Clinical Trials Administrative Start-Up Handbook

SECTION 1

Confidentiality Agreements

Usually a sponsor considers the study protocol, the "Investigator's Notebook," and other similar non-public information to be confidential and will not share this information with prospective investigators unless a confidentiality agreement is signed.

A signed confidentiality agreement allows you to evaluate the protocol, then to decide whether you are interested in conducting the study at the UW. The terms of the agreement assure the sponsor that its confidential information is protected from unauthorized disclosure for a specified period.

General advice about handling confidentiality agreements can be found in this section under Best Practices for Handling the Confidentiality Agreement. If you need advice about a specific confidentiality agreement, contact Karl Neumann (685-7117) or Adina Robinson (685-7119), at the Office of Sponsored Programs (OSP).

Best Practices for Handling the Confidentiality Agreement

When a sponsor first approaches you about a new clinical trial, ask whether the sponsor intends to require a confidentiality agreement.

If the sponsor intends to require a confidentiality agreement that names the UW as a party to the agreement, encourage the sponsor to accept the standard UW pre-approved "Pre-Clinical Trial Nondisclosure Agreement." Emphasize to the sponsor that this will minimize turn-around time and that the UW standard agreement contains typical provisions for the protection of both parties. Give the sponsor a copy of the standard UW agreement and follow these steps:

• Ask the sponsor to complete the "Protocol" section on page three of the agreement, sign the agreement, and return it to you. Note that the terms of this standard UW agreement cannot be changed in any way. If changed, the agreement must be negotiated and signed by OSP.
  
  
• Print your name and title, then date the agreement and sign on page three. Send or fax the agreement to your department chair (or division head, as appropriate), who has been authorized by memorandum to sign this standard agreement for the UW.
  
  
• Make three copies of the signed, executed agreement. Deliver the original to the sponsor, keep one copy for your files, send one copy to Ari Santander, Office of Technology Licensing, Box 354810, and send one copy to Michael Corn, Dean's Office, School of Medicine, Box 356340.
  
  

If the sponsor requires a confidentiality agreement that names the UW as a party to the agreement but declines to use the standard UW pre-approved agreement, you and the sponsor have two choices:

• Ask the sponsor to mail or fax its own standard agreement to you. Then, send the sponsor's agreement for institutional review, negotiation, and signature to Karl Neumann (PH: 685-7117; FAX: 685-1732) or Adina Robinson (PH: 685-7119; FAX: 685-1732) at the Office of Sponsored Programs, Box 355754, or
  
  
• Sign the sponsor's agreement only on your own behalf, making it very clear to the sponsor that you are not authorized to sign any agreements on behalf of the UW. Sign on your own behalf only if you feel that there is a strong reason to conclude an agreement on-the-spot and do so only after you have crossed out all references in the agreement to the UW, substituting your own name instead. Note the potential pitfalls discussed in the paragraph below, and remember that by signing such an agreement on your own behalf, you may incur unacceptable personal liabilities.
  
  
Usually confidentiality agreements are straightforward; however, there are some potential pitfalls. For example, the agreement may be overly broad, going beyond the purpose of protecting against disclosure the sponsor's protocol and other confidential information. An overly broad confidentiality agreement may extend into matters such as requiring confidentiality of the trial results or restricting your freedom to publish them, may require that you disclose your own confidential information to the sponsor, or may bind you for an excessive period of time. Such provisions may also be inconsistent with the UW's policies and may expose you to legal risks contrary to your best interests. If you see such provisions in the sponsor's proposed confidentiality agreement, you should either decline to sign the agreement or you should revise or delete the provisions and then require that your revisions/deletions be initialed by the sponsor's authorized representative.

Is your trial feasible?

Using the feasibility tool:  In determining whether a particular protocol is feasible, researchers need to assess many factors.  For example, Is the protocol well designed?  Is the workload manageable?  Are the sponsor's timelines reasonable?  As you weigh your interest in the trial, you may wish to use the Protocol Feasibility Checklist to guide your thinking.

Investigators planning to use Harborview Medical Center (HMC) facilities must complete and return to the HMC Compliance Office a "Faculty Notice of Intent to Initiate Research or New Clinic-Based Services." Note that this form is required, and HMC reserves the right to decline authorization of your study if it negatively impacts HMC's resources or clinic operations.

Using medical records

Many clinical trials fail because of inadequate subject enrollment, so it is essential to know whether the available patient population is large enough to support your enrollment goals. One way to make this assessment is to review patient medical records. Under the Health Insurance Portability and Accountability Act (HIPAA), patients’ medical records are Protected Health Information (PHI), and the records cannot be used for research purposes - including feasibility studies - without patients’ authorization to do so. However, researchers may apply to the Human Subjects Review Committee for a waiver of authorization.

• To obtain a waiver of authorization, complete and submit the Human Subjects Medical Records Review Form (under "Commonly Used Forms") along with a Confidentiality Agreement (hit "browse all," then select the Confidentiality Agreement). The Human Subjects Review Committee will use these documents to determine whether to approve your request for a waiver. The Committee’s decision will be based on criteria available on the Human Subjects Division’s HIPAA Compliance page (to view the criteria, scroll down to “What will researchers have to do to request a waiver of authorization?" ) Although approved waivers allow access to PHI, the waivers do not necessarily allow contact with prospective subjects. Below are listed the three categories of HIPAA-protected health information. Each of the three listings includes a brief definition, states how this category of information might be useful in your feasibility assessment, and explains how to request access to the information.

  Individually identifiable health information
  Limited Data Set
  De-identified Data  

Financial Planning

Indirect Costs - Does your project qualify as a "clinical trial?"

For industry-sponsored, fixed price, clinical trials the University of Washington indirect cost rate is a non-negotiable 25% of total direct costs (TDC). Studies eligible for this indirect cost rate are limited to those that fit the following definition:

A study designed to assess the safety and/or efficacy of drugs, devices, diagnostics, treatments, or preventive measures in humans.

Whether your industry-sponsored project qualifies as a clinical trial (rather than, for example, as a clinical study) is an important question that needs attention before you talk - even in general terms - to the sponsor about the budget. Failure to consider this question early in the process can result later in stalled budget negotiations or, possibly, in inadequate funding for your project because industry-sponsored clinical studies that do not meet this definition will carry the full indirect cost rate..

If you have questions about whether your study fits this qualifying definition, please contact the Clinical Research Budget and Billing (CRBB) office at 206-598-9490.

The Clinical Research Budget and Billing Office (CRBB)

At the beginning, an industry sponsor may ask you to develop a budget for their review, or the sponsor may quote an amount allocated to each site and ask you to work within it. In the latter case, the quoted amount may be adequate – or even generous – but this is not usually the case. Without an accurately prepared and skillfully negotiated budget, you may easily lose money on a clinical trial. Therefore, time spent on budget development is time well spent. Remember that the process of arriving at the final budget is usually one of negotiation. Almost always you will be able to reach a reasonable compromise, but occasionally it may be necessary to turn down a study because of an inadequate budget offer. 

Fortunately, assistance is available for the complicated tasks of preparing and negotiating budgets.  The Clinical Research Budget and Billing Office (CRBB) was established as a resource for investigators and staff, who are required - by the policy described below - to meet the responsibilities it imposes.

Why CRBB was created: 

Effective April 25, 2005 (Rev. 11/1/06), UW Medicine issued a Billing Compliance in Clinical Research policy.  The policy is central to financial planning for your clinical study. Its purpose is to establish uniform requirements for how UW Medicine and the Seattle Cancer Care Alliance will bill for professional and technical services provided as part of UW Medicine-based clinical research. The policy is structured to provide uniform guidance - regardless of the study’s funding source – for investigators at:

• Harborview Medical Center (HMC)
• University of Washington Medical Center (UWMC)
• Seattle Cancer Care Alliance (SCCA)
• Children’s Hospital and Regional Medical Center (CHRMC)

and for researchers covered by the following practice plans:

• University of Washington Physicians (UWP)
• Children’s University Medical Group (CUMG)

Although the policy is aimed primarily at clinical research billing compliance, its impact goes beyond billing into such areas as budgeting, AAA study registration, and record keeping. By reading this far-reaching policy, you will understand both what you need to do in order to comply with it and where to get help in order to meet the responsibilities it imposes.

How CRBB is organized:

To help you create a financial plan that complies with the billing policy, staff at the Clinical Research Budget and Billing Support Office (CRBB) are available for hands-on assistance and other advice, including training, budget development tools, and a strategy for successful ongoing financial management that is consistent across sites of practice. CRBB will also help to ensure that your financial plan is coordinated with other review offices and that it is reflected in the sponsor’s contract and the informed consent form.  CRBB’s stated goal is to help UW clinical researchers create a financial plan that delivers the right bill for the right amount to the right payor at the right time.

For help in determining the role that CRBB needs to play in your study, please refer to the decision tree.  In practice, the decision tree means:

• If your study is an industry-sponsored clinical trial, you are required to use the CRBB Detail Budget Tool and to follow the steps outlined in the CRBB Industry Checklist.  The CRBB Detail Budget Tool will help you to arrive at a realistic and defensible budget that will ease negotiations with study sponsors. The gains in efficiency offered by this automated budget tool should give you more time to focus on your actual research.
• If your study is not funded by industry, you are not required to use the CRBB Detail Budget Tool.  However, you must follow the steps outlined in CRBB's Non-Industry Checklist.

For a graphical display of services offered by the CRBB Office, consult these charts:

• Clinical Research Pre-Award Process (Budget Development) chart
• Clinical Research Billing Verification Process chart

Sponsor payment schedules are part of your study's financial plan. Although the sponsor may propose a payment schedule as part of their standard contract, you may wish instead to propose a payment schedule of your own. Negotiating a comfortable payment schedule is essential, both for determining whether the trial is financially feasible and for determining whether you stay ahead of expenditures or encounter case flow problems.  Advice about payment schedules is available both from CRBB (regardless of whether you use their Budget Tool) and under Best Practices for Developing a Payment Schedule.

Best Practices for working with CRBB:

In general:

• Refer to the decision tree to determine whether you are required to use the CRBB Detail Budget Tool for your study. Best practice (by far) is the use the Tool, even if not required to do so.

When building your budget:

• Determine whether it is financially feasible to conduct the study. You will need to review the protocol, develop a preliminary budget estimate, then compare the estimate with the sponsor’s initial offer. (The CRBB Office staff (206) 598-9490 can help you with this process, even if you do not use the Tool.)
  
• When reviewing the study protocol, use the "Budgets" section of the Protocol Feasibility Checklist to guide your thinking. The Checklist contains practical questions for assessing adequacy of the proposed budget, e.g., will the sponsor pay start-up costs, will the sponsor pay for an adequate number of screen failures?  Other items on the Checklist, although not directly related to the trial’s budget, may have financial implications, e.g., extra staff time may be required for dealing with unusually complex case report forms or for handling vulnerable subjects with special needs.
  
• Either attend the investigator’s meeting hosted by the sponsor or call the sponsor with specific questions. Be sure that you understand exactly what is required at each subject visit – this is not always clearly explained in the protocol.
  
• Make a complete list of all the required procedures, tests, patient visits, examinations, etc. (This task will be vastly simplified if you use the CRBB Detail Budget Tool.) Compare your list to the sponsor’s flowsheet or “Schedule of Events.” Note any discrepancies between your list and the sponsor’s – it is unlikely that they will be a perfect match. Use your list (not the sponsor’s list) to guide your thinking as you develop the budget and financial plan.
  
• If you are planning an investigational device study, look for information in the protocol designating the device as either a “Category A” or a “Category B” device. These categories are FDA designations with important budget implications. For a discussion of budget implications and more information about investigational device studies, see Implant and Investigational Device Review.
  
• Remember to plan for price increases at the beginning of each fiscal year. The fiscal year is from July 1 through June 30. Annual price increases for some procedures are expected to be about 5%.
  
• Remember to send to CRBB all required information about your study before beginning budget negotiations with the industry sponsor.  (Consult the CRBB Industry Checklist or the CRBB Non-Industry Checklist to determine what information is required by CRBB.)  CRBB needs to review and verify your work. Without first verifying your budget with CRBB, you risk the possibility of needing later to re-open budget negotiations that the sponsor had considered to be closed.
  
• As you select the services required for your study, go to Section 2 of the Handbook and read the relevant information about that service center. By reading this information, you will avoid mistakes and save time. Throughout your study, maintain connections with the service center key contact people so that you can discuss issues such as subject enrollment, timing of procedures, and protocol changes.

When negotiating your budget:

• When CRBB returns to you the completed, verified study information (such as CRBB Detail Budget Tool, the AAA Packet or the Billing Grid), you are then ready to negotiate your budget and payment schedule with the industry sponsor. Think about how you want to conduct budget negotiations. You may choose to negotiate independently with the sponsor, to discuss negotiation tips with CRBB prior to independent negotiation, to request CRBB help in the negotiations, or to request that CRBB conduct the negotiation for you. CRBB offers this help, even if you have not used the Detail Budget Tool.
  
• If you do not ask CRBB to conduct the budget negotiations for you, notify CRBB when you have reached agreement with the industry sponsor. CRBB will then sign off on the study so that it can move forward for approval in the School of Medicine.
  
• Remember that if your financial plan or your service requirements change during negotiations with the sponsor, the plan will need to be re-approved by CRBB.

 

When sending your eGC-1 package for review:

• Consult Section 3. of the Handbook for information about the review process necessary for transmittal of your study materials through the School of Medicine to the Office of Sponsored Programs (OSP). When they receive the materials, OSP will negotiate the terms and conditions of the clinical trial agreement (not the budget or payment schedule) with the sponsor. OSP will notify you via email message when they have signed the clinical trial agreement with the industry sponsor.
  
• Request an advance budget number for your study. Read about UW budget numbers and keep in mind that you will not be able to register your study at UWMC or HMC until you receive a UW budget number.
  
• Send your UW budget number to CRBB. Bills will not drop into your study’s account until CRBB receives the budget number and activates the research account.
  
  
  

Requesting a Budget Number

You'll need a budget number in order to use your study account. Budget numbers are assigned by Grant and Contract Accounting (GCA), upon authorization from the Office of Sponsored Programs (OSP).

When OSP receives the sponsor's first check, OSP will match the check with your signed research contract and send a "Notice To Establish Account" (NEA) to GCA. GCA will then establish the account and send you an email message notifying you of the assigned budget number, which you can then report to CRBB, enabling CRBB to activate your account.   You are then free to begin using the account.

If you want to receive your budget number prior to the receipt of the sponsor's first check, or even before the clinical trial agreement has been signed, you may request an "advance" budget number. To request an advance budget number, enter SAGE. At the top of the page, select the "My Advance Requests" tab. Then, you can either take the tutorial entitled "How to Request a New Advance Budget Number" or you can go directly to the "Create Advance Request" tab. By completing the data fields at that tab, you will be able to access both your study record and the actual request form. Complete the request form, route a paper copy of it for departmental signatures, then send it to GCA. GCA will send you an email message notifying you of the assigned budget number, which you can then report to CRBB to activate your account. Note these important points when considering an advance budget number:

• An advance budget number cannot be assigned until the financial disclosure - if applicable - has been reviewed favorably.
  
• Although an advance budget number enables you to complete requisition forms and to charge to the account, if the sponsor's check(s) do not arrive, your department is responsible for covering all advance expenditures.
  
• You may not contact or enroll study participants until the research contract has been signed both by the UW and by the sponsor and until the IRB has approved your study.

The AAA Trial Registration System

Accurate and timely registration is important because the research billing system depends on it. Failure to register the trial carries the risk that the wrong payer will be billed for a clinical trial activity. This is a serious compliance issue. It is also potentially damaging to your relationship with the trial participants if they (or their third party payers) receive misdirected bills. To register your study, use either the “AAA Registration Form” tab on the CRBB Detail Budget Tool or go directly to the AAA Packet on the CRBB Web site. Note that even if your clinical study does not have billable services – that is, even if you do not need to complete the pricing pages of the AAA Packet – you must register your study by completing and sending the AAA [Account] Registration Form to the CRBB Office by mail to Box 359104; by FAX to 206-598-4935, or by email.

Key Contacts:

Department/Division Budget Contacts: If you do not know your department/division's key budget person, call CRBB at 206-598-9490 for the most up-to-date information.

CRBB Contacts:

General email address: crbb@u.washington.edu
Box number: 359104

	CRBB CONTACT	PHONE	EMAIL
General Questions	MAIN LINE	206-598-9490	crbb@u.washington.edu
Director	Diane Merz	206-598-9493	merz@u.washington.edu
Project Manager	Dorsee Zaballero	206-598-9143	dorsee@u.washington.edu
AAA, Budgets, & Pricing	Cassie Kim Audrey Lee Stephanie Lewis Robert Wisdom	206-598-9489 206-598-8780 206-598-3233 206-598-5751	cykim@u.washington.edu audreyl@u.washington.edu lewiss@u.washington.edu rwisdom@u.washington.edu
Billing	Connie Hickam Colyna Ha	206-598-9171 206-598-8397	conniejh@u.washington.edu colyna@u.washington.edu
Operations	Rose Dycus Laurel Weigler	206-598-2332 206-598-4798	rdycus@u.washington.edu lweigler@u.washington.edu

Timeline:

When developing your study’s financial plan, contact CRBB and your department/division administrator for help and advice as early in the process as possible

Enrollment/Recruitment Incentives - What is UW's policy?

For industry sponsors of clinical trials, time is money.  Bringing a new drug to market is costly and time-consuming.  Slow subject recruitment is one of the most common reasons for delay in drug development.  For this reason, industry sponsors sometimes offer incentives to investigators to boost the speed of subject enrollment or the number of subjects  enrolled.  By policy, the University of Washington prohibits these and other forms of enrollment incentives, such as bonuses, gifts, or finders' fees.

If early budget talks reveal that your sponsor is planning to provide an enrollment incentive, inform the sponsor that you cannot accept it.  Such incentives may be worded as follows:

• Time/enrollment incentives: An additional payment of $100 per patient will be issued for sites that randomize 15 or more qualified patients by October 1, 2005."
• Milestone-based incentives:  "For patients who are discontinued appropriately or complete the entire study appropriately, an additional stipend of $1,000 per patient will be paid when all Case Report Forms are clean."
• Enrollment-based incentives:  "If site randomizes more than 5 patients, site shall be be paid an additional $400 per patient.  If site randomizes 18 patients, site shall be paid an additional $2,300 per patient."

It is important to remember that the University of Washington policy prohibiting enrollment incentives does not refer to reasonable payments made to subjects for their participation in research or to the actual costs that investigators incur when enrolling subjects.

Credentialing - Do I need to be credentialed?

If for the purposes of your research project you intend to interact with patients at the University of Washington Medical Center (including the General Clinical Research Center) and/or at the Seattle Cancer Care Alliance, you need to be credentialed. Credentialing helps to establish that "...individuals who interact with patients at UWMC or SCCA are appropriately licensed, registered, or certified. It also ensures that they are competent to practice in their proposed role and have the appropriate immunizations/immunities..." to ensure patient safety. Another purpose is to protect you in the event of an adverse patient outcome.

This is an important process. Physicians, nurse practitioners, and physician assistants employed by the UWMC or SCCA have already been credentialed as part of their employment process and therefore do not need to be re-credentialed for research purposes. However, aside from those job titles:

You need to be credentialed prior to beginning your research project if:

• You are not employed by UWMC or SCCA but need access to UWMC or SCCA patients or patient records for research purposes and if your role will bring you on site to the UWMC or the SCCA, or
• You are employed by UWMC or SCCA and your research role with patients falls outside your normal job description.

You do not need to be credentialed prior to beginning your research project if:

• You will not be on site at UWMC or SCCA for your research project and you need access only to patient records (no direct patient interaction) for research purposes. In such cases, you need only to contact Johanna Taylor in the UWMC Privacy Office at UWMC or Health Information Management at SCCA.

Helpful information, including the application forms and online training modules are available at the credentialing Web site. If after reading this information, you have questions about credentialing, contact Shawn Banta at (206) 598-6810). If you complete your application form correctly, the process will take about one or two weeks, perhaps less.

Hazardous Substance Training and Certification - Do I need to be certified?

As part of a clinical trial, you may be required either to package and ship hazardous material or to provide packaging to another party (such as a study subject or an investigator at a participating site) for shipment.  According to the United States Department of Transportation (DOT), you must be trained and certified to perform either of these tasks.   Hazardous material includes not only such items as blood, tissue, and infectious substances – it also includes hazardous chemicals such as dry ice. The UW Environmental Health and Safety Office offers a “Shipping and Transporting Hazardous Materials” class that meets DOT requirements. You must be re-certified every two years.

The consequences of shipping improperly include high fines. Be sure to read about training options and shipping regulation updates at the Environmental Health and Safety Web site.

Good Clinical Practice Training - Fourteen training modules are available on the Web

Good Clinical Practice (GCP) is an international ethical and scientific quality standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials that involve human subjects. Compliance with GCP provides assurance that the data and reported results are credible and accurate, and that the rights, safety, confidentiality, and well-being of trial subjects are protected.

If you new to clinical research, or if you want or need a GCP refresher, an online training course is available through the Collaborative Institutional Training Initiative (CITI) at the University of Miami. The course is available at no cost to faculty, students, trainees, and staff at the university of Washington through self-registration on the CITI site. For detailed information, including how to register for the course, go to Good Clinical Practice (GCP) Training on the UW Office of Clinical Research Web page.

The course consists of fourteen modules:

• GCP introduction
• Overview of new drug development
• International Conference on Harmonization (ICH) - Part 1
• FDA-regulated research and ICH
• International Conference on Harmonization - Part 2
• Conducting investigator-initiated studies according to FDA regulations and Good Clinical Practices
• Investigator obligations in FDA-regulated clinical research
• Managing investigational agents according to GCP requirements
• Conducting clinical trials of medical devices
• Informed consent: An ongoing process
• Detection and evaluation of adverse events
• Reporting serious adverse events
• Audits and inspections in clinical trials
• Monitoring of clinical trials by industry sponsors

Registering and Publicizing Your Study - National and local Web sites

National Web site - "ClinicalTrials.gov"

Over the past ten years, government agencies and the International Committee of Medical Journal Editors (ICMJE) have issued laws and directives on the subject of clinical trial registration. All parties have consistently agreed that the purpose of trial registration is to promote the public good by ensuring that the existence and design of clinically directive trials are publically available.

The definition of clinical trials that must be registered and the penalties for failing to register are variable. All parties agree, however, that the principal investigator is ultimately responsible for determining that registration requirements are met. Over time, ClinicalTrials.gov has become the registry of choice and is now the registry required by the Food and Drug Amendments Act of 2007. ClinicalTrials.gov is a service of the NIH, developed by the National Library of Medicine.

For complete information about the registration requirements and for detailed instructions about how to register your study, see "Registering Studies at ClinicalTrials.gov - FAQs about the FDA/NIH/ICMJE Requirements."

Local Web site - "Studies Seeking Volunteers"

Advertising your study is a win-win proposition. 

• You (the investigator) win by enabling study recruitment.  Failure to recruit subjects is the single most important reason for clinical trial delays.
• The public wins by obtaining health-related information for themselves, their families, and their friends.  Millions of people search the internet regularly for information about clinical trials - both people who wish to participate as healthy volunteers and people who have been recently diagnosed with an illness.

Investigators at the Health Sciences Schools at the University of Washington may post their IRB-approved studies on the Research Studies Seeking Volunteers Web site.  At this site you will find information about searching for studies, definitions of commonly used terms, FAQs, and related links of interest.  Instructions for posting a study on the Website are available by scrolling to the bottom of the index page, hitting "Staff Only," then "Website Instructions."