Attachment_3_Statement_of_Work.pdf

March 16, 2011 1

Attachment 3

STATEMENT OF WORK

Independently and not as an agent of the Government, the Contractors shall be required to furnish all the necessary services, qualified personnel, material, equipment, and facilities, not otherwise provided by the Government, as needed to perform the Statement of Work.

Scope of Work:

The National Cancer Institute (NCI), Division of Cancer Prevention (DCP) Phase 0/I/II Cancer

Prevention Clinical Trials Program supports early clinical trials to rapidly evaluate the clinical activity and biologic effects of cancer preventive agents of interest to DCP. The agents to be studied shall include agents developed by the pharmaceutical industry and provided to DCP for collaborative development, commercially available agents, and agents developed by DCP. The subject contract will be one of a pool of Contractors that shall provide approximately 450 to

1000 study participants accruing to Phase 0 - Phase II clinical trials, with the emphasis primarily on Phase II trials.

The Contractor shall provide essential clinical trials infrastructure and laboratory support to assess the cancer preventive potential of various agents. The goals of the program are:

To efficiently design and conduct early phase clinical trials necessary to assess the potential of cancer preventive agents of various classes, many of which are directed at molecular targets which have been shown to be expressed in intraepithelial neoplasia

(IEN).

To characterize the biological effects of new cancer preventive agents on their defined molecular targets as well as on multiple endpoints associated with carcinogenesis, such as proliferation, apoptosis, growth factor expression, oncogene expression, and others.

Correlation of these effects with clinically relevant endpoints is required.

To develop further scientific insights into the mechanisms of cancer prevention by the agents examined and to continue to develop novel potential markers as determinants of response.

The Contractor shall be able to initiate approximately 1 to 5 clinical trials per year, accruing 75 or more study participants each year, using DCP-specified cancer preventive agents as well as agents obtained by the Contractor. The size of each trial will vary depending on the phase of development and the organ site. The Contractor shall have the capacity to perform studies in multiple organs (i.e., more than 2).

The Contractor shall have a Principal Investigator (PI) who is responsible for the overall implementation of the awarded contract and who serves as the key contact for scientific and technical aspects of the project. The PI shall be a physician with an active medical license or shall possess a PhD or equivalent degree. If the PI is not a licensed physician, a medically responsible physician with an active medical license shall be part of the leadership team.

The Contractor shall establish teams of clinicians, statisticians, data managers, research nurses

March 16, 2011

Attachment 3 2 and others with early phase clinical trial expertise with investigational agents in cancer prevention. The Contractor shall also establish infrastructures composed of one or more collaborating institutions to enhance their capability to conduct these clinical trials and to provide specific technical expertise for biomarker studies in a timely manner. However, the

Contractor should expect to perform the majority of studies at its own institution.

Specific Requirements

1. Conduct Clinical Trials

The Contractor shall conduct early clinical trials (Phase 0, I, and II) of DCP-sponsored agents, evaluate biologic effects of these agents on their molecular targets, evaluate other relevant biologic effects, and determine clinically relevant outcomes/correlates. Major emphasis shall be on Phase II studies, although Phase 0 and Phase I studies designed to develop or assess dose, schedule, pharmacokinetic, and pharmacodynamic questions shall also be conducted, as well as pilot protocols that explore promising combination therapies. Specifically, the Contractor shall:

a. Set up the infrastructure, with the appropriate number and mix of clinical, laboratory, and support personnel, to conduct early phase cancer prevention clinical trials.

b. Respond to DCP agent announcements by submitting Letters of Intent (LOIs -see http://prevention.cancer.gov/clinicaltrials/management/consortia/step-

1/protocol#loi ) for individual protocols, followed by protocol development within the specified time frame.

c. Upon LOI approval, DCP will initiate a Contract Work Assignment (W.A.) to be completed by the Contractor and submitted with the protocol.

d. Accrue participants to clinical trials to assess the potential for cancer preventive activity according to agreed upon protocol timeline and carry out the development plans for DCP-sponsored agents of varying classes. The expected rate of accrual and timelines will be defined at the time of LOI submission. Since the duration of each study will depend on the target organ site, the Contractor shall specify the time required in each Letter of Intent.

e. Conduct studies in compliance with Good Clinical Practice (GCP) guidelines and other regulatory requirements governing the safe conduct of research involving human subjects.

f. Obtain and process blood and other body fluids, tissue harboring intraepithelial neoplasia (IEN) and matched histologically normal tissue; and carry out imaging evaluations for research purposes from the study participants when required by the protocols.

http://prevention.cancer.gov/clinicaltrials/management/consortia/step-1/protocol#loi

March 16, 2011 3

g. Study relevant biologic effects of new agents.

h. Study relevant pharmacology, including, but not limited to serum drug levels, tissue drug levels, pharmacokinetic and pharmacodynamic profiles, etc.

i. Determine the cancer preventive potential of select combinations of agents.

j. Conduct the clinical trials in accordance with the instructions from the DCP, NCI.

See http://prevention.cancer.gov/clinicaltrials/management/consortia

These instructions describe the procedures and requirements that shall be used for:

1) Protocol Development and Submission

2) Case Report Forms, which include the mandatory use of Common Data

Elements (CDEs)

3) Reporting Adverse Events (AEs)

4) Pharmacokinetic and Biomarker Methods Development

5) Reporting of Results to DCP

2. Protocol Development and Submission Requirements

DCP will solicit Letters of Intent (LOIs) from the pool of Contractors within the

Consortium.

a. The Letter of Intent (LOI) Process

DCP will announce requests for LOIs for Phase 0, I, or II trials periodically, based on agent availability and program priorities. The LOI process requires the

Contractor to have a study concept/design reviewed and approved by DCP prior to the preparation and submission of a formal protocol document.

DCP will request LOIs up to 3 times per year and will also make known the availability of agents on a periodic basis. The Contractor shall respond to those

LOIs for which the Contractor is capable of performing the requested trial.

Deadlines for LOI submissions will be 60 calendar days after DCP announces a request for LOIs. DCP will also review unsolicited LOIs if investigators have access to agents from non-DCP sources. LOIs for unsolicited studies will be due and reviewed at the same time as solicited study LOIs.

The Contractor shall submit a written LOI to the DCP Protocol Information

Office (PIO) using the approved format to declare interest in conducting a particular clinical study (see URL below). The DCP LOI Review Committee may disapprove, approve (with or without required changes), or defer (e.g., request revisions to) the LOIs. Upon approval of a LOI, a Work Assignment will be http://prevention.cancer.gov/clinicaltrials/management/consortia

Attachment 3 4 initiated for the protocol.

The process for LOI submission and review is available at http://prevention.cancer.gov/clinicaltrials/management/consortia/step-

1/protocol#loi.

1) For any proposed trial, the Contractor shall document the ability to accrue the required number of study participants within a specified, anticipated time period. Accrual rate is expected to vary according to cohort and target organ, but most studies should be fully accrued within 1-3 years.

When collaborations are planned, letters of commitment with documentation of accrual shall be provided. Statistical design issues shall be addressed in the LOI.

2) Since correlative translational studies are an integral component of clinical cancer prevention trials, the Contractor shall submit with each LOI a description of and a budget for laboratory biomarker analyses and associated research costs. The Contractor shall provide evidence of capability to carry out the proposed studies/analyses. Evidence shall include reference to standard protocols for established markers and may include unpublished data or publications for experimental markers.

Statistical design issues shall be addressed in the research plan for the laboratory analyses.

The objectives of correlative studies shall be:

a) to characterize the effects of new agents on their targets through clinically relevant endpoints;

b) to develop new scientific insights into drug mechanisms and determinants of response, and;

c) to identify relevant biomarkers that could serve as intermediate endpoints in cancer prevention trials.

b. The Protocol Process

Within 60 calendar days after notification of approval of the LOI, the Contractor shall submit the clinical protocol to the NCI PIO. A protocol as defined herein is the detailed written plan of a clinical experiment. The essential features of a protocol are provided at:

http://prevention.cancer.gov/clinicaltrials/management/consortia/step-1/protocol, as are protocol templates developed by DCP that will facilitate and speed development of a protocol. For translational studies, the Contractor shall provide, along with the protocol, a rigorous description of the rationale and methodology for the laboratory components of the study, as well as a description of how the results will be analyzed in conjunction with the results of the clinical trial. A http://prevention.cancer.gov/clinicaltrials/management/consortia/step-1/protocol#loi http://prevention.cancer.gov/clinicaltrials/management/consortia/step-1/protocol

March 16, 2011 5 budget shall be provided by the Contractor, detailing the costs of the laboratory translational studies.

The protocol will be reviewed by the DCP Protocol and Safety Review

Committee (PSRC) within 4 weeks from the date of submission to the PIO. The

PSRC will review each protocol, and the PIO will send the Contractor a

Consensus Review indicating review outcome and any required or recommended changes. Consensus Reviews will be sent to the Contractor within 2 weeks of

PSRC review. The Contractor shall submit a revised protocol within the deadline indicated on the Consensus Review (usually within 4 weeks). The Contractor shall address each numbered comment point by point in a cover letter that accompanies the revised protocol. Timelines may be adjusted and may become more stringent as determined by NCI policy.

c. The Contractor shall activate protocols only after review and approval by the

Contractor's Institutional Review Board (IRB), receipt of the Final Study

Approval letter from the PIO, and receipt of a signed Work Assignment and contract modification obligating funds to the protocol. Final budgets will be approved by each study‟s medical/scientific monitor in conjunction with the

Contracting Officer‟s Technical Representative (COTR).

d. The Contractor shall send and receive documents (for example, protocols, amendments, and correspondence) as attachments via e-mail.

3. Study Initiation and Completion Requirements

The Contractor shall:

a. Initiate approximately 1 to 5 clinical trials each year, with the intent of accruing at a rate of 75 or more subjects per year onto DCP-sponsored trials.

b. Complete each trial within the time frame specified and agreed to in the protocol.

Progress will be monitored on the basis of adequate progress towards study participant accrual (defined as enrollment of subjects onto the study with acceptable retention rates) as specified in the approved protocols. An accrual rate of at least one subject per week on average per study site is expected. While acceptable rates of accrual will vary widely depending on target organ and population, most studies should intend to take no more than three years from approval of the LOI to completion of accrual. The duration of each study will be specified at the time of study approval. Shorter study completion times are preferred and higher accrual rates, increasing over the time of the contract, are desirable. In some cases, inter-contract studies may be required or with the approval of the Contracting Officer‟s Technical Representative (COTR) and

Contracting Officer, the Contractor shall subcontract with additional institutions for specific technical expertise to support individual studies. In rare

Attachment 3 6 circumstances, the Contractor shall consider re-organizing the participating sites by inclusion of new sites or exclusion of non-performing sites. This will require prior approval of the COTR and Contracting Officer

c. Multi-institution studies shall be conducted in accordance with DCP guidelines on performance of multicenter investigations (see http://prevention.cancer.gov/clinicaltrials/management/consortia/step-1/multi).

The strategy for such studies shall include a Multi-Institution Monitoring Plan

(MIMP) for the Contractor to monitor, audit, and ensure the quality of data from any Participating Organization (PO) sites. To minimize delay in initiation of studies at PO sites, the Contractor shall negotiate template subcontracts with all

POs promptly after award of their prime contract so that approved studies can open expeditiously upon Final Study Approval. The Contractor shall present a plan to provide study-related information and education to all sites. The

Contractor shall ensure that the following areas are addressed in this MIMP:

1) Each Participating Organization (PO) has an appropriate assurance on file with the Office of Human Research Protection (OHRP) and that the protocol is conducted as a single research effort. Data from each

Participating Organization shall be included in the analysis of results.

2) IRB approval has been obtained at each PO site prior to participant enrollment at that site.

3) Study progress is monitored (including reviews of all case report forms from each Participating Organization), and shall report all study data to

DCP.

4) The procedures for monitoring the progress of multi-center trials are adhered to, including, but not limited to: 1) how adverse drug reactions will be reported, 2) the frequency by which the required records will be sent to the Contractor by the PO, and 3) composition and functioning of a

Data and Safety Monitoring Committee if such a Committee is formed for a particular study.

5) The methods are outlined by which the accuracy of data submitted from the collaborating institutions will be verified (quality assurance).

4. Study Participants

The Contractor shall ensure that each study participant:

a. Meets protocol eligibility requirements for the target organ specified [e.g., ensure that biopsy documentation of intraepithelial neoplasia (IEN) at the target organ site or documentation of genetic cancer predisposition such as BRCA1 mutation is obtained if appropriate].

b. Has been treated according to ethical medical standards of care where these have been defined.

http://prevention.cancer.gov/clinicaltrials/management/consortia/step-1/multi

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c. Receives appropriate initial evaluation and follow-up of hematologic, biochemical, radiologic and immunologic investigations, and undergoes required correlative studies as specified in the protocol.

d. Has given signed informed consent indicating that the participant is aware of the investigational nature of the studies involved.

5. Quality Control

The Contractor shall establish mechanisms for quality control of therapeutic and diagnostic modalities employed in the trials. Quality control, at a minimum, shall consist of:

a. Pathology: Review and verification of pathologic diagnosis in all cases. Review of other pathology data such as special stains or other studies, if diagnosis or management decisions were based on these.

b. Surgery: Assessment of adequacy of protocol-specified surgical and endoscopic procedures (where relevant) through review of operative/procedure notes and study-specific surgical/procedure forms.

c. Imaging: Assessment of adequacy of protocol-specified imaging procedures. This includes: (1) methods for acquisition and display of images; (2) methods for monitoring quality of image interpretation including quantitative measurement of lesions as appropriate; and, (3) methods for data archiving and retrieval.

d. Laboratory: For correlative studies, quality assurance procedures for the laboratory assays shall be instituted. Examples of such procedures include elements such as assay validation procedures, calibration curves, check samples, standards for accepting or rejecting data, positive and negative controls, etc., as well as external quality assurance, if it is available. Detailed protocols shall be in written form to assure that assays will be performed in a standardized way.

6. Study Conduct

The Contractor shall establish mechanisms for study conduct. The Contractor shall ensure accurate and timely documentation of the progress of each study through:

a. Registering, tracking and reporting of subject accrual and adherence to defined accrual goals;

b. Ongoing assessment of case eligibility, evaluability, and evaluation of response;

Attachment 3 8

c. Timely medical review and assessment of study participant data;

d. Data management support capabilities that ensure appropriate reporting of clinical trials data to DCP;

e. Interim evaluation and consideration of measures of outcome, as consistent with study participant safety and good clinical trials practice;

f. Timely communication of results of studies;

g. Providing methods to ensure rapid communication of information within the consortium (e.g., for adverse events, accrual, and response data);

h. Providing electronic reporting capabilities for serious adverse event reporting at all research centers.

7. Data Management and Analysis

The Contractor shall ensure that data collection and management:

a. support achievement of study objectives and scientific and regulatory needs;

b. are adequate for quality control and analysis; and,

c. are commensurate with the needs of the study in order to encourage maximum participation of physicians entering patients and to avoid unnecessary expense.

8. Use, Accountability and Storage of Investigational Agents

DCP will provide investigational agents for use in DCP-approved protocols to registered investigators with a current FDA-1572 on file with the NCI. The Contractor shall meet the drug accountability requirements established by DCP

(http://prevention.cancer.gov/clinicaltrials/management/consortia/step-1/agent). The

Contractor, as well as all affiliated clinical sites (POs), shall provide research pharmacy facilities and resources for the management of investigational products according to protocol-specific requirements. This includes:

a. The development and implementation of Standard Operating Procedures (SOPs) for research pharmacy functions.

b. The development and implementation of appropriate procedures and policies to provide for, store appropriately, and monitor controlled access to the specific requirements for various investigational agents.

c. The receipt of investigational products from the DCP Drug Repository Contractor or other supplier, and the returning of investigational products to this repository or http://prevention.cancer.gov/clinicaltrials/management/consortia/step-1/agent

March 16, 2011 9 disposing of investigational agents as specified in the protocol or Manual of

Operations.

9. Compliance with FDA and OHRP Regulations

The Contractor shall comply with Food and Drug Administration (FDA) regulations for studies involving investigational agents and the DHHS Office for Human Research

Protections (OHRP) (http://www.hhs.gov/ohrp/policy/index.html#human) requirements for the protection of human subjects. Procedures for compliance include, but are not limited to:

a. Methods for assuring that the Contractor has a current, approved assurance on file with the OHRP; that each protocol is reviewed and approved by the Contractor‟s

Institutional Review Board (IRB) prior to study participant entry; that each protocol is reviewed at least annually by the IRB(s) as long as the protocol is active; that amendments are approved by the IRB; that each investigator is registered with DCP with a current form FDA 1572 on file; and that each study participant (or legal representative) gives written informed consent prior to entry on study.

In the case of multi-center protocols, the Contractor shall ensure that full IRB approval is also obtained prior to participant entry at any subcontracted institution; that yearly re-approvals are conducted in a timely fashion; and that amendments and serious adverse events are properly reported to each subcontracted institutions‟s IRB. The Contractor shall maintain documentation of initial approval, yearly re-approval, amendment reviews, and reporting of serious adverse events for all participating institutions.

b. A system or process for ensuring timely reporting of all serious and unexpected adverse events to DCP.

10. Data and Safety Monitoring Guidelines

For all phases of DCP-sponsored cancer clinical trials, the Contractor shall comply with the NIH guidelines for Data and Safety Monitoring (DSM, see http://prevention.cancer.gov/clinicaltrials/management/consortia/step-3/guide;

http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines). A Master Data and

Safety Monitoring Plan shall be developed for the contract and approved by DCP prior to receipt of Final Study Approval.

11. Requirements for DCP Clinical Trials Documents and Reporting

This section describes the information that the Contractor shall submit to DCP for each http://www.hhs.gov/ohrp/policy/index.html#human http://prevention.cancer.gov/clinicaltrials/management/consortia/step-3/guide http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines

Attachment 3 10 protocol performed under this contract. Submission of the required information falls into three time frames: 1) Documents required prior to initiation of a clinical trial, 2)

Documentation required during the conduct of a clinical trial, and 3) Documentation required at the completion of a clinical trial. Each of these items is detailed below:

a. Documents required prior to the initiation of a clinical trial:

1) DCP approved protocol, consent form(s), and case report form set. Case report forms shall be modeled on the DCP template and data fields shall be represented as Common Data Elements (CDEs). The templates for creating these documents are available at http://prevention.cancer.gov/clinicaltrials/management/pio/instruction. A submitted protocol shall include all the elements as described in these templates; however, an institutional format may be followed, if required.

2) Biomarker and Pharmacokinetic Method Development Report form: refer to the template document at http://prevention.cancer.gov/clinicaltrials/management/consortia/step-

1/protocol (see section entitled “Additional Study-Related Documents).

All laboratory techniques, assays, and procedures shall be validated according to the parameters described below and a Report shall be prepared for DCP approval prior to Final Study Approval for each study.

The Report shall include the analytical and computational documentation resulting from the below validation efforts. Validation of analytical methods shall include, but not be limited to:

a) Linearity

b) Specificity

c) Sensitivity: limit of detection, limit of quantitation, and 95% confidence interval of standard curve

d) Precision

e) Accuracy

f) Inter-day and intra-day variability

g) Ruggedness: demonstrated as variability between operators, instrument, columns, etc.

h) Sample of chromatograms or endpoint measurements from method development, as appropriate:

i) Blank plasma, urine, or tissue

ii) Drug in solution (aqueous buffer), plasma, urine, and/or tissue

iii) Examples of measurements to demonstrate limit of quantitation, specificity, recovery, inter- and intra-day variability. Chromatogram, densitometric scans, photographs, etc. may be presented as appropriate.

http://prevention.cancer.gov/clinicaltrials/management/pio/instruction

March 16, 2011 11

3) Data and Safety Monitoring Plan: A Data and Safety Monitoring Plan shall be included with each protocol and shall address the “Essential

Elements of a Data and Safety Monitoring Plan for Clinical Trials Funded by the National Cancer Institute” located at the following URL:

http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines. An IRB and NCI-approved institutional plan may be referenced; however, it shall appropriately address any unique needs of the specific chemoprevention trial.

4) Regulatory and/or Administrative Documentation, including, but not limited to, the following:

a) Principal Investigator Form FDA 1572, biosketch and Sub-Investigator biosketches.

b) Any additional documentation that may be required by a pharmaceutical partner

c) IRB approval of protocol and consent form

d) IRB review and approval of promotional materials

e) IRB committee membership roster (if requested)

f) Lab certifications [e.g., Clinical Laboratory Improvement

Amendments Certification (CLIA), College of American Pathologists accreditation (CAP)]

g) List of lab normal ranges

h) Delegation of authority form, as appropriate

i) Human Subjects Education verification

b. Documentation required during the conduct of each clinical trial.

The Contractor shall provide timely and accurate reporting of participant data from each clinical trial to DCP PIO so that DCP can meet its obligations under

FDA regulations to monitor studies and submit annual reports of current findings to that agency for all studies testing under an Investigational New Drug application (IND).

1) Clinical trial data for each participant: The Contractor shall provide data to

DCP for studies performed under this contract using an electronic method as specified by DCP. For each participant enrolled on the clinical trial, the

Contractor will provide Cancer Biomedical Informatics Grid (CaBIG)-compatible minimal data sets consisting of administrative data elements, treatment administration details, adverse events, and response data.). The frequency of data reporting will be determined by the Protocol and Safety

Review Committee based on study phase, cohort, agent, and safety issues, but will likely occur on a monthly basis or as directed.

2) Reporting of Adverse Events (AEs) http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines

Attachment 3 12

All adverse events shall be graded using the most recent version of the

NCI Common Terminology Criteria for Adverse Events (CTCAE).

(NOTE: A complete set of the toxicity tables and instructions for their use are available at:

http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.ht m#ctc_40

All adverse events shall be documented and reported in compliance with the DCP Adverse Events Policy:

http://prevention.cancer.gov/reporting-tracking-saes and the form can be found under, http://prevention.cancer.gov/clinicaltrials/management/pio/instructions

Those adverse events meeting the criteria for Expedited Reporting shall be submitted using either the DCP Serious Adverse Event (SAE) Reporting

Form (current system) or a future replacement electronic system.

3) Protocol Amendments

Changes to protocols after DCP approval are called amendments. Each change to a DCP approved protocol shall be documented and reported as a protocol amendment. There are two types of amendments:

a) Editorial or Administrative amendments are changes to a protocol document, including informed consent, that do not affect the scientific intent of the study, study design, participant risk, or human subject protection. Examples of editorial or administrative amendments:

Reformatting the document

Rephrasing for clarity

Typographical errors, except if the change involves subject risk, such as drug dosage

Addition or deletion of a non-physician investigator or non-key non-physician.

b) All other amendments are considered scientific amendments and may also require a modification to the Work Assignment.

Examples of scientific amendments

Change in sample size

Change in eligibility criteria

Change in study design, evaluation, or analysis

Change in Principal Investigator or other Key Personnel

Addition or deletion of a participating organization or physician investigator

Rephrasing or reformatting that results in a change in scientific http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 http://prevention.cancer.gov/reporting-tracking-saes http://prevention.cancer.gov/clinicaltrials/management/pio/instructions

March 16, 2011 13 intent, study design, or participant protection

c) Amendment approval:

i) DCP approval required prior to implementation:

a) All amendments to DCP-sponsored IND protocols

b) All scientific amendments.

c) All changes to the model consent

ii) Implementation allowed prior to DCP approval

a) All changes are strictly editorial/administrative and do not involve changes to the model consent form and do not involve a DCP-sponsored IND.

b) The Principal Investigator shall notify DCP and submit the amendment within one week of its activation.

c) DCP may disapprove the amendment following receipt and review.

iii) For those rare studies where an immediate scientific change is imperative for patient safety, the Medical Monitor for that study shall be contacted by telephone, and the written amendment shall be sent to the PIO within 3 working days.

c. Documentation Required at the Completion of a Clinical Trial

1) Study Manuscript: A „draft‟ or „submission‟ manuscript shall be submitted to DCP within 120 calendar days of the time that all participants have met the primary study endpoint (for example, response evaluation at 3 months). All submitted manuscripts shall be clearly labeled on the cover page as either 1) draft or 2) submission version.

When the manuscript is marked for submission to a journal, DCP will forward a copy of the report/manuscript to collaborating companies according to the terms of any existing Clinical Trial Agreements, as applicable. See additional instructions below related to manuscript submission.

In the event that the Contractor provides a „draft‟ within the time frame stipulated above, but anticipates the necessity for significant manuscript revisions with additional follow-up prior to submission for publication, the

Contractor shall provide a clear scientific rationale for the delay in submission for publication and shall provide an estimated date for submission of the manuscript for publication. Delay should not be due to incomplete components of the study or report when completion is possible. DCP may request additional information at the time of receipt of a draft manuscript and/or revision to the proposed date for submission for

Attachment 3 14 publication.

The final study manuscript will serve as the Final Study Report. A separate Final Study Report is not required.

A manuscript shall contain:

a) Introduction explaining why the trial was performed and stating its goals;

b) Detailed methods section describing eligibility, assessment of endpoints and conduct of correlative studies (the author may refer to other existing publications for details when available, as is customary in scientific publications);

c) Detailed results including accrual, response, toxicity and correlative studies; and,

d) Conclusions and discussion.

Prior to submission for publication of any manuscript reporting any results from a clinical trial (whether the manuscript is submitted during the contract period of performance or subsequently), the manuscript shall be provided to DCP for immediate delivery to collaborating companies for advisory review and comment. The cover page shall clearly indicate that the manuscript is for submission. This shall be done by marking

“Submission” in the top right hand corner, and indicating the Journal to which the manuscript will be submitted. The Contractor shall anticipate

30-60 calendar days for collaborators to review the manuscript and to ensure that confidential and proprietary data, as well as intellectual property rights, are protected. Copies of abstracts shall be provided for courtesy review by collaborators as soon as possible, but no later than the time of submission to the relevant organization for abstract publication/presentation. Copies of any manuscript and/or abstract shall be sent to the Medical/Scientific Monitor assigned to a particular study, to the

Protocol Information Office (PIO) at nci_dcp_pio@mail.nih.gov.

Copies of published manuscripts shall also be provided to the DCP PIO and to the NIH National Library of Medicine‟s (NLM) PubMed Central

(PMC) archive (see Section H of the contract) within one month of publication.

2) Data set for analysis

Final clinical and safety data shall be submitted to DCP PIO within three months of the last patient‟s exit from the clinical protocol; biomarker data shall follow within the timeframes agreed upon between the Contractor and the DCP Medical/Scientific Monitor for each study. The data set provided shall be a copy of the final complete, cleaned, audited, locked data set used for analysis.

mailto:nci_dcp%1f_pio@mail.nih.gov

March 16, 2011 15

3) Biomarker Report

Results of all (e.g., secondary) biomarker analyses may not be completed until after the primary manuscript is written. All biomarker analyses stipulated in the protocol shall be submitted to DCP either in manuscript format (if submission is planned, using the manuscript guidelines above) or as a report that contains a brief background, materials and methods, results, and conclusion. The due date of this Report will be negotiated with the DCP Medical/Scientific Monitor.

12. Monitoring and On-Site Audits

FDA regulations require IND Sponsors to maintain a monitoring program for clinical trials (http://clinicaltrials.gov). Therefore, the Contractor shall be audited on their site annually or more frequently if necessary. DCP will provide direct oversight of the monitoring programs, including on-site auditing to document the accuracy of submitted data and to verify the Contractor‟s compliance with protocol and regulatory requirements.

The Contractor shall be responsible for on-site monitoring of their Participating

Organizations (POs) on an annual basis or more frequently if problems are encountered, for providing monitoring reports to DCP, and for making the data from monitoring visits available to DCP‟s Monitoring Contractor during on-site audits of the Contractor. An overview of this process can be found at http://prevention.cancer.gov/clinicaltrials/management/consortia/step-3/visits.

The Contractor shall be available for on-site audits by DCP's audit team annually, and for specifically designated studies, as often as twice a year. In order to facilitate conducting the audit, records from PO sites shall be made available at the Contractor site.

Subcontractors/POs may also be audited by DCP.

The examination/audit will include, but may not be limited to, a review of the following:

a. Full and non-contingent Institutional Review Board (IRB) approvals and reapprovals. Copies of the approvals, including approvals for all amendments, shall be made available.

b. Copies of the annual reports on the progress of the study and copies of

IRB reapprovals for studies continuing beyond the first anniversary of the

IRB approval date.

c. Written informed consent obtained on the form approved by the IRB and the documentation of written informed consent for all the participants entered onto a study. The informed consent form signed by the participant at the time of study entry shall be the most current version approved by the

IRB.

http://clinicaltrials.gov/ http://prevention.cancer.gov/clinicaltrials/management/consortia/step-3/visits

Attachment 3 16

d. Adherence to the protocol details. Records that verify that the protocol treatment and follow-up requirements have been performed, as specified in each protocol, will be required. These include copies and/or reports of imaging studies, if appropriate for the clinical trial, and inpatient, outpatient, and clinic/research records, including any computer generated printouts.

e. Adverse event reports and medical records to review classification of adverse experiences and the reporting to DCP of unusual or unexpected events.

f. Record keeping and record retention in accordance with DCP PIO, NIH, and institutional regulatory requirements (NIH policies:

http://oma.od.nih.gov/ms/records/).

g. Investigational agent accountability. The NCI Drug Accountability Record

Forms shall be available for review.

h. An inspection of the investigational drug storage area

The Contractor‟s site visit participants shall include, but may not be limited to, the following:

a. A physician/ administrator to discuss the Contractor‟s overall organizational structure, protocol development, protocol monitoring, participant selection and data collection.

b. The Principal Investigator, who shall meet with the audit team leader to discuss the protocol(s) for audit.

c. An institutional staff member to describe the institution‟s chart organization, and demonstrate where the auditors would usually find various types of data.

d. A responsible individual from the investigational drug storage area with whom to discuss inventory control methods, agent storing and dispensing.

13. Participation in the Cancer Prevention Early Phase Clinical Trials Program Executive

Committee

The Contractor‟s Principal Investigator shall participate in an Executive Committee composed of the Principal Investigator from each consortium Contractor‟s site and DCP staff. This Committee shall be formed to enhance operational coordination. This http://oma.od.nih.gov/ms/records/

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Committee shall meet in person once or twice yearly and shall hold quarterly conference calls. The Committee shall be tasked with developing operational guidelines to enhance overall program efficiency, including cross–institution collaborations, as well as scientific endeavors such as target identification, biomarker development, and setting the agenda for yearly Principal Investigator scientific meetings.

14. Specimen Ownership and Shipping

Biologic specimens collected during the conduct of each clinical trial that are not used during the course of the study will be considered deliverables under the contract and thus be the property of DCP. At study completion, DCP reserves the option to either retain or relinquish ownership of the unused biologic specimens. If DCP retains ownership of specimens, the Contractor shall collect, verify, and transfer the requested biologic specimens from the site to a DCP-specified repository or laboratory at DCP‟s expense.

All transfer of biological materials under this contract shall include packaging, marking, shipping in accordance with the Department of Transportation (DOT) (domestic shipments in the United States) and the International Air Transport Association (IATA)

(international air shipments worldwide).

15. Meetings and Communication with DCP

The Contractor‟s Principal Investigator and Site Coordinator shall attend the contract site initiation visit at NCI in Bethesda, MD within 6 weeks after contract award. Thereafter, on a yearly basis, the Principal Investigator shall attend a PI meeting at NCI and an administrative Consortia meeting at one of the major scientific meetings, such as the

American Association for Cancer Research (AACR) Frontiers of Cancer Prevention meeting or the AACR Annual meeting. The Site Coordinator shall attend the yearly Site

Coordinators Opportunity for Research Excellence (SCORE) meeting held at the NCI.

Annual site visits at the Contractor‟s site shall be conducted by the Contracting Officer‟s

Technical Representative (COTR). Additional communications will include the Cancer

Prevention Early Phase Clinical Trials Program Executive Committee meetings as described above in Item 13. It is expected that teleconferences between the Principal

Investigator and the COTR will be held as needed, but communications either in person or by telephone shall occur no less frequently than quarterly.