era of chemotherapy? J Surg Oncol, 2016. 114(5):
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37. Sunil R. Hingorani, W.P.H., Joseph Thaddeus Beck, Boris A. Berdov, Stephanie Ann Wagner, Eduard M. Pshevlotsky, Sergei Tjulandin, Oleg Gladkov, Randall F. Holcombe, Ping Jiang, Craig E. Devoe, *Final results of a phase Ib study of gemcitabine plus* PEGPH20 in patients with stage IV previously untreated pancreatic cancer. J Clin Oncol, 2015. 33(suppl 3).  
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Tabernero, J., Hidalgo, M., Van Cutsem, E., Goldstein, D., Wie, X., Iglesias, J.L.,
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40. Ho, C.K., et al., *Complications of pancreatic surgery.* HPB (Oxford), 2005. 7(2): p. 99108.  
41. Lin, J.W., et al., Risk factors and outcomes in postpancreaticoduodenectomy pancreaticocutaneous fistula. J Gastrointest Surg, 2004. 8(8): p. 951-9.  
42. Bartoli, F.G., et al., Pancreatic fistula and relative mortality in malignant disease after pancreaticoduodenectomy. Review and statistical meta-analysis regarding 15 years of literature. Anticancer Res, 1991. 11(5): p. 1831-48.  
43. Bassi, C., et al., *Management of complications after pancreaticoduodenectomy in a high* volume centre: results on 150 consecutive patients. Dig Surg, 2001. 18(6): p. 453-7; discussion 458.  
44. Poon, R.T., et al., *Prevention of pancreatic anastomotic leakage after* pancreaticoduodenectomy. Am J Surg, 2002. 183(1): p. 42-52.  
45. Tsiotos, G.G., M.B. Farnell, and M.G. Sarr, Are the results of pancreatectomy for pancreatic cancer improving? World J Surg, 1999. 23(9): p. 913-9.  
46. Balcom, J.H.t., et al., *Ten-year experience with 733 pancreatic resections: changing* indications, older patients, and decreasing length of hospitalization. Arch Surg, 2001.  
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47. Yeo, C.J., et al., *Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s:*
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48. Bassi, C., et al., *Postoperative pancreatic fistula: an international study group (ISGPF)*
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49. Callery, M.P., et al., *A prospectively validated clinical risk score accurately predicts* pancreatic fistula after pancreatoduodenectomy. J Am Coll Surg, 2013. 216(1): p. 1-14.  
50. Pratt, W.B., et al., *Clinical and economic validation of the International Study Group of* Pancreatic Fistula (ISGPF) classification scheme. Ann Surg, 2007. 245(3): p. 443-51.  
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52. Moore, M.J., et al., *Erlotinib plus gemcitabine compared with gemcitabine alone in* patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol, 2007. 25(15): p. 1960-6.  
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Hezel, Wen Wee Ma, Venu Gopal Bathini, Xionghua W. Wu, Ping Jiang, Andrea J.  
Bullock, *Interim results of a randomized phase II study of PEGPH20 added to nabpaclitaxel/gemcitabine in patients with stage IV previously untreated pancreatic cancer.* J
Clin Oncol, 2016. 34(suppl 4S): p. abstr 439.  
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appendix 1 ucsf policy/procedure for

This policy defines the required Regulatory Documents for Single Site and Multicenter Investigator Initiated Oncology Clinical Trials at the Helen Diller Family Comprehensive Cancer Center (HDFCCC) where the Principal Investigator (PI) holds the IND.
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background

The International Conference on Harmonization (ICH) Good Clinical Practices (GCP) Guidelines define Essential Regulatory Documents as those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of data produced. These documents serve to demonstrate compliance with standards of GCP and with all applicable regulatory requirements. Filing essential documents in a timely manner can greatly assist in the successful management of a clinical trial.  
The Regulatory Documents will consist of electronic files in both iMedRIS and OnCore®, as well as paper files in the Regulatory Binders for both the Coordinating Site and the Participating Site(s) in the HDFCCC Investigator Initiated Oncology Clinical Trials.
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procedures documents filed in oncore

Package Insert (if the study drug is commercial) or Investigator Brochure Protocol Review Committee (PRC) approved protocols, protocol amendments and Summary of Changes (SOC)
Patient handouts Screening/enrollment log Data and Safety Monitoring Committee (DSMC) monitoring reports OnCore® Case Report Form (CRF) completion manual  
1. HDFCCC Essential Regulatory Documents Documents Filed in iMedRIS:
IRB approvals for initial submission of application, all modifications, and continuing annual renewals Current and prior approved protocol versions with signed protocol signature page(s)
Committee for Human Research (IRB) approval letters and Informed Consent Form(s) (ICF)
Current and prior versions of the Investigator Brochure (IB). Serious Adverse Event Reporting Protocol Violations and Single Patient Exception (SPE) Reports to IRB with supporting fax documentation
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documents filed in regulatory binder

Completed Food and Drug Administration (FDA) 1572 document with Principal Investigator's signature For all Principal Investigators and Sub-Investigators listed on the FDA 1572, will need Financial Disclosure Forms, CVs, MD Licenses, Drug Enforcement Agency (DEA) Licenses, and Staff Training Documents (i.e. Collaborative Institute Training Initiative (CITI), etc.)
Site Initiation Visit (SIV) minutes and correspondence with participating site(s). As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion Center Serious Adverse Event (SAE) reports to IRB and sponsor. MedWatch reporting to FDA and sponsor Delegation of Authority Form Drug Destruction Standard Operating Procedure (SOP)
For all laboratories listed on the FDA 1572, will need CLIA certifications, CAP certifications, lab licenses, CVs of Lab Directors, and laboratory reference ranges Appendix 2 UCSF Policy/Procedure for Required Regulatory Documents for Single Site and Multicenter Investigator-Initiated Oncology Clinical Trials
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purpose

This policy defines the required Regulatory Documents for Single Site and Multicenter Investigator Initiated Oncology Clinical Trials at the Helen Diller Family Comprehensive Cancer Center (HDFCCC) for both IND and IND-exempt trials.
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background

The International Conference on Harmonization (ICH) Good Clinical Practices (GCP) Guidelines define Essential Regulatory Documents as those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of data produced. These documents serve to demonstrate compliance with standards of GCP and with all applicable regulatory requirements. Filing essential documents in a timely manner can greatly assist in the successful management of a clinical trial.  
The Regulatory Documents will consist of electronic files in both iRIS and OnCore®, as well as paper files in the Regulatory Binders for both the Coordinating Site and the Participating Site(s) in the HDFCCC Investigator Initiated Oncology Clinical Trials.
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procedures 1. single site (hdfccc)

Current and prior versions of the Informed Consent Form(s) (ICFs). IRB approvals for initial submission of application, all modifications, and continuing annual renewals.  
Current and prior approved protocol versions. Current IRB roster Current and prior versions of the Investigator Brochure (IB). Serious Adverse Event (SAE) Reports.  
Subject diary and handouts (if applicable).  
Single Patient Exception (SPE) Report(s) to IRB with Approval Letter(s) from IRB. Protocol Violation (PV) Reports with acknowledgement from the IRB.
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documents filed in oncore

Package Insert (if the study drug is commercial).  
Protocol signature page(s) with Pl signature(s) for all protocol versions.  
Protocol Review Committee (PRC) approved protocols, protocol amendments and Summary of Changes (SOC) document.
Screening/enrollment log.  
Data and Safety Monitoring Committee (DSMC) monitoring reports.  
DSMC dose escalation approvals with study status summary forms.  
Case Report Form (CRF) completion manual.  
Drug Destruction Standard Operating Procedure (SOP). Completed Food and Drug Administration (FDA) 1572 document with Principal Investigator's signature.  
For all Principal Investigators and Sub-Investigators listed on the FDA 1572, will need Financial Disclosure Forms, CVs, MD Licenses, and Staff Training Documents (i.e., Collaborative Institute Training Initiative (CITI), etc.).  
As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion Center.  
Serious Adverse Event (SAE) reports to IRB and sponsor. MedWatch reporting to FDA and sponsor. Drug Destruction Standard Operating Procedure (SOP). For all laboratories listed on the FDA 1572, will need CUA certifications, CAP
certifications, lab licenses, CV(s) and Medical License(s) of Lab Director(s), and laboratory reference ranges.
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documents filed in regulatory binder

Delegation of Authority Log with signatures (to be scanned in OnCore once the trial is complete).
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2. additional essential documents for

Institutional Review Board (IRB) approval letters, IRB roster, Informed Consent Form
(ICF), and Health Insurance Portability and Accountability Act {HIPAA) Consent Form for the Participating Site(s).  
For all Principal Investigators and Sub-Investigators listed on the 1572 at the Participating Site(s), will need Financial Disclosure Forms, CVs, MD Licenses, and Staff Training documents (i.e. Collaborative Institute Training Initiative (CITI), etc.) (for investigational New Drug Application).  
Site Initiation Visit (SIV) minutes and correspondence with the Participating Site(s).  
As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion Center for the Participating Site(s).  
Protocol Violations (PV) Reports to IRB with acknowledgement from IRB for Participating Site(s).  
Single Patient Exception (SPE) Reports to IRB with IRB Approval Letters for Participating Site(s).  
Drug Destruction Standard Operating Procedure (SOP) for the Participating Site(s). Data and Safety Monitoring Committee (DSMC) monitoring reports for the Participating Site(s).  
For all laboratories listed on FDA 1572, will need CUA certifications, CAP certifications, lab licenses, CVs and Medical License(s) of Lab Director(s), and laboratory reference ranges for the Participating Site(s).  
Copy of the Data and Safety Monitoring Plan (DSMP) Monitoring Plan for all participating site(s) in Multicenter studies or Contract Research Organization (CRO) Monitoring Plan (if an outside CRO is used for the study).  
Serious Adverse Event (SAE) forms submitted to the IRB for the Participating Site(s).
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4. required essential regulatory documents

For IND Exempt studies, the Essential Regulatory Documents for UCSF would include all documents in Section \#1 of this policy. The Essential Regulatory Documents from the participating site(s) for Multicenter Trials when UCSF is the Coordinating Center would only include the signed protocol signature page, CV of the Pl, and the IRB approval letters. All other documents in Section \#2 of this policy would be the responsibility of the Participating Site(s).
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5. required essential regulatory documents

For Single Site non-therapeutic trials, all Regulatory Documents in Section \#1 of this policy are required except for: current and prior versions of the Investigator Brochure (IB), package insert (if the study drug is commercial), DSMC dose escalation approvals with study status summary forms, approvals for Biosafety Committee, Radiation Committee, and Infusion Center, and drug destruction SOPs.
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6. required essential regulatory documents

For Multicenter non-therapeutic trials with UCSF as the Coordinating Site, all required Regulatory Documents listed above in Section \#5 for Single Site nontherapeutic trials are required for the Coordinating Site. The only required Regulatory Documents from the Participating Site(s) will be: IRB approval letters, IRB roster, and ICF and HIPAA consent forms, the Delegation of Authority Log (with NIH or CITI human subject protection training certificates or GCP training certification), Protocol Violations and Single Patient Exception (SPE) reports to the IRB with supporting fax documentation (if applicable), Serious Adverse Event (SAE) forms submitted to both the IRB and the sponsor, and the Data and Safety Monitoring Committee (DSMC) monitoring reports for the Participating Site(s). If applicable, a copy of the Data and Safety Monitoring Plan (DSMP) Monitoring Plan for all participating site(s) in Multicenter studies or Contract Research Organization (CRO) Monitoring Plan (if an outside CRO is used for the study) will be required.
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alternate procedures

There are no alternate procedures to the HDFCCC policy for requirements for Essential Regulatory Documents for Multicenter Investigator-Initiated Oncology Clinical Trials.
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references

ICH Guidance for Industry: E6 Good Clinical Practice: Consolidated Guidance
(current version).  
International Conference on Harmonization: Good Clinical Practice: Consolidated Guideline (current version).  
International Conference on Harmonization: Essential Documents for the Conduct of a Clinical Trial (current version).  
21CFR50  
21 CFR56.11 45CFR46 21 CFR312
Required Regulatory Documents for Sub-sites Participating in Therapeutic UCSF Investigator Initiated Multicenter trial Directions: Scan the documents in a zip drive and upload to OnCore.
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1572

PI and Sub investigators:  
CV and Medical license Financial disclosure form NIH or CITI human subject protection training certification
Laboratories:  
CLIA &CAP and Lab Licenses CV and Medical License of Lab Director Laboratory reference ranges
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local institutional review board

IRB Approval letter Reviewed/Approved documents Protocol version date: ___________ Informed consent version date: ___________ Investigator Brochure version date: ___________ HIPAA
Current IRB Roster
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other

Delegation of Authority Log Include NIH or CITI human subject protection training certificates or GCP training certification Pharmacy Drug destruction SOP and Policy Protocol signature page Executed sub contract