The Research Support Services Office Taskforce has divided and reviewed all of the processes involved in getting a proposal submitted and approved and broken these into their component parts. The order in which these process steps appear is intended to suggest the order in which these activities typically occur. It should be noted, however, that several of the approval processes do, and will continue to, occur simultaneously if we follow the process for concurrent, timely approvals for grants and contracts to the greatest degree possible.

In this introduction, background information gathered by the Research Support Service Office committee is provided regarding the current performance of each research process step. Some of the individual steps are directly related to the function of institutional committees. These functions are discussed more completely in the sections of this document devoted specifically to each group. Goals and recommendations for change are also included in this introduction.

3.1.1 Current Performance

3.1.11 Proposal/Protocol Review of Industry Sponsored Trials

Most commonly a PI receives an industry-sponsored research protocol. Before the study can be started, approval must be obtained from the PI's department head and dean. These approvals may require a department peer review of scientific merit and appropriateness to that department's discipline(s).

Before the department head and dean will approve a study, a review of the budget by a departmental financial administrator is usually required to assure salary/effort budgeting for the faculty member is included and fringe benefit rates are calculated correctly. The department head, center or institute director/dean must sign a BA 23 form, Subjects Protection Programs application form, and a letter to the Conflict Review Committee all indicating approval of the research.

The PI must apply to Subjects Protection Programs for approval if the protocol requires the use of human or animal subjects in the research. This review for approval is discussed elsewhere in this document.

In studies that require the use of the General Clinical Research Center (GCRC) for "maintaining" the patients and for data collection, the protocol must be reviewed and approved by the GCRC's scientific advisory committee (Dr. Paul Robertson, chair).

As is now required by the National Cancer Institute, the Cancer Center has recently created a scientific review and protocol coordinating committee (Dr. Phil McGlave, chair). Research studies that involve the study of cancer or patients with cancer must be reviewed and approved by this scientific advisory committee.

With respect to determining the feasibility of the proposed research, general experience suggests that many researchers often overestimate the number of potential subjects that might be available for a study. This tendency to overestimate is created by the PI's recall or impression of how many patients have been admitted, or might be available, with a specific disease state. It is not easy to fully recognize the limitations most study protocols place on the study subjects (inclusion and exclusion criteria) when determining the available subject population. In addition, simple over-enthusiasm, or the desire of the PI to use a new drug or device which may have the potential for additional research or clinical funding that aids the investigator's scholarly career, can sometimes bias the PI's judgment regarding the feasibility of enrolling a given number of patients.

In general, the General Clinical Research Center and hospital have not facilitated many investigators interested in industry-sponsored research. This is understandable since this is not their primary function. The GCRC protocol review process sometimes or often requires responses to stipulations that have already been defined and approved by the sponsor, investigator, and Food and Drug Administration, and usually cannot be changed, at least not without considerable difficulty.

Laboratory, clinic, and hospital services are frequently difficult to obtain or coordinate. There is no place to call to get comprehensive information or one place or person to negotiate with. Rates for these services are hard to determine and personnel frequently are not very service-oriented when dealing with PIs. It is often difficult for PIs to find nursing services to assist in protocol administration without having to hire their own staff - which they often do out of necessity. There is an overall lack of trust in the efficiency, ease of use, responsiveness and cost competitiveness of the system.

There is a wide range in the comprehension and understanding by PIs of federal and University research study requirements. For example, PIs are often not aware that "clinical judgment" (except in life-threatening circumstances) is preempted by the need for strict "protocol compliance." This can create potentially serious compliance problems. In addition, PIs have often not fully considered or realized the time required to perform the duties they have agreed to by signing the study contract. Also, there are circumstances where PIs have not determined in advance which study tasks will be delegated, what the oversight mechanism for the study team will be, or that it is in place to assure successful completion of the research.

Some PIs are not aware that industry-sponsored clinical trials require that anyone treating subjects, assisting with research procedures and making assessments, or administering the study drug to subjects must have reported their credentials to the FDA. The FDA Form 1572 is often not updated as medical professionals are added to, or leave the study team.

3.1.12 Conflict of Interest and Academic Misconduct

Assuring scientific integrity at the University of Minnesota is directed by the Board of Regents' Conflict of Interest Policy and the Board of Regents' Academic Misconduct Policy. The AHC will apply these policies in the firm belief its researchers are honest, and committed to protecting the public interest and their own integrity by adhering to the highest ethical standards in the conduct of their research. Little or no ongoing support is provided to the faculty and other research investigators to aid in their understanding of or compliance with these policies.

3.1.13 Budget Preparation and Negotiation

Currently, there are no University guidelines for creating a budget for industry-sponsored research. Preparation of budgets is done on an individual basis by the PI with support staff from his/her department. We are aware of no training or guidelines that are available for budget preparation and negotiation. PIs developing budgets have little or no help and oftentimes lack experience estimating the actual costs of a study.

There are many reasons why this may be the case. Many factors make it difficult, if not virtually impossible, to accurately predict costs and then manage budgets and finances. While there is an intent to do this as best is possible, often there is no penalty for doing a poor job and in many cases organizational dysfunction precludes this.

After the direct costs are finalized, the indirect cost rate is applied to the budget. For industry-sponsored research, 20% of direct costs is the fixed rate. We have heard from anecdotal industrial feedback that for many, the concept of indirect cost is an anomaly to them. They are much more used to and comfortable with the concept of fully allocated or fully burdened costs and might accept this more easily.

Commonly, the PI will negotiate budgets with the sponsor - and may accept the per patient reimbursement offered without precisely knowing whether that amount will cover the cost of doing the project at the University or not. For whatever reason, if the precise actual costs were not developed before creating the budget, there is a distinct possibility of negotiating a contract below cost. There are a number of examples of shortfalls on contracts. Department staff often do not get involved until the BA 23 is reviewed at the department level even though ultimately the department must take responsibility for the consequences of over expenditures relative to the budget. For industry-sponsored fixed price contracts - "the bottom line" has often already been established once it reaches the department level and there is a need to assure that this adequately covers costs.

3.1.14 Contract Review and Negotiation

In the current system, contracts from industry sponsors are sent directly to PIs. Faculty may review these contracts and/or elect to have a department administrator review them. After all internal approvals are obtained SPA staff review the contract, negotiate with the sponsor and PI any changes requested, and sign on behalf of the University of Minnesota.

It may take SPA anywhere from several weeks to several months to accomplish the review, negotiation and acceptance of a contract from an industry sponsor. This leads to extreme frustration on the part of sponsors and PIs who are often left in limbo with corporations; it leaves corporate sponsors, the business community and government with the feeling that we just don't care and that we have no appreciation for their position nor how valuable time is to them.

3.1.15 Subjects Protection Programs

Many investigators are not fully aware of all the regulations, guidelines, and community standards by which their research will be judged, and with which they must comply throughout the project. The applications and consent forms research investigators submit for IRB review often reflect their lack of familiarity with regulations, guidelines, and local standards.

Little ongoing support or education is currently provided to faculty on an ongoing basis in understanding and complying with human subjects research regulations.

3.1.16 BA 23 and Account Assignment

The Application for External Research, Training or Public Service Support (BA 23) is used to provide the approvals necessary to submit an application for external research or training support. In addition, it provides information for the institutional databases on grants and contracts.

The BA 23 form must be completed and submitted with all applications for new projects, continuations, renewals and supplements, and must also accompany agreements for the transfer of proprietary research materials (MTA's - Materials Transfer Agreements). The BA 23 form is not required by ORTTA for preliminary proposals and revised budgets.

The application must be submitted to the department head or unit director for review and signature. As centers and institutes proliferate around the University these may become the administrative "home" for grants, i.e., where authority and accountability rests. There may need to be some policy to make this clear. The application must then be processed in the same manner through the appropriate collegiate office. Again, centers and institutes may cause alterations in this procedure. Once these approvals are obtained, the application is submitted to ORTTA for final review, execution, and submission to the agency/sponsor.

After the agency/sponsor and ORTTA have reviewed and signed the research agreement or contract, a CUFS number is assigned to the project. The PI may begin charging expenses related to the project to the account as soon as it is established.

PIs may request that a preaward account be established when there is sufficient certainty the grant will be received and work on the project cannot be delayed. The PI's department, institute or center must guarantee payment of any charges to preaward accounts not covered by grant funds.

The BA 23 form is initiated by the PI who signs it and passes it on to the PI's department head and dean who are required to review and sign the BA 23. Approval signatures by the department head and dean indicate the following role or responsibility2:

• b>Department head: approval authority for on and off campus space, prorating department credit, the academic and management qualifications of the PI, the adequacy and correctness of the budget, equipment requests, cost sharing arrangements, and conflict of interest review.

• Dean: approval authority for on and off campus space and requests for indirect cost waivers. Local oversight authority for prorating department credit, affirming PI qualifications, determining the adequacy and correctness of the budget, appropriateness of equipment requests, cost sharing arrangements, and whether there has been approval of the conflict of interest review; these are all attested by the dean's signature.

• PI: signature indicates that the information provided is correct and that the equipment budgeted in the application is not otherwise available for use on the project from existing departmental or collegiate inventories. The PI indicates his/her agreement to abide by all applicable institutional and sponsoring agency policies and procedures (including the Patent and Technology transfer Policy of the University of Minnesota) and to follow commonly accepted scientific practices in recording and maintaining records of their research.

CUFS numbers to establish the specific accounts are assigned by SPA upon final acceptance of the contract, research agreement or award statement. An SPA grant administrator expedites assignment of the account number. SPA attempts to provide a CUFS number to the PI and his/her department within 48 hours after the contract or research agreement is approved by the University.3 If SPA were able to achieve this it would be tremendous; however, it is not uncommon for months to elapse from the time the BA 23 is delivered to SPA to the time a CUFS number is assigned to the project.

3.1.17 Managing Project Changes

Changes to approved research projects may require additional review and approval when the changes involve: (1) a change in the faculty member's external relationship with the research sponsor, (2) a change in the budget or contract, (3) a change in the proposed conduct of human or animal subjects research, or (4) any change in the use of hazardous materials.

The principal and associate investigators are responsible for knowing that proposed changes in the research plan cannot be implemented without approval of local oversight committees or offices. Making application for approval of any proposed changes to the research plan is the responsibility of the research investigator and their collaborators.

3.1.18 Managing Research Funds

The responsibility for management of grant funds is shared between the PI, the department or unit administrator and the department head or institute or center director as follows:

• PI: initiates or approves the project budget and purchases in accordance with the budget, initiates documentation of mandatory cost sharing or matching, rebudgeting, cost transfers, and resolution of overdrafts. The PI is responsible for assuring he/she is in compliance with the effort reporting policy and that it is accurate. The PI is also responsible for approving payment of subcontractor invoices.

• Department/Institute/Center Administrator: administers the project budget and purchases in accordance with the budget, initiates documentation of mandatory cost sharing or matching, rebudgeting, cost transfers, and resolution of overdrafts. Department administrators are also responsible for developing the effort reporting.

• Department Head/Institute/Center Director: provides local oversight in project budget management, approval of cost transfers, overdraft resolution, and rebudgeting.

There is variability across departments in how well sponsored research accounts are managed. In some cases it is outstanding, in other cases the department administrators given responsibility are too far removed from the activity of the project to be able to participate effectively in the management of the funds. Perfunctory financial review may occur, but the reviewer (perhaps a department administrator) may have difficulty and cannot accurately judge whether a charge is appropriate, a payment due, etc. While a misappropriation of funds may occur infrequently, we have many examples locally of this problem and the consequences can be rather severe.

Currently, PIs must request approval from their ORTTA grant administrator (who often knows even less about the project than does the local department administrator) to spend grant funds beyond a single purchase dollar threshold.

Monitoring contract benchmarks and payment schedules is performed by the PI's own support staff or department administrator or their designees. The same is the case for monitoring charges by internal service providers.

Currently, PIs are very compromised by the University due to the difficulty of accurately gathering and having financial information presented to them in a way that makes sense. Compliance with effort certification continues to be problematic and in some cases questionable. Effort reporting is often less of an accurate reflection of effort extended than it is a financial juggling act to avoid over-commitment.

3.1.19 Closing the Project

PIs and department heads, center or institute directors are responsible for various activities required to close a sponsored project. These include, but are not limited to, review of regulatory documents, final reports, review of final account status and contract terms and closing the budget account at the University.

Current performance surrounding project closing responsibilities varies with the experience level of the PI and department administrator. In some cases financial closing of a project can be as difficult for a department administrator as was the management of the contract or grant funds. One of the factors contributing to this is the "distance" between the project activity and the responsible manager or administrator.

3.1.2 Goals and Recommendations

3.1.21 Proposal/Protocol Review of Industry-Sponsored Trials

The Academic Health Center should develop a check list that defines what each investigator (and Research Support Service Manager working with the PI) must consider before agreeing to an industry-sponsored (or any) research proposal or protocol. This statement or policy should be in sufficient detail such that the PI, Research Support Service Manager, and Research Support Service Office, are fully informed of their responsibilities when making a decision on whether or not to accept the proposal/study protocol.

This statement or policy should start with the mission statement: "The mission of the Academic Health Center is to be a leader in the ethical, innovative, and efficient discovery and dissemination of knowledge to enhance the health and well-being of Minnesota, the nation, and the world." It should include clear statements of what it is to be a scientist, responsibilities to the University and society, etc.

To assist with feasibility review, the Research Support Service Office will provide detailed demographic data on the patients in the University-Fairview health care system. Data on inpatient and outpatient admissions such as medical problem lists, treatments received, etc. would be used to estimate the potential subjects available and at what sites.

In order to meet the need for research facilities, the AHC must develop a cost-based, affordable inpatient and outpatient "facility" for clinical research. This facility doesn't have to be a specific hospital unit (though it can be), but must provide a detailed list of services (lab, radiology, clinical) and their costs, how to gain access, etc., in the form of "one stop" shopping. In addition, the AHC needs to develop the ability to purchase these services outside the University if they cannot be provided at a cost competitive rate.

Existing services such as the General Clinical Research Center, may have difficulty servicing a broader group of clinical investigators. Therefore, establishing a clinical trials unit or a "virtual" clinical trials unit would be highly desirable. The Research Support Service Office will need to employ a staff of experienced research nurses who can function in a "virtual" clinical trials unit. The research nurses will be assigned to PIs for each study. Since the working relationship between the Research Support Service Manager, Research Nurse and PI is critical to the success of each study, compatibility and consistency must be considered when forming these research teams. The research nurses will need to have flexible working hours, be able to cover for other nurses, and be willing to see and be involved with various types of research subjects.

The Research Support Service Manager will explain the study team requirements to the PI and assure all the federal and University compliance checks have been satisfied. A database of faculty expertise will be created to assist the Research Process Manager with locating potential sub-investigators.

3.1.22 Conflict of Interest and Academic Misconduct

Complete details of recommendations for the Conflict Review Committee can be found elsewhere in this document. With respect to the services which could be provided by the Research Support Service Office, we recommend that the AHC provide assistance to PIs in reviewing the PI's specific situation regarding the conflict of interest policy, his/her external relationships, and in choosing the best management plan for assuring scientific integrity when a potential conflict of interest may appear that could potentially bias or be perceived to have potential to bias the outcomes of the research. The Research Support Service Taskforce also recommends that the institution allow Department heads/Directors and Deans to delegate authority for review of potential conflict of interest to the Research Support Service Office. If this were to occur the Research Support Service Office, Research Support Service Office director, Vice Provost for Research or senior administrator or director of research in the AHC, would then be the arbitrators.

The Research Support Service Office will assist investigators in writing soundly designed studies. Importantly, this would include assuring that the statistical analysis used in reporting results is consistent with the planned analysis used to design the study. The AHC should provide random reviews of research conducted by potentially "conflicted" investigators where the integrity of the research data may be called into question.

3.1.23 Budget Preparation and Negotiation

It is highly desirable to develop a centralized function within the AHC to aid researchers, to the greatest degree possible, to ensure that research projects are budgeted correctly relative to what the real costs are expected to be. It is also desirable to create a centralized audit function for PIs who voluntarily want to ensure that they have budgeted for actual costs and have charged the account appropriately once the project has started.

The Research Support Service Manager will work with the PI to take responsibility for determining "actual costs" of the project and creating a budget. The Research Support Service Manager will use a data base developed to identify the median costs for performing a given study. The Research Support Service Manager will work with the PI to determine, as closely as possible, the actual costs of the project. Every effort will be made to estimate actual hours required to perform the study - and the likelihood that the work will be completed on budget. In no case, except with the concurrence of the faculty member, will a budget be used by the Research Support Service Office for its services in an amount greater than that agreed upon with the PI and reflected in the prospective budget.

As they now do, departments will continue to be able to participate in this process to the degree they wish - within the guidelines of 1) the research must pay for itself and 2) expenses cannot exceed allocated dollars. The Research Support Service Office will work with departments (who will still assume ultimate responsibility for the accounts in their areas) to provide faculty and departments with well-researched and well-written industry-sponsored research budgets, and all the accompanying forms and information they require.

The anticipation is that via a database, having more accurate costing information, and by including staff most intimately aware of the project, the faculty member will be properly supported in developing the budget based on truly actual costs plus a stated amount of indirect costs.

Because expediency will be at a premium (with no compromise in quality), and the investigator will have participated in developing the budget, departments will have one working day, ~8 hours, to review proposed budgets and respond to the Research Support Service Manager with any requests for changes.

Upon initiation of the studies, and given an accounting system that works, the Research Support Service Managers should monitor expenditures on a monthly basis and report any unanticipated expenses over budget to the PI, department administration and the Research Support Service Office finance director/Research Support Service Office director.

3.1.24 Contract Review and Negotiation

The AHC should provide assistance and support to faculty and research investigators and be a liaison/support to SPA through preliminary contract review and negotiation in the areas in which most problems occur: intellectual property rights, publication rights, etc. SPA should identify the areas of common problems in proposals and award processes and develop an appropriate management plan in an attempt to remedy these problems before they start. This information should be provided to the Research Support Service Office. This could be in the form of standardized positions or terms that might represent a range of terms that are acceptable to the institution. More recommendations regarding the role of SPA can be found in the ORTTA section of this document.

3.1.25 Subjects Protection Programs

The quality of research plans, applications, and consent forms submitted to the IRB and IACUC should be improved by providing assistance to faculty and associate investigators as applications are prepared and research plans developed. More recommendations about Subjects Protection Programs can be found in the section so named elsewhere in this document.

3.1.26 BA 23 and Account Number Assignment

PIs should receive assistance from the Research Support Service Office to complete research applications, including the BA 23. The department head, institute or center director and dean approval authority, if continued to be required, could indicate delegation of review authority to the Research Support Service Office for the academic and management qualifications of the PI, the adequacy and correctness of the budget, and the conflict of interest review. It is clearly uncertain what importance, if any, the perfunctory "sign-offs" by deans and department heads accomplishes. It seems that the powers that be within the institution could agree that one person who was responsible and accountable could adequately do this for everybody currently involved in the chain of signatures, i.e., department head, dean, ORTTA. For the time being, space, department credit, equipment, and cost sharing issues will continue to be reviewed and approved by an institutional authority outside the Research Support Service Office.

ORTTA should provide a CUFS number to the investigator and his/her department within 24 hours of signing the research agreement or contract from the corporate sponsor.

The rationale for these recommendations is that providing assistance and support to PIs will increase the quality of the supporting material in research applications and budgets. With respect to the current meaning of review signatures, department heads and deans, in many cases, have already informally delegated review authority to the PI or department administrators. It is known that there is great variability among PIs and department staff with respect to their knowledge of research regulations and policies. The Research Support Service Office will be staffed with individuals with sufficient skills to whom department heads and deans might more reasonably delegate review and approval authority for PI eligibility, budgets, and conflict of interest review. Research Support Service Office staff can also assist department heads and deans by identifying space, appropriate credit, equipment, and cost-sharing issues department heads and deans should consider.

Abbreviating the contract negotiation process should make the time from BA 23 submission to CUFS number assignment significantly shorter. Requiring ORTTA to provide a CUFS number within 24 hours of signing the contract or research agreement will allow PIs to proceed with the project as quickly as possible.

3.1.27 Managing Project Changes

PIs should be assisted by the Research Support Service Office in assuring that all proposed changes to approved research are approved by the appropriate local oversight committee or office. Compliance with regulations will be increased by Research Support Service Managers assisting research investigators in notifying local oversight committees and offices of proposed changes to research plans. When proposed changes must be approved by a local oversight committee or office, the Research Support Service Manager will assist the PI by completing the application and tracking it through the system as was done during the initial review and approval phase. The same aforementioned timeliness of approvals within 10 working days will be expected.

3.1.28 Managing Research Funds

The Research Support Service Office should provide grant management support to the PI and department or unit administrator. The Research Support Service Manager responsible for working with the PI in developing the budget and negotiating the contract should also be responsible for working with the PI to manage the grant funds within the current or any new grants management system.

Research Support Service Managers should review requests to spend grant funds and make approval recommendations to ORTTA. In conjunction with the PI, the Research Support Service Manager will be responsible for monitoring progress on the study and assuring that the sponsor is following the payment schedule in the contract.

The Research Support Service Manager should be responsible for preparing and distributing a monthly financial report to the PI and his/her or local grants management unit, i.e., department, institute or center. The Research Support Service Manager will also assist the PI to assure compliance with the effort certification policy.

Centralizing these grant fund management responsibilities in the Research Support Service Office will assure that staff knowledgeable of not just policies and regulations, but also the project, budget, and contract are managing the funds. This should remove the "disconnect" which so often appears to interfere with the provision of adequate grant funds management information to faculty, and especially in providing this on a timely basis.

3.1.29 Closing the Project

The Research Support Service Office should assume responsibility for review of any regulatory documents, final reports, review of final account status and contract terms, and closing the account. The Research Support Service Manager will assist the PI in completing the end of study requirements and will provide information to the PI and to the PI's department, center or wherever the grant is administratively housed.

Centralizing the end of the project management responsibilities in the Research Support Service Office will increase the probability of assuring compliance with regulations. In addition to this, the institution is interested in developing or monitoring long term relationships with corporate sponsors. Therefore providing the sponsor and regulatory bodies with the appropriate information in a timely manner is important so that corporate sponsors believe that they have invested their money wisely. Also, the Research Support Service Manager will assure that all payments from the sponsor have been received, bills paid, and that any approved cost overruns are billed to the sponsor.

The following sections describe the services we recommend the project service division of the Research Support Service Office should provide. These services expand on the recommendations listed in this introduction.

3.2 Research Support Services

3.2.1. Proposal/Protocol Review

One of the Research Support Service Office responsibilities is to serve as an administrative advocate for the PI within and outside of the institution. The Research Support Service Manager will review the study protocol overall, including but not limited to: reviewing the project for scientific merit, for consistency with the mission and goals of the AHC, for feasibility (such as subject population, resources), and for determining the composition of the research team. In conjunction with the PI the Research Support Service Manager will work to complete a series of steps toward documenting the consideration given these issues. The intended purpose of this is to provide a process in which the PI can consider the merit of the research, the likelihood the project can be successfully performed, and to determine the staff and services support the project will require.

The Research Support Service Manager has the authority to complete all approvals in the protocol review process. The project will be forwarded beyond the Research Support Service Manager only in the event there is a question that cannot be resolved by the Research Support Service Manager and the PI. It is not anticipated that this would occur with any frequency but when it does, the Vice Provost for Research, Dean for Research, or most senior official dealing with research in the AHC would arbitrate this.

3.2.11 Review for Scientific Merit and Consistency with Mission and Goals of the AHC

The research proposal/protocol will be reviewed by the Research Support Service Manager and the PI. The PI will be responsible for helping the Research Support Service Manager provide information and answers to basic questions upon which the scientific merit of the proposed research will be defended. The questions or information collected will be:

• A brief description of the drug or device,
• The proposed subject population,
• The hypothesis being tested,
• Study endpoints,
• Statistical plan,
• A brief statement of the principal investigator's time commitment to the project.

The Research Support Service Manager will use the information provided in this preliminary step to complete other internal or external regulatory committee forms and applications. To assess scientific merit, these are examples and questions that will be discussed and documented:

• Is this new drug or device just starting clinical testing, or is it a study to allow the PI to gain experience with the drug or device?
• Does the study involve a vulnerable population? Has the investigator thought about how to justify the use of this population?
• Is there a hypothesis being tested?
• Will the endpoints answer the research question?
• Is there a statistical plan that would provide a definitive answer?
• After considering these issues, why do this study?

3.2.12 Feasibility Review

The PI and Research Support Service Manager will determine what resources are needed to conduct the trial or study, whether the PI has access to these resources, and if not, if is there a plan to obtain resources not currently available in the AHC. The areas of review will include among other things:

3.2.13 Patient Population

The PI and Research Support Service Manager will review the subject population. The PI will be responsible for assuring that an adequate number of potential subjects exists from which to recruit for the study. The PI and Research Support Service Manager will discuss the recruitment strategy for reaching the potential subjects. Human subjects rules for recruitment will be addressed with the PI during this discussion. The Research Support Service Manager will use this information to complete the human subjects application as the study passes the protocol review stage.

3.2.14 Core Facilities and Resources

The PI and Research Support Service Manager will discuss the need for core facilities: inpatient and outpatient services, laboratory services, other clinic and hospital services, and research nurses. The availability of these services will be determined. The Research Support Service Office will negotiate with existing internal service providers, on behalf of the PI, in an attempt to obtain the optimal prices or service. The Research Support Service Manager will also try to obtain facilities or resources that are needed but not available internally. In addition, to optimize efficiency of relative costs and services, outsourcing will be considered to fulfill any of the needs generated by a project.

3.2.15 PI Commitment - Time and Other

The Research Support Service Manager and PI will discuss the PI's commitment to following the protocol. Any potential risks for non-compliance will be identified, i.e. does the PI have time to complete the assessments they are agreeing to make.

The Research Support Service Manager will document concerns regarding PI commitment, if any, and review the responsibilities the PI agrees to accept by signing the FDA 1572 form.

3.2.16 Naming the Research Team

The Research Support Service Manager and PI will review the protocol and sponsor requirements to determine the need for other professionals to assist with performing and managing the trial. The Research Support Service Manager will facilitate finding any needed sub-investigators for the study. However, the PI will have the ultimate authority for determining the addition of any co-investigators or sub-investigators. The PI must assume authority and be responsible for the conduct of all other members of the research team involved with the clinical trial.

3.2.17 Sponsor Regulatory Documents

The Research Support Service Manager will be responsible for completing all the required regulatory documents and assisting the PI in organizing and executing the long term document retention requirements. The Research Support Service Manager, in consultation with the PI, will complete the FDA form 1572; collect the C.V.s or biosketches of all staff members listed on the form, provide the IRB committee the staff member list, and collect laboratory certification documents, normal ranges, and lab directors' C.V.s.

3.2.2 Conflict of Interest Review and Management

The Research Support Service Manager will assist the PI in complying with the University of Minnesota conflict of interest policy. The Research Support Service Manager, the Research Support Service Office, and the Vice Provost or dean for research will share the ultimate responsibility for identifying and managing potential conflicts of interest with the PIs.

The PI is responsible for providing complete and accurate information in disclosing external relationships and commitments. The Research Support Service Manager is responsible for assuring the information provided is properly defined, and for identifying a plan to manage any potential for a conflict of interest that could be perceived to bias the research outcome. The Conflict Review and Management Committee will review cases where there is a potential for conflict of interest or commitment, making recommendations to the Research Support Service Office Director, or AHC Vice Provost or dean for Research, as to whether the management plan should be approved. The senior AHC person overseeing research is responsible for final approval of the plan. The University has an institution-wide conflict resolution group - the Public Private Partnership Committee. Recommendations of the Public Private Partnerships Committee may be solicited to assist the AHC in making the final determination.

The Research Support Service Manager will also assure that research investigators are familiar with their rights and responsibilities with respect to the Regents' Policy on Academic Misconduct.

Regents' Policy on Conflict of Interest will guide the conduct of research in the AHC when a research investigator's external financial relationships may be perceived to potentially compromise the integrity of data produced by a study. The Research Support Service Manager will guide research investigators through the policy and the procedures in cases where there is a potential for conflict of interest.

3.2.21 Review of Faculty Members and Research Investigator's External Relationships

The Research Support Service Manager will check the PI database for the completed Report of External Relationships for the PI, and for any co-PI/sub-investigator serving in a capacity which could be perceived to allow any potential bias in the outcome of the study. The report will be reviewed by the Research Support Service Manager, and the PI(s) will be contacted (via e-mail) to ask if there have been any changes since the report/data base was last updated (if more than 30 days have passed since the report was last updated). If there have been changes, the PI will be asked to make the changes and the report will be printed for the Research Support Service Office file. If there have been no changes, the e-mail response to that effect will be printed and placed in the Research Support Service Office file. The Research Support Service Manager will review funding sources for the PI's entire research program.

3.2.22 Review of the Study Research Design

More rigorous management of potential for conflict of interest is required for studies in which the evaluation of bias resulting from conflict of interest is difficult to assess by other means.1 Studies falling into this category include: open label, unblinded studies of a non-pharmacokinetic nature, study designs with subjective endpoints, single investigator studies, or multicenter studies in which the University of Minnesota is expected to provide a disproportionate number of subjects. In these situations, a review to assure appropriate experimental design and documentation, coupled with the review of data generated and performed with industry is required to comply with federal regulations. This will objectively address circumstances surrounding a research study where concern about bias might exist in a more meaningful way, perhaps, than through inferences drawn from financial disclosure statements.1

If it is determined that no significant potential for conflict of interest. exists, the Research Support Service Manager will note this in the Research Support Service Office file and the review of external financial relationships for the project will end. A copy of the report of external relationships will be sent to the Department head and to the Dean and, as appropriate, to any relevant center or institute director.

When it is determined that a potential for conflict of interest exists, the Research Support Service Manager will inform the PI of the potential conflict and a management plan will be developed. If the PI opts to end the relationship with the sponsoring corporation, written documentation of the end to the relationship must be provided. If the financial relationship is terminated, the application will be noted as acceptable by the Research Support Service Manager on the BA 23 and the application will be forwarded to the AHC SPA representative for review.

Only in cases in which a potential conflict of interest is determined to exist will applications be reviewed by the Conflict Review and Management Committee (CRMC). The Committee will meet as often as necessary (no less often than bi-weekly) to review applications. The Conflict Review and Management Committee review process will be limited to addressing the issue of investigators' external financial relationships, and review and approval of the proposed plan to manage the conflict. The Committee will review applications in less than 10 working days, and may recommend approving or denying the plan for managing the potential conflict. The final decision authority rests with the AHC, e.g., Vice Provost or dean for Research who may seek the advice and recommendation of the Public Private Partnerships Committee.

3.2.23 Responsibility Indicated by Conflict Review Document Signatures

PI: Signature by the PI, co-investigator, or sub-investigators means that he/she has complied with all the disclosure requirements of the Regents' Policy on Conflict of Interest, and that the management plan for any potential conflict of interest will be followed.

Research Support Service Manager: Signature by the Research Support Service Manager means that the proposed activities have been administratively reviewed, a conflict of interest management plan has been developed and that the affected academic employees have received information about the action plan, the disclosure requirements, other University policies, and any pertinent federal or local regulations.

Conflict Review and Management Committee: This Committee will have authority to approve cases in which a potential for conflict of interest exists, to approve a proposed management plan, or to recommend management plans which mitigate this situation and make a potential conflict acceptable. It is expected that the norm will be to approve corporate sponsored research where a management plan has been developed to deal with a potential conflict of interest. Thereafter University administration at all levels will vigorously defend the employee and the activity so long as the academic employee complies with the plan of action, the disclosure requirements, other University policies, and any pertinent regulations.

Provost's Office: Depending on the ultimate organization of the Provost's Offices, the Research Support Service Office director, Vice Provost or Dean for Research signature on the BA 23 indicates final approval of the research project with respect to conflict of interest.

3.2.3 Budget Preparation and Negotiation

The Research Support Service Office responsibility for working with the PI in the preparation of the budget is to assure that the funds budgeted will cover all the anticipated research costs - including the PI/co-investigator/sub-investigator efforts. The Research Support Service Manager, working with the PI, will determine the costs of the study and prepare the proposed budget for review by the PI. The PI and Research Support Service Manager will negotiate the budget with the sponsor. The PI may elect to give the major share of the responsibility for budget negotiation to the Research Support Service Manager but the PI would have final review authority.

The Research Support Service Manager will have the authority to complete all approvals in the Research Support Service Office protocol review process. The project will be forwarded beyond the Research Support Service Manager only in the event there is a question/concern about performing the study at a financial loss that cannot be resolved by the Research Support Service Manager and the PI. In a case where the PI, Research Support Service Manager and sponsor can't come to agreement on a fiscally sound budget the senior authority, Vice Provost for Research and unit head of the PI would make a determination on whether or how to go forward and who would assume financial risk.

3.2.31 Determination of Actual Costs

During the early stages the Research Support Service Manager will work with the PI and his or her colleagues to develop a list of all procedures and services required to perform the study. Given this, all personnel required to perform the study and fulfill its requirements will be determined.

• Negotiation with Internal Service Organizations (ISOs)/Other Internal Service Providers

• Separation of Standard Care from Research Procedures for Clinical Trials

The Research Support Service Manager will determine, in consultation with the PI, which (if any) procedures, diagnostic tests, clinic and hospital charges, etc., are related to standard care. Charges that are explicitly part of standard care will be billed to the patient/subject and/or his third party payer. All charges not explicitly part of the patient/subject's standard care will be built into the study budget.

• Personnel

Over time experience will allow the Research Support Service Office to determine the Research Support Service Manager time necessary to develop the proposal through the point of submission to the sponsor This cost will be borne by the Research Support Service Office. The Research Support Service Manager and the PI will discuss the extent to which other Research Support Service Office support during the project management phase will be required, e.g., biostatistics, etc. The ongoing Research Support Service Office effort during the project management phase will be projected and determined with the PI based on the PI's need. A schedule of tasks, projected time required to perform them, and the hourly rate of staff (including fringe benefits) will be prepared for the PI's approval. With the PI's approval, these personnel costs will become part of the study budget.

The costs of PI/co-investigator/sub-investigator effort will be reflected in the budget, as will the costs associated with research nurses required to oversee and perform clinical assessments.

3.2.32 Preparation of the Draft Budget

The Research Support Service Manager will prepare the draft budget and attach worksheets for calculating Research Support Service Office charges and all personnel charges. (Worksheets will be for internal distribution only.)

• Process of Review, Change, Approval

In the interest of expediency, no one other than the PI and the Research Support Service Manager will be required to review the budget. However, departments or other units that wish to review proposed budgets prior to budget negotiations with the sponsor will have 8 hours in which to respond to the Research Support Service Manager with requested changes. Again, in the interest of minimizing unnecessary steps, avoiding duplication, and expediting proposals, communication between Research Support Service Managers and department staff will be solely electronic at the stage of draft budget preparation.

Research Support Service Managers and PIs will have the authority to approve the budget and proceed to negotiation with the sponsor.

• Indirect Costs and "Margin"

3.2.33 Negotiation with the Sponsor

The Research Support Service Manager will fax the proposed budget and the standard U of M contract to the sponsor. The Research Support Service Manager (or the PI if he/she prefers) will negotiate the budget with the sponsor. Agreement will be reached between the PI and the Research Support Service Manager, prior to negotiation, to assure clarity in the areas in which there may be room for negotiation. In no case will the PI or the Research Support Service Manager negotiate downward without the express knowledge and agreement of the other. The PI and/or Research Support Service Manager will continue the process of negotiation until the budget is negotiated to their satisfaction.

3.2.4. Contract Review and Negotiation

It is a desirable and laudable goal to create mutually beneficial, highly effective and respectful relationships between the University (in accordance with its mission and rights) and a sponsor (with its mission, rights and market demands) that does not compromise either party's position. Understanding this operating principle is the basis on which these contracts need to be written, negotiated, executed, and monitored. Without this foundation for the relationship, a contract has yet to be written that will be sufficiently detailed or litigation-proof to assure absolute respect for each party's rights. Absent this understanding neither party should enter into an agreement.

The Research Support Service Office will work on behalf of the PI and institution and will be responsible for reviewing the contract or grant to assure that the:

• intellectual property rights of the faculty member and University are protected,
• projected income schedule is structured to be compatible with the expense schedule,
• academic freedom of the faculty member and research is maintained, and
• confidentiality of the sponsor's assets is protected.

3.2.41 Initial Contract Review

Preliminary contract review will be performed by the Research Support Service Manager. To the degree possible, the standard University contract will be used.

• Standard University and AHC Contract

Terms will be developed by the PI, any collaborating investigators, and the Research Support Service Manager. General concurrence on the terms of agreement will be reached prior to submitting it to the sponsoring organization for their review. Any review by legal counsel will also be performed at this time. Changes that the sponsor requests will be negotiated by the Research Support Service Manager, in conjunction with the PI, the Research Support Service Office director, and Research Support Service Office legal counsel, the Research Support Service Office financial leader, as needed.

• Sponsor's Contract

The Research Support Service Manager will review the sponsor's proposed contract in all aspects. The Research Support Service Manager, functioning with or on behalf of the PI and in conjunction with Research Support Service Office finance and legal counsel as needed, will negotiate any changes that are desired. These will be agreed upon and signed for by the PI. The financial terms will also be reviewed by a financial officer in the Research Support Service Office/Provost's Office.

3.2.42 Negotiation and Approval of Contracts

• Proposed Long-Term Plan

In order to save faculty time (with the concurrence of the faculty member) the Research Support Service Manager will lead the negotiation process with Research Support Service Office financial and legal assistance, as needed. The Research Support Service Manager will sign off on all contracts where intellectual property is not involved. If intellectual property is or may be involved, the Research Support Service Office staff member designated to review intellectual property, will guide the review and negotiation process. In the interest of efficiency, delegation of responsibility and accountability to the Research Support Service Office would be such that they should have the authority to sign contracts for the Board of Regents. In any of the dealings with corporate sponsors there may be faculty who wish to lead these negotiations, and if so, the Research Support Service Manager will work with them to facilitate and expedite this process.

• Proposed Short-Term Plan

The Research Support Service Manager, functioning on behalf of the PI and with the Research Support Service Office legal and financial assistance as needed, will lead the negotiations and keep the site-based ORTTA representative apprised of these. Upon reaching closure, the site-based ORTTA representative will review (with <4 hr turnaround) the contract. If acceptable, the ORTTA representative will sign the proposal, indicating the University's acceptance of the agreement and that the interests of the University and the faculty member will be protected.

Experience suggests that there may be a variety of questions that arise when a contract is reviewed by ORTTA. Ideally, associated with the new process envisioned, most of the kinds of issues that ORTTA has been concerned with in the past would already have been resolved. Notwithstanding these good intentions however, there may be issues that need to be resolved with the sponsoring organization. Over time, continual fine tuning should reduce this time to a minimum.

In the current system, the Conflict Review Committee reviews "batches" of contracts and grants, and then sends these same "batches" on to Sponsored Projects Administration for approval. Given the nature of this work flow, it has added to the backlog at Sponsored Projects Administration. Some contracts are managed in a more expeditious manner than others. In the new system, as a general operating principal, we recommend that verbal or electronic contact with sponsors occur within 24 hours of receipt of the contract. For any changes that must occur we recommend that a university official must contact a sponsor within 24 hours of a need to execute some modification or negotiation, and to do so in an iterative fashion if needed.

In all cases, the PI's signature on a contract indicates the faculty member's awareness and acceptance of the terms of the agreement and a willingness to abide by the same.

3.2.5 Protection of Human Subjects

The Research Support Service Office will be responsible for assisting and supporting faculty members so that they can, as best as possible, follow regulations which govern research involving human subjects. The support and assistance provided by the Research Support Service Manager will allow the PI to develop the best planned and developed materials for the IRB; the better the preparation the greater the likelihood that investigators will get IRB approval for their protocols as expeditiously as possible. The Research Support Service Manager will review and develop human subject research plans with PIs and their associates, provide information, and support faculty and their associate investigators as they prepare applications and consent forms.

Research Support Service Managers will be responsible for knowing human subjects research regulations, and for assuring, to the greatest degree possible, principal investigator compliance with regulations through all the steps of the project approval phase.

3.2.51 Protocol Review

The PI and Research Support Service Manager will review the protocol to discuss the overall management of the study and to determine whether or not the study would qualify for an expedited review (almost none will). Through this discussion, the Research Support Service Manager can assist the PI in identifying issues critical to managing the project with the highest regard for each subject's safety, confidentiality, and right to be completely informed before deciding whether or not to participate in the research study. This process will provide answers to questions the Research Support Service Manager will answer as he/she completes, or assists the faculty member in completing, the human subjects application form. Among other things, the Research Support Service Manager will address these types of issues:

• Roles and Responsibilities of Principal and Associate Investigators

• Identification and Recruitment of Subjects

The Research Support Service Manager and PI will discuss the method by which potential subjects will be identified. The Research Support Service Manager will be responsible for developing an alternative method that will be acceptable to the IRB if, in the judgment of the Research Support Service Manager, the PI's approach appears one that might prove unacceptable to the IRB.

• Vulnerable Populations

As the protocol is reviewed, the Research Support Service Manager will identify any vulnerable populations that the study may involve. The Research Support Service Manager and PI will discuss the regulations that apply to studies involving a vulnerable population(s). Together, the PI and the Research Support Service Manager will apply the tests IRBs must use to approve research in a vulnerable population. This process will improve the faculty/research investigator's understanding of the IRB guidelines and processes, improve the quality of the application, and assure the IRB that the PI has made the necessary special considerations required. Documentation that a clinical investigator has considered, answered, and justified (where necessary), the questions IRBs must ask regarding the recruitment of vulnerable subjects will raise the level of awareness, knowledge and compliance with these requirements throughout the entire research process.

• Financial Considerations

The Research Support Service Manager and PI will discuss plans for paying incentives to research participants. Together, decisions can be made about the appropriateness of payment, the "approvability" of the amount, the plan for payment, and how a subject who is terminated from the study before completion will be compensated.

• Assessment of Risks and Benefits from Participating in a Study

The PI and Research Support Service Manager will assess the potential benefits and risks to subjects participating in the trial. Proposing research in vulnerable populations requires particular attention to this issue. Determination and an accurate description of the alternative treatment the subject could receive (if any) will be made at this step. Assessing the benefits and risks for subjects participating in the study must be reviewed in the context of the subject's general condition. Principal investigators will be encouraged to objectively consider the patient's assessment or recognition of risks.

• Plan for Managing Emergencies

After considering the potential risks to study subjects, the PI and Research Support Service Manager will develop a plan for dealing with emergencies that may occur. This will include describing the roles of the members of study team in an emergency, and what other treatments will be available in the case of emergency.

• Confidentiality and Records Retention

The Research Support Service Manager will be responsible for determining the most appropriate plan for maintaining confidentiality of study records. The Research Support Service Manager will be responsible for consulting the PI and informing him/her about the importance of adhering to the plan for maintaining confidentiality. The Research Support Service Manager will be responsible for informing the PI about federal records retention requirements for IRB documents and communications. In order to facilitate this, the Research Support Service Manager will assist the PI and/or his/her staff in developing a master plan for records retention.

• Consent Process

The PI and Research Support Service Manager will determine the process by which informed consent will be obtained. The Research Support Service Manager will assume responsibility for developing a consent process that will assure that no subject is enrolled without an approved member of the study team participating in the process of obtaining informed consent with the potential subject. During this process, the research protocol will be explained to the subject, the subject will be allowed to ask questions and receive answers, the study team member will ask questions of the subject to assess his/her understanding of this, and given full understanding on the part of the patient the consent form will be signed if the potential subject agrees to participate. The PI will be informed and educated about the importance of obtaining consent before any study related procedures are performed, allowing the potential subject time to consider what is being asked of him/her, using language the potential subject can understand, and taking time to consider each individual in precisely the manner in which he/she would hope a parent, spouse, or child of his/her own might be regarded.

• Consent Form

The PI and Research Support Service Manager will discuss the sections of the consent form not previously addressed. The PI will be informed of the importance of assuring none other than the most currently approved version of the consent form is used when recruiting subjects. A consent form log will be given to each PI for the purpose of recording each subject, the version of the consent form signed and the date consent was (or was not) obtained. Research regulated by the FDA must have complete and accurate records about consent forms for subjects who agree to sign, and also for potential subjects who decline the invitation to participate.

3.2.52 Preparation of Human Subjects Application and the Consent Form

The Research Support Service Manager will prepare the application and draft the consent form. The PI/co-investigator/sub-investigator will review and approve the application and the consent form before it is submitted to the IRB. The Research Support Service Manager and the PI will have thoroughly discussed the research and will have addressed the questions that it is well known the IRB must ask. The Research Support Service Manager will complete these tasks, but will do so only after thorough consultation with the PI. Throughout this process, the Research Support Service Manager is working on behalf, not in lieu, of the PI. It is common for the sponsors of industry supported research to request their own review of the proposed consent form prior to submitting the application and consent form to the IRB.

• Review and Approval Prior to Submission to the IRB

The PI/co-investigator/sub-investigator must all sign the human subjects application form before it is submitted to the IRB. Their signatures indicate agreement with the information in the application, a pledge to make no changes without first informing the IRB (except in life-threatening circumstances), and a promise to follow the plan for the research outlined in the application form. This means, for instance, enrolling no more subjects than the application indicates will be enrolled, drawing no extra blood or other fluid samples than those indicated in the application, and assuring the consent process outlined in the application is followed. The Research Support Service Manager will certify that no other application for the project has been submitted to the IRB, and that all items the IRB will check during its "triage" process are addressed and included in the application.

3.2.53 Protection of Human Subjects Application Review Process

Human subjects applications and consent forms prepared by the Research Support Service Office will be approved by the IRB within 10 working days of receiving the completed application. The Research Support Service Manager will be informed of the IRB committee meeting date and whether the faculty member/research investigator might be needed to answer questions via some telecommunications method such as video conferencing. The Research Support Service Manager will assist the faculty member in preparing his/her response.

3.2.54 Management of Protocol Changes

Changes to industry-sponsored protocols must be approved by the FDA prior to being distributed to the clinical sites involved in the trial. These changes come in the form of what is termed "protocol amendments" from industry sponsors. These protocol amendments cannot be implemented prior to review and approval by the IRB. When the PI receives a protocol amendment, it will be given to the Research Support Service Manager as quickly as possible. (Ideally, they would be notified contemporaneously.) The Research Support Service Manager will review the amendment in the same manner in which the original protocol was reviewed. In conjunction with the PI, the Research Support Service Manager will determine whether or not the protocol amendment involves any change in the risk to study subjects. The changes will be listed and addressed in a letter to the IRB. If the consent form requires changes as a result of the amendment, these will be made by the Research Support Service Manager and a proposed new version of the consent form will be sent to the IRB Committee for review and approval. Any protocol amendments, changes, or corrections will also be reviewed and approved within 10 working days following the IRB Committee's receipt of the information.

3.2.55 Reporting Serious Adverse Events (SAEs)

• Local Site

The Research Support Service Manager will discuss with each PI the protocol specific requirements for reporting serious adverse events to the sponsor of the study and to the IRB. The FDA has defined a list of events as "serious", however, due to the nature of some protocols and subject populations, the definitions listed in each protocol should always be reviewed for what represents a serious adverse event in the given study. Prior to beginning the clinical trial, the Research Support Service Manager and PI will discuss assessing the causality of any adverse events, and how to assess the relationship of the test article to the event. If a serious adverse event occurs, the PI will report the event to the Research Support Service Manager as quickly as possible after learning of the event. A report (usually a sponsor form) will be completed by the PI and/or a study nurse and faxed to the sponsor within 24 hours of learning of the event. This report will then be given to the Research Support Service Manager so that the essential facts known at that time can be included in a notification letter to the IRB. The Research Support Service Manager will prepare this notification letter within 24 hours of receiving the information from the PI or members of their team. If more information becomes available regarding resolution of the event, the PI will provide this information to the Research Support Service Manager for notification of the IRB. There will be instances in which the IRB will ask for more information. There will also be instances in which a change to the consent form may be required resulting from the occurrence of an adverse event for which a specific risk is not already listed. The Research Support Service Manager will discuss this possibility with the PI. If a change is required, the Research Support Service Manager will modify the consent form and send the proposed revised version to the IRB with the serious adverse event notification letter.

• Other Sites

Industry sponsors of multicenter clinical trials are required to report serious adverse events (SAEs) experienced in a clinical trial at one center to all participating centers. (Many sponsors refer to the notification letters as "IND letters".) Investigators at each center are required to consider each event that may occur at any participating center and to report it to the IRB at their own institution. The IRB will consider whether or not the local consent form must be changed based on the SAEs reported at other centers. The Research Support Service Manager will review the IND letters, organize the information for the PI, and prepare an IRB notification letter (and revised consent form, if necessary). These sponsor IND letters will be batched and submitted to the IRB no less often than quarterly. The sponsor may require a more frequent than quarterly submission of the information to the IRB.

3.2.56 Retention of Records

The Research Support Service Manager and PI will discuss the requirements for records retention related to IRB documents and correspondence. The FDA requires that all correspondence between the IRB and the PI be retained in chronological order. In addition, the complete original application, protocol, Investigational Drug Brochure (IDB), and all approved consent form versions must be retained. Each subject's consent form bearing the original signature must be retained by the PI. All of these documents are subject to review by the sponsor and by the FDA.

3.2.6 Protection of Animal Subjects

The Research Support Service Office will be responsible for supporting research investigators so that they are guided in how to effectively follow regulations that govern research involving animal subjects. The Research Support Service Manager will review and develop animal subject research plans with PIs, provide information, and support PIs and their staff as they prepare the University of Minnesota Animal Usage Form .

Research Support Service Managers will be responsible for knowing animal care and use regulations, and to the degree possible, for assuring PI compliance with various regulations in the project approval phase.

The Institutional Animal Care and Use Committee (IACUC) is guided by the following principles in making determinations about the acceptability of animal use applications:

U.S. Government Principles

• The transportation, care, and use of animals should be in accordance with the Animal Welfare Act (7 U.S.C. 2131 et seq.) and other applicable federal laws, guidelines and policies.
• Procedures involving animals should be designed and performed with due consideration of their relevance to human or animal health, the advancement of knowledge, or the good of society.
• The animals selected for procedures should be of an appropriate species and quality, and the minimum number required to obtain valid results. Alternatives such as mathematical models, computer simulation, and in vitro biological systems should be considered.
• Proper use of animals, including the avoidance or minimization of discomfort, distress, and pain is imperative when consistent with sound scientific practices. Unless the contrary is necessitated, research investigators should consider that procedures causing pain or distress in human beings may cause pain or distress in other animals.
• Procedures with animals that may cause more than momentary or slight pain or distress should be performed with appropriate sedation, analgesia, or anesthesia. Surgery, or other painful procedures, should not be performed on unanesthetized animals paralyzed by chemical agents.
• Animals that would otherwise suffer severe or chronic pain or distress that cannot be relieved, should be painlessly euthanized at the end of the procedure or, if appropriate, during the procedure.
• The living conditions of animal should be appropriate for their species and contribute to their health and comfort. Normally, the housing, feeding, and care of all animals used for biomedical purposes must be directed by a veterinarian or other scientist trained and experienced in the proper care, handling, and use of that species. In any case, veterinary care must be provided as indicated.
• PIs and other personnel shall be appropriately qualified and experienced in the proper care, handling, and use of the species being maintained or studied. In any case, veterinary care must be provided as indicated.
• Where exceptions are required in relation to the provisions of these principles, the decision should not rest with the research investigator directly concerned but should be made, with due regard to Principle 2, by an appropriate review group such as an institutional animal research committee. Such exception should not be made solely for the purposes of teaching or demonstration.

Research Support Service Managers will be responsible for knowing animal subjects research regulations, and for assuring to the greatest degree possible investigator compliance with regulations through all the steps of the project approval phase.

3.2.61 Protocol Review

The PI and Research Support Service Manager will review the protocol to discuss the overall management of the study. Through this discussion, the Research Support Service Manager can assist the PI in identifying issues critical to managing the project with the highest regard for compliance with regulations governing the care and use of animals in research. This process will provide answers to questions the Research Support Service Manager will ask as he/she completes, or assists the researcher in completing, the University of Minnesota Animal Usage form. The Research Support Service Manager will address these issues:

• Experiments Which May Produce Pain or Distress

Pain is defined as the sensation resulting from a stimulus which (1) would be perceived as painful by people, (2) produces escape behavior in animals, or (3) approaches or exceeds tissue damaging proportions.1 Distress is defined as any disruption of physiologic equilibrium manifested by abnormal or maladaptive behavior.2 The Research Support Service Manager will assist the PI in identifying procedures which may produce significant pain or distress, including but not limited to: survival surgery, experimental induction of disease, testing procedures, sampling procedures, use of adjuvants, dietary or environmental manipulation, physical trauma, or restraint. If any of these procedures are to be used in the proposed research project, the Research Support Service Manager will assist the PI in writing a justification to indicate the alternative approaches that were considered, and how pain and distress will be alleviated.

• Euthanasia

The Research Support Service Manager will assist the PI in identifying the/an acceptable method for euthanizing laboratory animals. The University of Minnesota has adopted a chart of acceptable methods.

• Experiments Involving Nonsurvival Surgery

The Research Support Service Manager will assist the PI and their staff in completing the required documentation for these experiments. This documentation includes: a description of the surgical procedure, the location of surgery, the personnel responsible, anesthetic and other drugs that would be used, and the method of euthanasia.

• Experiments Involving Survival Surgery

The Research Support Service Manager will assist the PI and their staff in completing the required documentation for these experiments. This documentation includes: a description of the surgical procedure, the surgeon's name and qualifications, the building and room number where the surgery will be performed, provisions for post-surgical care, generic names of all anesthetics, analgesics, tranquilizers or other drugs used during surgery or post-operatively, including dosage, route of administration and persons responsible for their administration. The Research Support Service Manager will assure that the PI provides justification for any distress or functional deficit that may result in animals from the surgery and that he/she will describe how the distress will be alleviated.

• Dietary Manipulation

Nutritional distress is defined as a level of malnutrition that significantly interferes with the normal physiology and behavior of the animal. Nutritional distress may occur as a result of feeding nutritionally unbalanced, physically unfamiliar, inappropriate or unpalatable food. If significant nutritional distress may be induced by the proposed research, the Research Support Service Manager will assure that the PI provides a description of the methods, a justification of the rationale and a description of the way in which each animal will be monitored and evaluated.

• Environmental Stress

If the study requires that environmental conditions vary from those proscribed by the NIH Guide, the Research Support Service Manager will assist the PI in providing a description of the conditions, the rationale for this, the proposed duration of treatment and the methods of monitoring animals.

• Studies Involving Physical Restraint

The Research Support Service Manager will assist the PI in assuring that any research involving animal restraint is adequately justified. A course of action will be developed for any instance in which the restrained animal shows signs of distress (inappetence, abnormal behavior) or clinical abnormalities (e.g., decubitus ulcers, etc.).

• University Animal Usage Form Signature

The form must be signed by a member of the faculty and the Research Support Service Manager assisting with the application. The PI signing the form takes responsibility for all work done on the research protocol, and agrees to execute the work as described. The signature indicates that the PI agrees to execute the work as described; will request approval from the IACUC for any changes; will comply with the guidelines in the University Animal Care and Use Manual; will follow Environmental Health and Safety guidelines, and will be responsible for the work and supervision of staff. The signature of the PI further indicates that the proposed research activities described in the study do not unnecessarily duplicate previous experiments or the general working knowledge in the field, and that the use of animals described in the protocol matches the use of animals described in all grant applications covered by the protocol.

• Animal Certification Statement

The Research Support Service Manager will assure that the principal and associate investigators, as well as all personnel who will have animal contact, have completed an animal certification statement and filed it with the IACUC.

3.2.62 Protection of Animal Subjects Application Review Process

It is recommended that animal usage applications prepared by the PI working with the Research Support Service Office be approved by the IACUC within 10 working days of receiving the completed application.

3.2.63 Management of Research Protocol Changes Using Animals

Changes to protocols cannot be implemented prior to review and approval by the IACUC. When the PI decides to amend a protocol, the Research Support Service Manager will be notified. The Research Support Service Manager will review the proposed amendment in the same manner the original protocol was reviewed. In association with the PI, the Research Support Service Manager will determine whether or not the protocol amendment involves any change to the risks of pain, distress, etc. for animal subjects. The changes will be listed and addressed in a letter to the IACUC. It is recommended that protocol amendments/changes/corrections will also be reviewed and approved within 10 working days following the Committee's receipt of the information.

1Kitchell RL, Erickson H, Carstens E, and Davis LE, editors, Animal Pain: Perception and Alleviation, Am. Physiol. Soc., 1983, Williams and Wilkins, Baltimore.

2ILAR News, Fall 1991; Committee on Pain and Distress in Laboratory Animals, Institute of Laboratory Animal Resources, National Research Council, National Academy of Sciences.

3.2.7 Biohazards and Other Health and Safety Compliance

The Research Support Service Office will be responsible for assuring, to the greatest degree possible, research investigator compliance with any biohazard and/or other environmental health and safety compliance regulations the proposed research may be required to follow. The Research Support Service Manager will assist the investigator in obtaining any approvals required and for documenting the approvals by other internal committees and/or departments.

3.2.71 Review of Potential Hazards

The Research Support Service Manager and research investigator will review the proposed research plan to identify the following hazards:

• Recombinant DNA, Biological Toxins, or Infectious Agents

If the proposed research involves any biological hazards, the Research Support Service Manager will provide the PI with the appropriate application forms, assist in completing the forms, and consult as necessary with the Biosafety Officer to develop an appropriate plan to procure, store, handle, administer, and dispose of the agent.

• Radiation

If the proposed research involves radiation, the Research Support Service Manager will provide the research investigator with the appropriate application form, assist in completing the form, and consult as necessary with the University's Radiation Officer.

If the proposed research is a clinical trial involving radiation exposure, the Research Support Service Manager will assist the research investigator in applying to the Health Sciences Radiation Committee.

• Highly Toxic, Flammable, or Reactive Chemicals

To our knowledge, there is currently no institutional committee in place to review the use of hazardous chemicals in research.

• Known or Suspected Carcinogens

To our knowledge, there is currently no institutional committee charged to review the use of known or suspected carcinogens in research.

3.2.8 BA 23 and Account Assignment

The Research Support Service Office will be responsible for reviewing the research proposal and completing the BA 23 on behalf of the PI. Information needed to complete the form (including required approvals) will be obtained by the Research Support Service Manager. Issues for review will be identified, and supporting documentation will be provided to departments/units/centers as required to attempt to iron out any problems. The Research Support Service Manager will be available to attempt to resolve any questions raised prior to sending the proposal forward for any approvals.

3.2.81 Completing the BA 23

In working with and on behalf of the PI, the Research Support Service Manager will complete the BA 23. The Research Support Service Manager will determine, where appropriate, PI eligibility, the potential for DEHS hazardous materials issues that may need to be resolved, and the potential for conflict of interest. Issues of the space to perform the studies, credit to what department, equipment, and cost-sharing will all be identified by the Research Support Service Manager prior to routing the BA 23 for signature (if it continues as it currently has). This will be discussed with the PI so that they are cognizant of these issues. The budget and contract will have been approved by the PI and in the Research Support Service Office prior to routing the BA 23 for signature.

3.2.82 BA 23 Review and Approval

The BA 23 will be signed by the Research Support Service Manager and the PI. The BA 23 will then be routed for review and signature as required by each department/unit/center, if necessary. The PI will be responsible for informing the Research Support Service Manager of the review and approval signatures required by his or her department/unit/center. Alternatively, a data base will be established that provides this. This will be integrated with recommendations forthcoming from the Interdisciplinary Taskforce which is developing a model for assigning advisory and accountability functions between departments, programs, centers and institutes.

3.2.83 Responsibility Indicated by Approval Signatures

Research Support Service Manager: The Research Support Service Manager's signature on the BA 23 will indicate that all information on the form is true, complete, and accurate to the best of his/her knowledge.

Principle Investigator: The PI's signature on the BA 23 indicates that the information provided is correct and that equipment budgeted in the application is not otherwise available for use on the project from existing departmental or collegiate inventories. The PI indicates his/her agreement to abide by all applicable institutional and sponsoring agency policies and procedures (including the Patent and Technology transfer Policy of the University of Minnesota) and to follow commonly accepted scientific practices in recording and maintaining records of research.

Department head or other similarly designated head of a "unit": They will assume approval authority for on and off campus space, prorating department/institute/center credit, equipment requests, and cost sharing arrangements.

Dean: The dean will share approval authority for on and off campus space, and approval of requests for indirect cost waivers. Local oversight authority for prorating department credit, equipment requests, and cost sharing arrangements is indicated by the dean's signature.

Provost's Office: For certain grants and activities of interdisciplinary programs, centers and institutes the provost's office or a vice provost would take the place of a dean's signing. Also, a director of one of these centers, programs, or institutes might take the place of a department head.

3.2.84 Reporting the Project to Departments/Institutes/Centers

The PI will be responsible for informing the Research Support Service Manager of the project reporting requirements of his/her department. The Research Support Service Manager will send the department a copy of all study documents upon request.

3.2.85 CUFS Account Number Assignment

A CUFS number will be assigned to the account within 24 hours after the contract or research agreement is signed. The site-based ORTTA representative will assure the account number is provided to the PI, the department administrator, and the Research Support Service Manager within 24 hours.

3.2.9 Managing and Reporting Investigator and/or Protocol Changes

The Research Support Service Office will provide project management service to PIs. The Research Support Service Manager will manage changes with the local oversight committees or offices that require notification, review, or approval of changes to the research plan. The Research Support Service Manager will manage changes in the following areas:

3.2.91 Conflict of Interest

All investigators associated with a study will be reminded to report any changes within 30 days of the change in external financial relationships and/or time commitments. The Research Support Service Manager, in conjunction with the Research Support Service Office director and senior academic official in the Provost's Office, e.g., Dean or Vice Provost for Research, will assume responsibility for identifying changes that may require review of a current potential conflict of interest management plan. Changes that may require a potential conflict of interest management plan will also be identified and developed by the Research Support Service Manager.

3.2.92 Budget

Budgets may need to be reviewed and amended during the course of conducting sponsored research. Industry sponsors will often amend a protocol to add a test, or an overnight stay, or a study visit, without suggesting the budget be amended. The Research Support Service Manager will review all proposed amendments or changes that may or should affect the budget. The Research Support Service Manager will be responsible for re-writing the budget and obtaining approvals much as in the protocol approval phase.

3.2.93 Contract

A contract may need to be amended during the course of conducting sponsored research study. Some examples of these changes occur when the sponsor amends the protocol to extend the length of the study or increases the number of patients to be enrolled at a center. The Research Support Service Manager will assist the PI in proposing, reviewing and seeking approval of contract changes. The site-based ORTTA staff will also review any proposed changes to the contract to assure protection of the interests of the University and the investigator.

3.2.94 Biohazards

The Research Support Service Manager will assist PIs in identifying the proper course of action to take when a change is made in the use or management of a biohazard.

3.2.95 Human Subjects

The Research Support Service Manager and the PI will be responsible for assuring that the protocol is executed in exactly the manner reflected in the application and consent form. Whenever any change to the most currently approved version is proposed, it must be reported to the IRB. IRB approval is required prior to instituting the change (except in cases of responding to life-threatening circumstances - these can be reported after the fact).

• Changes in Protocol or Staff

Any time there is a change in the manner in which the protocol is executed, the IRB must be informed. Essentially any change made to the plan outlined in the original application to the IRB, and any subsequently approved change, must be reviewed and approved prior to implementation. The PI will be responsible for informing the Research Support Service Manager of any such changes proposed to be made. All changes in staff, particularly those responsible for making any study related assessments and/or individuals authorized to participate in the consent process, must be reported to the IRB.

• Serious Adverse Events (SAEs)

If a serious adverse event occurs, the PI will report the event to the Research Support Service Manager as quickly as possible after learning of the event but within no more than 24 hours. A report (usually a sponsor form) will be completed by the PI and/or a study nurse and faxed to the sponsor within 24 hours of learning of the event. This report will then be given to the Research Support Service Manager so that the essential facts known at that time can be included in a notification letter to the IRB. The Research Support Service Manager will prepare a notification letter within 24 hours of receiving the information from the research investigator. If more information becomes available regarding the resolution of the event, the PI will provide this information to the Research Support Service Manager, and the Research Support Service Manager will notify the IRB. There will be instances in which the IRB will ask for more information. There will also be instances in which a change to the consent form may be required by the occurrence of an adverse event for which a specific risk is not already listed. The Research Support Service Manager will discuss this possibility with the PI. If a change is required, the Research Support Service Manager will modify the consent form and send the proposed revised version to the IRB with the serious adverse event notification letter.

• Protocol Deviations

While every effort will be made to avoid these situations, there will be instances in which the protocol is not followed. There are some cases, however, in which the PI may receive approval from the sponsor to make an exception to the protocol. These instances must be fully documented. Should such a circumstance occur, the PI will inform the Research Support Service Manager as quickly as possible after it occurs. The Research Support Service Manager will collect information and then document the protocol exception/deviation in a letter to the sponsor (copied to the IRB). In this way, the PI and the University will have documentation of the circumstance and report in the event the study is selected for a quality assurance review by the sponsor or FDA review. Every effort will be made to keep protocol deviations and exceptions to a minimum. Although a research sponsor may approve a protocol deviation, the FDA will document all protocol deviations as deviations without regard to the fact that the sponsor may have granted approval for them.

• Consent Form and Consent Process Changes

As is the case with any changes to the IRB approved plan for implementing the protocol, changes to the consent process or the consent form must be reviewed and approved by the IRB prior to their implementation. The Research Support Service Manager will make any changes the PI proposes to make to the consent form and guide him/her in making the changes so that they are as "likely as possible to be approved" by the IRB. Changes to the process will be discussed with the PI and the IRB will be informed by way of a letter.

• Continuing Review of Approved Research

Once each year the IRB will request the PI to complete a form called Continuing Review of Approved Research. The Research Support Service Manager will complete this form for the PI's review and signature. If the PI has worked closely with the Research Support Service Office from the beginning of the project, the Research Support Service Manager will have most of the information required to complete the form. If the PI has not, this will be more problematic.

3.2.96 Animal Subjects

• Changes in Protocol

Any time there is a change in the manner in which the protocol is executed, the IACUC must be informed. Essentially any change made to the plan outlined in the original application to the IACUC, and any subsequently approved change, must be reviewed and approved prior to implementation. The PI will be responsible for informing the Research Support Service Manager of any such changes proposed to be made.

3.2.97 FDA 1572

Any changes made to staff listed on the FDA Form 1572 must be reported to the FDA on a new 1572 FDA form The Research Support Service Manager will be responsible for completing the new form, obtaining the relevant faculty member or research investigator's signatures, and sending it to the sponsor (with a copy to the IRB.)

3.2.98 Data Monitoring and Audits by Sponsor/CRO/FDA

A copy of the site visit reports filed by the sponsor/Contract Research Organization after each monitoring visit will be sent to the Research Support Service Manager. If there are problem areas indicated in which the PI or staff need more information in order to improve data collection or retention, the Research Support Service Manager will be responsible for providing such information and suggestions for improving their processes. If the study is chosen at any time for a sponsor quality assurance audit or an FDA audit, the Research Support Service Manager will be responsible for managing the audit with the PI and his/her staff.

3.2.10 Managing Research Funds

In conjunction with the PI and their staff, the Research Support Service Office will be responsible for oversight and managing project funds. The Research Support Service Manager will have assured, to the greatest degree possible, proper budget writing, contract negotiation and will also assume responsibility for the proper administration of the funds.

This will be completed in cooperation with the PI and the PI's department administrator where the grant is administered. It is expected that the Research Support Service Manager's involvement will vary slightly in working with departments across the AHC. The Research Support Service Manager will fulfill a role in administering the funds that may range from minimal review to extensive responsibility for the account in conjunction with the PI and their staff.

The critical review of financial information for industry-sponsored research is important for providing assurance that no fixed price contract is performed at an unexpected loss to the AHC. This review can be very difficult for staff to perform if they are unfamiliar with the project. The Research Support Service Office and Research Support Service Manager will be aware of the budget, the protocol requirements, the agreements/arrangements for internal services, and the payment schedule in the contract.

3.2.101 Approving Purchases

The Research Support Service Manager will review and provide approval recommendation of charges currently reviewed only by ORTTA (>$500). In the interim, the Research Support Service Manager will be responsible for getting or expediting approval of the expenditure from the site-based ORTTA person.

3.2.102 Monitor Contract Benchmarks and Payment Schedules

The Research Support Service Manager will monitor the progress of the study and assure that payments are being received in a timely manner for the sponsor according to the agreement with the sponsor. The Research Support Service Manager will negotiate with sponsors for any late payments.

3.2.103 Monitor Charges by ISO's and Other Internal Services

The Research Support Service Manager will review the charges assessed against the study account for any internal services. Experience suggests that it is easy to make errors - particularly when a study subject is admitted as a patient to the hospital. The Research Support Service Manager will likely be unable to review every charge - but will review at least some charges for all studies against which internal services may bill.

3.2.104 Report to Investigators and Departments

The Research Support Service Manager will provide a "usable" report of the financial status of the account once each month to the PI and their department or unit administrator.

3.2.105 Monitor Effort Certification for the Project

The Research Support Service Manager will work with the PI and the PI's department to assure the proper assignment of and billing of effort for the project. While the PI will retain approval authority on the project, the Research Support Service Manager will provide corrected information to the PI to assure that effort drives salary and that funds are available to pay for personnel.

3.2.11 Study Close Out

The Research Support Service Office will be responsible for reviewing regulatory documents for the final study record. The Research Support Service Manager will write the final report to the IRB for the faculty/research investigator's review and signature.

The Research Support Service Office will be responsible for final financial review of the research study account. This final review will include: review of the contract terms, the performance, and the payments received, total expenses, shortfalls or funds left above expenses. The Research Support Service Office will provide a final financial report to the faculty researcher and to the PI's department or other appropriate administrative unit. After the report is accepted by the PI and his/her department, the account will be closed by the site-based ORTTA representative.

3.2.111 Regulatory Documents Review

The Research Support Service Manager will provide the PI with a checklist of all the regulatory documents which must be retained at the end of the study. A final review by the sponsor/CRO will be reviewed by the Research Support Service Manager and s/he will provide any assistance which may be required to obtain/provide any outstanding documents that the PI, their staff or others within the institution may have.

3.2.112 Final Report to the IRB Study sponsors require a final report be filed with the clinical site's IRB. The essential elements of the report vary from sponsor to sponsor. The Research Support Service Manager will be responsible for writing the final report for the PI's review and approval. The original report is sent to the IRB and a copy is sent to the sponsor/Contract Research Organization.

3.2.113 Final Report to the Sponsor

The Research Support Service Office will provide assistance to PIs in writing the final research reports for the sponsors.

3.2.114 Review of Final Account Status and Contract Terms

The Research Support Service Manager will review the final account status. Payment terms will be reviewed and any deviations noted. Any expenses not covered by the contract will be documented and sent to the sponsor for collection (i.e. subjects screened but not enrolled). The Research Support Service Office will assure that all funds due the University are collected or take steps to accomplish this.

3.2.115 Closing the Account

After it is certain that all funds have been collected and all bills paid, the Research Support Service Manager, in cooperation with the PI, the investigator's department or unit, and the site-based ORTTA representative, will close the study account. There are a variety of things that might be done with any balance of funds remaining after the completion of a study. These could be, for example, deposited in the faculty members discretionary fund or as determined by prior arrangement with their department or unit or distributed as indicated in the initial agreement with the Research Support Service Office.

3.2.116 Final Report to the Department

A final financial report will be provided to the research investigator and if applicable, to the department, center, or institute. This same report will be used to document the fund close-out request made to the site-based ORTTA representative.

3.3 Business Development Office

3.3.1 Introduction

Corporate sponsorship is one of many funding sources that faculty may use to support their research. In contrast to applications for competitive funds, pursuit of corporate support is somewhat more complex, inefficient and in the opinion of many, is in need of optimization within the AHC. That is, generally, individual faculty take it upon themselves to seek out corporate partners and the AHC corporate research program is what these faculty make of it. It appears that insufficient resources have been allocated to develop this very important area. The result of this situation is that: