Attachment-1-PumpKIN_Clinical_Trial.pdf

NHLBI PumpKIN Clinical Trial Attachment 1 Data and Clinical Coordinating Center; RFP NHLBI-HV-12-03

A. Background Information

The need for viable mechanical circulatory support devices for young children with advanced heart disease is well-established. Each year in the U.S. nearly 1,800 infants die as a result of congenital heart defects and another 350 develop cardiomyopathy which, for many, will lead to myocardial failure. Approximately 60 infants and children less than five years old who are placed on the heart transplant waiting list die before receiving one. If available, mechanically assisted circulatory support could be used to bridge these young patients to recovery or heart transplantation. Unfortunately, in the U.S. the options for chronic circulatory support in this vulnerable population are limited to a very few number of devices which all have substantial risks for serious adverse events.

By leveraging the advanced technologies used in adult devices, appropriately designed and developed mechanical circulatory support (MCS) devices are expected to substantially improve the outcomes for infants and young children who need them. With this in mind, the National Heart, Lung, and Blood Institute (NHLBI) launched the Pediatric Circulatory Support Program in 2004 by funding the development of five novel circulatory support devices for infants and young children with congenital and acquired cardiovascular disease. The goal of the program was to encourage development of innovative approaches to circulatory support that overcome not only the current size and hemodynamic limitations for pediatric assist devices, but that also address issues of rapid deployment, ease of use, variations in cannulation methods, and the need to minimize priming volumes, infection, bleeding, and thrombus formation. The five devices in the NHLBI Pediatric Circulatory Support Program were designed to address these unique challenges in order to best serve the needs of pediatric heart failure patients who require circulatory support.

The Pumps for Kids, Infants, and Neonates (PumpKIN) Program is the next phase of NHLBI support for the development and clinical realization of novel pediatric circulatory support devices. The program’s goal is to complete the needed Investigational Device Exemption (IDE) clinical studies for some of the most promising investigational pediatric circulatory support devices. The clinical studies are needed to provide the clinical evidence required for approval of Humanitarian Device Exemptions (HDE) so that the devices can be marketed in the United States as Humanitarian Use Devices (HUDs). The clinical evidence collected in the PumpKIN IDE clinical study will be submitted to the US Food and Drug Administration (FDA) in the HDE applications for the pediatric circulatory support devices in the study. An HDE is similar in both form and content to a premarket approval (PMA) application, but is exempt from the effectiveness requirements of a PMA.

In January 2010, NHLBI awarded four contracts, with a duration of four years each, to four of the offerors who responded to RFP NHLBI-HV-09-14 for the pre-clinical phase of the PumpKIN program. The contracts were awarded to Ension, Inc., Jarvik Heart, Inc., the University of Maryland, Baltimore, and the University of Pittsburgh. Under the pre-clinical contracts, each contractor is performing pre-clinical work necessary to receive an approved IDE from the FDA for their investigational circulatory assist device for infants and children so that the appropriate clinical trials can be conducted. The work includes (1) manufacturing of devices for pre-clinical studies; (2) the design, conduct, and documentation of various pre-clinical in-vitro, computational, and in-vivo studies; and (3) the development of appropriately designed clinical studies for the devices.

Figure 1. The PumpKIN Program Timeline

As shown in the PumpKIN program timeline above (Figure 1), the design of the clinical trials of the devices will be developed during Years 2 and 3 of the existing PumpKIN pre-clinical program (2011 and 2012). The clinical trial design work will initially be performed by a Protocol Development Committee consisting of the PumpKIN pre-clinical contractors, NHLBI staff, and NHLBI-invited consultants on clinical trials, cardiovascular devices, and regulatory affairs.

This solicitation is for the PumpKIN Data and Clinical Coordinating Center (DCCC). NHLBI intends to award the PumpKIN DCCC five-year contract near the beginning of Year 3 of the existing PumpKIN pre-clinical program, which will be approximately January 2012. The DCCC will be responsible for finalizing the clinical protocols, Manual of Operational Procedures (MOP)*, data management and monitoring procedures, addressing other clinical issues, and running the IDE trials according to the planned timeline.

Each of the pre-clinical contractors will work with the PumpKIN DCCC, other pre-clinical contractors, the NHLBI, and the FDA when developing their IDE clinical trial designs. The clinical trial plans and protocols are expected to be submitted by the PumpKIN pre-clinical contractors to the FDA as part of their IDE applications during the third year of the existing program with approval targeted by the end of Year 3. The DCCC will be responsible for providing each pre-clinical contractor with a copy of the final Protocol Review Committee (PRC)-approved protocol that is to be submitted with their IDE application to the FDA for their device.

The pre-clinical contractors will provide regulatory and device technical support throughout the clinical study. Initially, these activities will be funded during the pre-clinical PumpKIN contracts.

After completion of the pre-clinical contracts, funds for such activities will be provided through subcontracts under the DCCC contract.

*Note: The Manual of Operational Procedures (MOP) will detail the procedures that must be followed for performing the various required functions at each clinical research site. The MOP will specify how individual clinical sites operate for administrative and management activities as well as activities related to the conduct of clinical trials. The MOP shall include, at a minimum, those documents that describe procedures routinely conducted at the clinical research site;

these may be documented in the form of a policy or Standard Operating Procedure (SOP). The documents will provide details on how the site addresses FDA requirements; standards for Good Clinical Practice (GCP); NIH and NHLBI policies and procedures; and any other applicable laws and regulations or institutional policies and procedures.

ARTICLE B.1 BRIEF DESCRIPTION OF SUPPLIES OR SERVICES

The contractor will be the Data and Clinical Coordinating Center (DCCC) for the Pumps for Kids, Infants, and Neonates (PumpKIN) clinical trials. The trials will explore the potential benefit of therapy offered by novel pediatric circulatory support devices to infants, neonates, and young children (<25 kg) with congenital and acquired cardiovascular disease who experience cardiopulmonary failure and circulatory collapse. The trials are intended to provide clinical evidence to be used in Humanitarian Device Exemption applications to the FDA for regulatory approval of the devices. As the PumpKIN DCCC, the contractor will have the overall responsibility for the operation of the trials and will provide the necessary administrative guidance, oversight, and support to achieve the trials’ objectives.

ARTICLE C.1 STATEMENT OF WORK

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

b. The contractor shall deliver the items specified in the deliverables section to the destination indicated.

c. The Program schedule is estimated to be as follows:

• Planning Phase for twelve (12) months

• Active clinical trials for thirty-six (36) months

• Closeout for twelve (12) months

The Contractor selected to be the PumpKIN DCCC shall conduct all aspects (administrative guidance, oversight, and support) of the PumpKIN clinical trials. The DCCC shall have overall responsibility for the operation of the clinical trials which includes clinical site coordination, data collection, management, and analyses, and preparation of clinical regulatory documents in support of an Investigation Device Exemption (IDE) clinical trial. Specific duties are described below by phases of the PumpKIN clinical program.

Phase 1-Planning Phase (12 months)

1) Work with NHLBI to identify competent clinical sites for the clinical trials and finalize subcontracts for the selected clinical sites.

2) Prepare Materials and Develop Infrastructure

a) Arrange meetings for the Steering Committee (SC), the Protocol Review Committee

(PRC), and Protocol Development Committee (PDC) to finalize and distribute protocols, the MOP, and associated materials. This activity includes:

i) Coordinate protocol and MOP writing activities, including protocol refinement and finalization, collaboratively with the PDC and SC.

Once the protocols are developed, they shall include each of the following elements (if appropriate):

• Scientific rationale for the proposed PumpKIN trial

• Participant selection, recruitment, monitoring, and follow-up, including inclusion/exclusion criteria and visit schedule

• Descriptions of device or devices to be used in the trial

• Participant safety and confidentiality

• Safety Monitoring (This must include definitions, grading and reporting procedure for significant and non-significant adverse events and a Data Safety and Monitoring Plan (DSMP). Guidelines on NHLBI’s Data and Safety Monitoring Policy and DSMPs can be found at http://www.nhlbi.nih.gov/funding/policies/dsmpolicy.htm.)

• Model informed consent document (including data and specimen sharing)

• Screening and Randomization Plan (including patient accrual benchmarks, provisions for monitoring, and correcting problems)

• Trial outcome measures including mortality, morbidity, cognitive function, safety, functional performance, quality of life, and costs and cost-effectiveness outcome measures

• Statistical design

• Quality control

• Data management and training

• Plan for measuring and maximizing patient adherence and retention

• Dissemination plan, including publication process

• Trial organization and timetable

The MOP shall, at a minimum, include detailed descriptions of the following elements:

• Procedures and processes for patient recruitment, selection, randomization (if appropriate), adherence, and retention (Note: Recruitment monitoring procedures must be designed to maximize enrollment, adherence, and retention of patients.)

• Trial interventions and measurements

• Procedures for staff training

• Proper collection of data

• Coordination of the trial

• Testing of forms and data entry

ii) Develop and distribute trial forms including those to be implemented in the electronic data capture and management system to the NHLBI, all participating clinical sites, and centralized laboratories that perform standardized assessments of data collected at the participating clinical sites (core laboratories). Develop, pre-test, reproduce, and distribute appropriate case report forms/data forms, and reporting tables and figures.

iii) Create trial logos, newsletters, brochures, posters, incentives, and checklists.

b) Regulatory Activities

i) Provide the following to the PumpKIN Pre-Clinical contractors for their IDE applications*:

- The Clinical Protocol and Monitoring Procedures for their device

- Example of an agreement to be signed by the clinical study investigators

- A list of names and addresses of all investigators

- Certification that all investigators have signed the agreement, that the list of investigators includes all investigators participating in the study, and that new investigators will sign the agreement before being added to the study

- A list of the names, addresses, and chairpersons of all Institutional Review Board (IRBs) that have or will be asked to review the investigation and a certification of IRB action concerning the investigation (when available)

- The name and address of any institution (other than those above) where a part of the investigation may be conducted

*The items listed above are those given as “Required Elements” for an IDE per the FDA website that are relevant to the clinical investigation and DCCC activities. (See http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarket YourDevice/InvestigationalDeviceExemptionIDE/ucm046706.htm#reqele)

ii) Register the clinical trials per the Food and Drug Administration Amendments Act

(FDAAA) of 2007.

iii) Assist the NHLBI in obtaining clearances required by the Paperwork Reduction Act.

c) Establish working groups and organize teleconferences to standardize (1) protocols for anticoagulation, de-listing, neurodevelopment, and cardiac function and (2) definitions of adverse events.

d) Establish quality standards for the clinical data to be collected.

e) Establish an electronic data capture and management system to collect and manage the clinical data for assessment of trial outcomes. This must involve a secure web-based data entry system that the clinical sites and core laboratories will use. All web pages designed under this contract shall meet the requirements of Section 508 of the Rehabilitation Act (http://www.access-board.gov/sec508/guide/1194.22.htm#Back).

Note: An electronic data capture system is imperative to ensure timely data collection and quality assurance in this study involving a high risk and vulnerable population where continuous monitoring must be implemented.

f) Develop a trial website for the distribution of PumpKIN information, documents, and forms to the clinical sites. The websites designed under this contract shall meet the requirements of Section 508 of the Rehabilitation Act. More information is available on the Web at: http://www.access-board.gov/508.htm

g) Provide training to clinical sites and core laboratories. Specifically, the DCCC shall provide centralized training for all aspects of the PumpKIN trial implementation, including the following: procedures for screening and eligibility determination; randomization (if appropriate); recruitment of trial participants; measurement and promotion of participants’ adherence to treatment; provision of trial treatment; data collection and follow-up procedures, including methods for ensuring patient retention. The DCCC shall also train core laboratories in standardized protocol implementation.

h) Finalize and submit the Data Analysis Plan for the clinical trials to the SC and NHLBI for review and to the PRC and DSMB for final approval.

i) Finalize and submit a Complete Data Set Distribution Plan to the SC and NHLBI. The plan should also describe any necessary transfer or distribution of software used to collect the data.

j) Assist clinical sites with IRB submissions and approval and completion of ”investigator agreements” (in accordance with 21 CFR 812.43(c)) and conflicts of interest documentation.

Option 1 - Phase II-Active Clinical Trials (36 months)

1) Manage Clinical Sites to:

a) Enroll the number of subjects that meet the selection criteria in the FDA-approved IDEs for each of the trials/devices

b) Implement the PumpKIN MOPs and Protocols developed in Phase I, and

c) Follow each of the enrolled patients for the specified time in the protocols

Note: The DCCC will drop and add clinical sites as needed during the trial per plans and procedures approved by the NHLBI in order to meet patient recruitment goals.

2) Monitor patient recruitment and provide weekly reports to the clinical centers, the NHLBI

Project Office, and core laboratories during the recruitment phases.

3) Provide weekly reports on patient adherence and retention to the clinical centers, the NHLBI Project Office, and core laboratories. Implement a monitoring plan that includes the responsibility for evaluating and correcting adherence and retention problems.

4) Maintain quality control (QC) at participating clinical sites and monitor their performance status; promote interactions among the clinical sites, coordinate trial activities among the clinical sites and core laboratories, and ensure uniformity of trial activities at all sites;

perform data audits and provide rapid feedback to the clinical sites and core laboratories on the quality of data submitted and proposed corrections; conduct periodic site visits to each clinical center in order to monitor and ensure high performance throughout each of the trials;

report to the NHLBI Project Office on QC and related matters periodically as specified for each report in the protocols and as needed.

5) As appropriate, analyze ongoing trial data per the data analysis plan.

6) Prepare trial publications, reports, and other scientific manuscripts in collaboration with the

SC.

7) Prepare and distribute technical and statistical reports per Article C.2.

8) At least weekly, review trial activities, including progress in recruitment.

9) Review data to ensure scientific validity and guarantee that the policies to ensure safety and to protect the privacy of the human subjects in the trials are being properly followed.

10) Establish and conduct timely reviews of adverse events to classify all clinical outcome events in a uniform fashion. Implement a plan for timely monitoring of adverse events to maximize patient safety. Monitor end point results, morbidity and mortality data, and adverse event reports for patterns that may warrant changes in the trials. Provide notification and reports per the trial protocols and MOPs. Adverse events shall be reported in accordance with NHLBI policies found at: http://www.nhlbi.nih.gov/funding/ethics.htm.

11) Prepare and submit required reports to the FDA. (See http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice /InvestigationalDeviceExemptionIDE/ucm046717.htm#sugforforidepro for information regarding IDE reports.)

12) Design and implement a plan for trial closeout, analysis, and dissemination, including final data collection, data transfer (if necessary), verification, analytical support for scientific writing groups, publication of trial results, and plans for the investigators’ dissemination of trial results.

Option 2 - Phase III-Closeout (12 months)

1) Analyze data and prepare trial reports, publications, and other scientific manuscripts in collaboration with the SC. In collaboration with NHLBI staff and other trial investigators, finalize the dissemination plan for trial results. This task includes trial closeout and dissemination activities for the PumpKIN trials. Additionally, trial reports shall be provided to each of the pre-clinical PumpKIN contractors for their HDE applications.

2) Create a public use dataset and implement the Data Sharing Plan. Prepare accompanying documentation that meets the requirements for a Limited Access Dataset. [See http://www.nhlbi.nih.gov/resources/deca/policy_new.htm#3b.]

3) Provide a final report that documents and summarizes the results of the entire contract work and a final complete data set with detailed, clearly understandable documentation.

4) Prepare and submit required final reports to the FDA and PumpKIN Pre-clinical contractors and/or sponsors of the IDEs.

Throughout the Contract Period

1) Work with the Clinical Sites to obtain and maintain IRB approval.

2) Organize and maintain all trial documentation, including IRB approvals, informed consents, Federal Wide Assurance documentation, conflicts of interest, and proof of human subjects training of PIs, Co-PIs, and Coordinators at the clinical sites.

3) Make travel arrangements and provide reimbursement for the SC Chair to participate in SC meetings and related activities.

4) Coordinate, plan, make arrangements for, and participate in the meetings of the SC and its subcommittees and other meetings related to the conduct of the trial.

5) Coordinate, plan, and make arrangements for members of the Data and Safety Monitoring Board (DSMB). DSMB Guidelines can be found at http://public.nhlbi.nih.gov/ocr/home/GetPolicy.aspx?id=8.

6) Facilitate communications among all organizational trial components, including the DSMB, ad hoc task forces or working groups, and subcommittees; prepare and/or distribute minutes and reports of the SC, Executive Committee, DSMB meetings, and subcommittee meetings, ensuring the quality and accuracy of data collection and report content. Maintain in the central trial website a repository of minutes and materials necessary to the functioning of the various committees and all other aspects of the trial. Specifically:

a) Coordinate, arrange, participate in, and provide information necessary for regular SC meetings.

b) Coordinate, arrange, participate in, fund, and provide any information for meetings and conference calls with the clinical investigators.

c) Prepare weekly reports of patient screening, recruitment, status of data collection and quality control, and all other matters needed to be discussed at SC meetings or during conference calls.

d) Arrange regular DSMB activities. Provide trial data to the DSMB per the trial protocols and as requested. Fund all DSMB-related activities, including travel expenses for meetings, honoraria to members, meeting room charges, meals and refreshments.

7) Computer Systems and Websites:

a) Maintain the computer system, secure trial database, and software needed for the collection, storage, and analysis of all trial data (including biological specimens) from all PumpKIN clinical sites and core laboratories. Provide computer backup systems in the event of a primary system failure. Maintain documentation of the data variables and maintenance of appropriate confidentiality and security of all computer files.

The computer systems designed under this contract shall meet the requirements of Section 508 of the Rehabilitation Act. More information is available on the Web at:

http://www.access-board.gov/508.htm

b) Maintain the trial website for the distribution of PumpKIN information, documents, and forms to the clinical sites.

The website designed under this contract shall meet the requirements of Section 508 of the Rehabilitation Act. More information is available on the Web at:

http://www.access-board.gov/508.htm

c) Execute plans and procedures to make data, associated data collection software, website information, and associated documentation transportable for future government use.

d) Submit an updated Information Systems Security Plan as required by the NHLBI Information Systems Security Officer.

8) Publications and Presentations

Work with the SC to establish a publications and presentations policy and infrastructure for review/prioritization of manuscripts and abstracts.

ARTICLE C.2 REPORTING REQUIREMENTS

In addition to those reports required by other terms of this contract, the Contractor shall prepare and electronically submit the following reports (unless otherwise stated) in accordance with ARTICLE F.1. DELIVERIES of this contract. Note: Beginning May 25, 2008, the Contractor shall include the applicable PubMed Central or NIH Manuscript Submission reference number when citing publications that arise from its NIH funded research.

a. Final Protocols, MOP, and Informed Consent Template: This shall include all draft versions and the final approved PumpKIN Trial Protocols, the MOP and any amendments thereto, and the final informed consent template. The protocols shall include detailed descriptions, objectives of the trial, numbers of patients to be randomized, trial procedures, and potential risks of participation. The MOPs shall describe all operating procedures of the PumpKIN trials. The informed consent template shall be developed for use by the clinical sites and shall include all basic and appropriate additional elements as described in the Office of Human Research Protections informed consent checklist (http://www.hhs.gov/ohrp/humansubjects/assurance/consentckls.htm).

b. Data Collection and Management Plan: This plan shall include the data entry system for use at clinical sites, procedures for data transmission, and provisions for training appropriate staff in data collection, entry, and transmission. The data collection and management plan shall provide methods for avoiding bias in data collection and ascertainment of major endpoints. Trial data is to be transmitted from individual clinical sites and clinical investigators recruiting patients directly to the DCCC and/or relevant core laboratories. Core laboratories will transmit data to the DCCC for central analysis. The data collection and management plan must address how problems with missing, delayed, or erroneous data will be corrected.

c. Final Data Analysis Plan: This shall include a detailed description of how the collected trial data will be analyzed throughout the duration of the contract. The plan shall include the beginning of analysis activities from the start of data collection throughout the trial and shall include DSMB reports.

d. Weekly Patient Screening and Recruitment Reports: These reports shall describe the progress and activities related to recruitment, adherence, and retention of patients during Phase II. These reports shall include, at a minimum, data by clinical site, sex/gender and racial/ethnic groups, with key indicators of data quality and completeness.

e. Quarterly/Annual Progress Report: This is a comprehensive progress report reflecting all activities conducted during the reporting period. Submit the report in a concise narrative format and include a table of contents, tabular material, and exhibits as needed. Extensive reference material is not desired, but such references needed to fully understand events may be included. The report shall be written in sufficient detail to be used as a reference document. A Quarterly Report will not be due when the Annual Report is due.

Quarterly/Annual Progress Reports shall include but not be limited to:

i. Cover page containing the following information:

1. Contract number

2. Contractor's name and address

3. Principal Investigator’s name

4. Reporting period

ii. Description of overall progress including:

1. List of current personnel.

2. Summary of study activities.

3. Statistical and graphical summaries of screening and recruitment, including reasons for exclusion of individuals who are screened but not enrolled. This information shall be provided by each Clinical Center and in total for all Clinical Centers.

4. If required for any of the trials, summary descriptions of blood and tissue specimens received by the DCCC.

5. Summary descriptions of data completeness, data quality, adverse events, and protocol compliance. This information shall be tabulated by Clinical Center and in total for all Clinical Centers.

6. Current problems which may impede progress along with proposed corrective actions.

7. Progress made in scientific research, including a list of manuscripts.

8. Dissemination activities.

9. Objectives and work to be performed during the next three months.

10. For the final annual report, the plan for trial closeout, analysis, and dissemination shall be included.

11. Technical Progress Report for Clinical Research Study Populations: For each trial, the Contractor shall submit information about the inclusion of women and members of minority groups and their subpopulations for the study being performed under this contract. The contractor shall submit this information in the format indicated in the attachment entitled, Inclusion Enrollment Report. The NIH Policy Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research, Amended, October 2001 applies. The Guidelines may be found at the following website:

http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.

f. Final Report (hard and electronic copies): This report shall summarize the work performed and results achieved for the entire contract period of performance. The report shall include

(1) recommendations and conclusions based on the experience and results obtained and (2) tables, graphs, diagrams, curves, sketches, and drawings in sufficient detail to comprehensively explain the results achieved under the contract. It shall include a description of the final analyses of study outcomes by sex/gender and racial/ethnic groups, as appropriate. An Annual Report will not be due when the Final Report is due.

g. Minutes of Meetings and Conference Calls: Minutes of SC meetings and telephone conference calls shall be provided within fifteen calendar days after the meeting. Minutes of the PDC, PRC and DSMB meetings and telephone conference calls shall be distributed within four calendar days after receiving them from the NHLBI-appointed PDC, PRC, or DSMB Executive Secretary.

h. Abstracts and Manuscripts: All abstracts and manuscripts accepted for presentation or publication shall be provided within 30 calendar days after publication.

i. Final Complete Data Set Distribution Plan: The contractor shall submit to the SC and NHLBI for approval a plan for the distribution of a complete set of the clinical trial data. The plan should also describe how the software used to collect, manage, and analyze the data will, if necessary, be transferred or distributed. The final plan should be based on the draft plan submitted in response to the solicitation.

j. Public Use Dataset and Documentation: The contractor shall provide a final limited access data set for the study with full documentation. The data set shall include all phenotypic and outcome data for all subjects with reductions and redactions only as needed to ensure subject privacy. The data set and documentation shall be prepared in accordance with the NHLBI Limited Access Data Clause: http://www.nhlbi.nih.gov/resources/deca/policy.htm.

k. Adverse Event Reports: Throughout Phase II, adverse events shall be reported in accordance with NHLBI policies found at: http://www.nhlbi.nih.gov/funding/ethics.htm.

l. Final FDA Reports: Any reports required to be submitted to the FDA per FDA regulations or trial protocols or manuals of operational procedures.

SECTION F – DELIVERIES OR PEFORMANCE

ARTICLE F.2. DELIVERIES

Satisfactory performance of the contract shall be deemed to occur upon performance of the work described in SECTION C, ARTICLE C.1. and upon delivery and acceptance by the Contracting Officer, or the duly authorized representative, of the following items in accordance with the stated delivery schedule.

- The items specified below, as described in SECTION C, ARTICLE C.2.,will be required to be delivered F.O.B. Destination as set forth in FAR 52.247-35, F.O.B. Destination, Within Consignees Premises (APRIL 1984), and in accordance with and by the dates specified below:

Item Description Quantity Delivered to Delivery Schedule

a. Final Protocols, MOP, and informed consent template

1 COTR Within 6 months after award

b. Data Collection and Management Plan

1 COTR Within 6 months after award

c. Final Data Analysis Plan

1 each Steering Committee and COTR; PRC and DSMB (after review by SC and

NHLBI)

Within 6 months after award

d. Weekly Patient Screening and Recruitment Reports

As directed by the Protocol and MOP Weekly or as directed by the Protocol and MOP

e. Weekly Patient Adherence and Retention Reports

As directed by the Protocol and MOP Weekly or as directed by the Protocol and MOP

f. Quarterly/Annual Progress Report (hard and electronic copies)

1 each COTR and Contracting Officer

Quarterly:

Annual: Within 30 Days of the Contract’s Anniversary Date

g. Final Report (hard and electronic copies)

1 each COTR and Contracting Officer

Contract Expiration

h. Minutes of Meetings and Conference Calls

As Directed by the Protocol and MOP Within 15 days of SC Event or within four days of receiving minutes from PDC, PRC, or DSMB Executive Secretary.

i. Abstracts and Manuscripts

1 each COTR Within 30 days after publication

j. Final Complete Data Set Distribution Plan

1 each Steering Committee and

COTR

Between 48 and 54 months after award

k. Public Use Dataset and Documentation

1 total COTR Per Public Use Data Clause

l. Adverse Event Reports

As directed by the Protocol, MOP, and NHLBI Policy for Reporting Clinical Study Serious Adverse Events

As directed by the Protocol, MOP, and NHLBI Policy for Reporting Clinical Study Serious Adverse Events

m. Annual Invention Report

1 each Contracting Officer In accordance with Article C.3.

n. Final Invention Report

1 each Contracting Officer In accordance with Article C.3.

o. Information Security Reporting

1 each COTR and Contracting Officer

In accordance with Article C.2.

p. Annual Section 508 Report

1 each COTR and Contracting Officer

In accordance with Article C.2.

q. Final FDA Reports As directed by FDA, Protocol, or

MOP.

As directed by FDA, Protocol, or MOP during Phase III of the trial.

The above items shall be addressed and delivered to:

Individual Deliverable Item

No Address

COTR

a - c, f, g, i - k, o, p

COTR PumpKIN Trial

Contracting Officer f, g, m - p Contracting Officer PumpKIN Trial

Steering Committee Members c, j To be determined

PRC and DSMB Members c To be determined

Addressee Item Quantity

COTR for PumpKIN National Heart, Lung and Blood Institute Division of Cardiovascular Diseases Rockledge Two Building, Room TBD

6701 ROCKLEDGE DR MSC 7952

BETHESDA MD 20892-7952

Contracting Officer for PumpKIN National Heart, Lung and Blood Institute Office of Acquisitions, DERA Rockledge Two Building, Room 6016

6701 ROCKLEDGE DR MSC 7902

BETHESDA MD 20892-7902

SECTION L – INSTRUCTIONS, CONDITIONS, AND NOTICES TO OFFERORS

ADDITIONAL TECHNICAL PROPOSAL INSTRUCTIONS

1. Project Description (Detailed Description of Technical Requirements)

The objective of the PumpKIN trials is to explore the potential benefit of therapy offered by novel pediatric circulatory support devices to infants, neonates, and young children (<25 kg) with congenital and acquired cardiovascular disease who experience cardiopulmonary failure and circulatory collapse. The trials are intended to provide clinical evidence to be used in Humanitarian Device Exemption applications to the FDA for regulatory approval of the devices.

a. Trial Design

The specific trials and the associated protocols to be conducted as part of the PumpKIN program will be developed by a Protocol Development Committee (PDC) consisting of representatives from each of the PumpKIN pre-clinical contractors, NHLBI staff, and NHLBI-invited consultants. Expertise represented on the panel will be in the areas of pediatric clinical trials, cardiology, cardio-thoracic surgery, biostatistics, bioengineering, neurology, nursing, and regulatory affairs. This activity will begin prior to the award to the PumpKIN DCCC. Refinements and modifications to the trial designs and protocols will be made during the Planning Phase (Phase I) of the DCCC contract. Per the statement of work in Section C.1., the DCCC will be responsible for the management of the remaining PDC activities once the award is made.

The final protocols will be reviewed by a Protocol Review Committee (PRC) appointed by NHLBI. Offerors must be willing to abide by design decisions of the PDC and the recommendations of the PRC.

So that offerors can best respond to this solicitation, descriptions and summaries of the preliminary designs of the trials for the PumpKIN devices are provided below. Offerors are expected to discuss their understanding of the trials in their proposals and present their technical approach to accomplish trial objectives based on these devices and the preliminary trial designs.

b. PumpKIN Devices and Preliminary Trial Designs

System descriptions and preliminary trial design summaries for each of the devices which are part of the PumpKIN pre-clinical program are provided below.

1) System Descriptions

a) Levitronix PediPL System

The PediPL System is comprised of a single-use integrated pump oxygenator, a motor, a primary drive console, a back-up drive console, circuit, and cannulae (see Figure 2). The PediPL is a direct descendant of the Levitronix CentriMag® VAS with the integration of an oxygenator with the blood pump. Like the CentriMag VAS, the PediPL is unique compared to other devices in that it is designed to operate without mechanical bearings or seals. This is possible because the motor levitates the rotor (the spinning component of the device) magnetically so that rotation may be achieved without friction or wear during operation. The lack of thermal damage due to frictional losses translates to a reduction in the risk of thrombus formation within the pump. In addition, eliminating bearings and resultant thermal damage reduces hemolysis.

The Levitronix PediPL is designed to serve as a “bridge-to-decision” for pediatric patients unable to be weaned from mechanical ventilator or cardiopulmonary bypass support who have failed conventional therapy and are in need of mechanical cardiopulmonary support to sustain life.

The PediPL is comprised of a continuous flow, centrifugal-type rotary blood pump and integrated oxygenator. Blood from the failing heart and lungs is directed to the inlet of the PediPL via an inlet cannula. Blood exits through the outlet port of the pump through the outlet cannula ultimately to the pulmonary and/or systemic circulation.

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ood rease the velocity of blood along the direction of the axis of rotation out through the pump outlet. The system is capable of operating over a range of speeds up to 5,500 revolutions per minute (RPM) generating flows up to 3.0 liters per minute (LPM) (device alone) and up to 1.7 LPM, using a 12Fr inlet cannula with a 10Fr outlet cannula.

b) Ension Pediatric Cardiopulmonary Assist System (pCAS)

The Ension pediatric cardiopulmonary assist system (pCAS) has been designed and developed as a next-generation extracorporeal membrane oxygenation (ECMO) system providing increased functionality and blood compatibility. The pCAS (shown in Figure 3) is intended to provide partial or complete cardiopulmonary support to patients from 2 kg to 25 kg for periods of up to two weeks using a single disposable blood-contacting pump-oxygenator. The system has been specifically design to accommodate extended support beyond this two-week period by rapid change-out of the pump-oxygenator in a procedure that can be completed in less than five minutes.

The system offers key advantages over currently available systems including improved blood compatibility, smaller surface area and blood priming volume, more rapid deployment, and a compact size that facilitates parent-child bonding.

Figure 3. The Ension Pediatric Cardiopulmonary Assist System (pCAS)

A heparin-based surface has been developed as part of Ension’s efforts to improve the blood compatibility of the pCAS pump-oxygenator. The Ension bioactive surface (EBS) has been engineered to be more stable, bioactive, cost-effective, and gas permeable (a necessary feature when treating the hollow fibers comprising the blood oxygenator).

The pCAS system consists of a pump-oxygenator, a controller console, and ancillary components, such as venous and arterial cannulae, and a bubble trap. The pCAS pump-oxygenator is a compact device featuring a pump impeller integrated with a blood oxygenator via a diffuser. A control console regulates pump speed, displays all operational parameters, monitors the system for fault conditions (displaying alarms if faults occur), and provides control of the purge fluid supplied to the blood seal. The control console incorporates an internal backup battery to provide over one hour of continuous operation if AC power is lost and for patient transport.

c) Jarvik 2000 infant size Ventricular Assist Device (VAD)

The infant size Jarvik 2000 heart (Figure 4) is a very small permanently implantable blood pump. At only 10.5mm diameter, 5.2 cm long and 4cc in volume it is small enough to implant in the ventricular apex of 3.5 Kg. newborns yet it has flow capacity over 3L/min - sufficient output for children up to 25 Kg. Animal implants have shown that the pump remains free of thrombus and operates at low power without causing hemolysis. The pump represents a completed design, incorporating all of the requirements for a long-term implant, including welded hermetic sealing of the motor stator and rotor magnet, miniature hermetic feed-throughs for the power cables, a very long life ceramic conical bearing design, and pacemaker type high flex life power cables from the external controller to the implanted blood pump. An advanced microprocessor based control system has just been completed, although only the software for the basic functions (speed setting, measured speed, battery remaining, power, display function management via membrane switches) is presently available.

This permits basic operation but does not yet implement some of the more advanced functions planned for the future.

Figure 4. The Infant Jarvik 2000 Heart System

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The blood pump rotor, formed in the shape of a cylinder with conical ends, is magnetically suspended within the pump housing. This forms a single annular flow path from the inlet port to outlet port, with no secondary or tertiary flow paths.

Impeller blades at the inlet end of the rotor constitute a mixed-flow pump. Stay vanes are located within the outlet end of the pump housing. Blood-contacting pump surfaces are polished titanium with a phosphorylcholine (PC) coating.

The pump incorporates a modular percutaneous lead that connects to the controller via an extension cable, permitting rapid replacement of this portion of the lead in case it is damaged.

External to the patient are a Controller (with internal reserve battery), Battery Pack(s), Battery Charger and System Monitor Display.

The Controller powers the implanted pump via the percutaneous lead. The Controller typically receives power from an external source – either from a Battery Pack (during untethered operation) or from an AC power supply (tethered operation).

Incorporated within the Controller is a reserve battery, which supports pump operation while the primary power source is being changed or if it is accidentally disconnected. The Battery Pack incorporates rechargeable lithium polymer cells, with associated charge control and monitoring circuitry. A display on the Battery Pack indicates remaining charge capacity or fault conditions. A desktop charger unit recharges multiple Battery Packs off-line.

The Controller can be connected to the System Monitor via a long cable, which provides detailed data display capability as well as the interface for operator input.

Controls are provided to start the pump, set rotor speed and adjust alarm limits.

2) Preliminary Designs of Trials

Preliminary trial designs are provided below. The actual trial designs, protocols, MOPs, etc. will be developed and finalized during year 2 (2011) and the first half of year 3 (2012) of the PumpKIN program during the pre-clinical phase (see Figure 1).

Two preliminary designs are provided, one for the two PumpKIN ECMO devices and one for the two PumpKIN VADs. For each type of device (ECMO or VAD), a hypothesis, patient population, inclusion/exclusion criteria, primary and secondary endpoints, and patient sample sizes are given.

While devices can share a common protocol or elements of a protocol, separate trials for each device are expected to be performed.

To avoid competition between similar devices at clinical sites, only one PumpKIN ECMO device and one PumpKIN VAD is to be investigated at each clinical site.

a) Extracoporeal Pump-Membrane Oxygenators (PediPL and pCAS devices)

Hypothesis: Survival of patients treated with the PumpKIN ECMO devices will meet or exceed survival of similar patients treated with a ventricular assist device or extracorporeal membrane oxygenation. The probable benefit to the patient is an anticipated reduction in serious, life-threatening complications associated with support.

Patient Population: Patients weighing 25 kg or less in need of emergent mechanical cardiopulmonary support that meet the inclusion/exclusion criteria defined below.

Inclusion Criteria:

• Body weight >2 kg and <25 kg, and

• An appropriate indication for ECMO including:

- Low cardiac output resulting from right, left, or biventricular failure following repair of congenital heart disease (CHD)

- Pulmonary vasoreactive crisis following repair of CHD leading to severe hypoxemia, low cardiac output or both

- Inability to wean from mechanical ventilator support, cardiopulmonary bypass (CPB) or other mechanical cardiac or pulmonary support

- Primary cardiac failure (due to myocarditis, cardiomyopathy, arrhythmia induced, renal failure)

- Bridge to cardiac transplant

- Respiratory failure in the setting of heart failure

- Intractable metabolic acidosis (pH<7.28)

Exclusion Criteria:

• Body weight >25 kg

• Duration of ventilation >10 days

• Severe aortic insufficiency

• Presence of disseminated intravascular coagulation

• On hemodialysis (excluding hemofiltration)

• Contraindications to systemic anticoagulation

• Major hemorrhage

• Active systemic infection unresponsive to antibiotics

• Unresolved malignancy

• Treatment with another investigation device or medication

• Immunosuppression

• Recent cerebral vascular accident

• Evidence of irreversible brain damage

• Lethal congenital abnormalities

Endpoints:

Primary endpoints:

• In patients who recover and do not go on to transplantation or a long-term device:

Survival to 30 days after removal of the device or to discharge, whichever is less.

• In patients who do not recover: Ability to survive to induction of anesthesia for device removal and implantation of a long-term device or heart transplantation.

Secondary Endpoints:

• Recovery from renal and/or liver dysfunction as established by standard clinical values.

• Acceptable neuro-cognitive function

• Reduction in oxygenator failures requiring device change-out as compared to ELSO registry data for similar patients.

• Acceptable level of device-related adverse events and serious adverse events.

Patients Sample Size: 30 for the PediPL device and 30 for the pCAS device.

b) Ventricular Assist Devices (PediaFlow and Infant Jarvik 2000)

Hypothesis: The survival of patients treated with PumpKIN VADs will meet or exceed survival of similar patients treated with VADs or ECMO devices as evidenced in literature or the INTERMACS or ELSO registries.