Before a new drug or medical device can be marketed, it must be proven safe and effective in a series of carefully controlled clinical trials. Such trials are carried out in academic medical centers, hospitals, clinics and doctor's offices with oversight by the Food and Drug Administration, and are often funded by the pharmaceutical companies developing the study drug. For each trial a contract is negotiated between the investigator and the sponsoring company so that the costs of carrying out the trial are reimbursed.

Sometimes investigators feel overmatched by the other party in these negotiations. For that reason we provide these tips for negotiating a good clinical trials contract :

What goals might be met by carrying out this trial? Your goals may include wanting to make experimental treatments available to patients who otherwise wouldn't have any good treatment alternatives, contributing to the body of scientific knowledge, or building collaborative relationships across sites or with sponsors.

Read the protocol critically to see if these goals could be met. A trial that evaluates a drug formulated in a slight differently way from a standard drug that works well is certainly less compelling than a trial of a wholly new treatment approach for a serious disease that has no effective standard treatment. Remember that participating in any trial will require extra time and attention from you, your staff and your patients. If the potential clinical or scientific gains are slight, these commitments may not be justifiable.

Note that the money involved is rarely a good reason to perform a trial. If you do a realistic analysis of all costs (see below) reimbursement from a trial will rarely do better than cover the costs.

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Can you carry it out successfully? Review the protocol with these points in mind:

• Are your colleagues and staff willing and able to take on the extra work?
• What are the inclusion/exclusion criteria?
• How many visits are required, and of what intensity?
• How many procedures are required?
• What labs and other tests will be required?
• To what extent will Pharmacy services be needed?
• Are there off-site responsibilities?
• Is there a need for in-patient days?
• What is the trial length?
• What are the logistics of study visits?
• What is the time commitment required of patients?
• Will you need to hire extra personnel?
• Will this study compete with other ongoing trials for recruitment or resources?
• Is there a "competitive recruiting" structure (i.e., recruiting will continue until 3500 subjects have been recruited across all sites)?
• Is there a minimum number of patients you will agree to recruit? Can you reach this goal?
• Is there a maximum number of patients your site can enroll? Is this a sufficient number to justify the costs and work commitment?
• Does your staff have the skills required?
• What will be the IRB requirements?
• What are the potential benefits to patients?
• What are the potential risks?
• At what Phase is this study?
• If it is an early Phase trial, are the risks reasonable?
• Is there a possibility to participate in later Phase trials if you agree to do this one?
• What clinical supplies will be needed?
• Will tests results have to be confirmed by a physician?
• How will results be recorded and reported? Who needs to sign?
• What work will be needed after each visit?
• What work will be needed to close out the trial?
• What is the time frame from the end of accrual to the end of the study (how soon do you close out?)

Prepare two budgets. One budget ("Per-Protocol Budget") reflects the cost per patient during the protocol's implementation: all the tests, procedures, staff time, etc., called for by the actual experimental protocol.

The other budget ("Overall Budget") reflects overall costs that you will incur regardless of the number of patients enrolled, e.g., preparation of IRB documents, travel to investigators' meetings, preparation of internal documents to track patient flow. Many times the budget supplied to you by the sponsor reflects only those per- protocol costs and does not offer to reimburse you for all the time and other resources you will put into preparing for the study, maintaining its operation, or closing out the study.

You should always prepare an Overall Budget and append it to the Per-Protocol Budget. Your total contract should reflect the sum of these two budgets.

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Include "hidden" costs in your budget and contract. If you know you will incur these costs, include them in your Overall Budget. In addition, contractual contingencies should be written to cover unanticipated costs whenever possible. For instance, if an adverse event requires hospitalization of a patient, will that cost be reimbursed? If patients drop out after enrollment, will your costs to that point be covered? Will you be reimbursed for screening costs prior to enrollment?

The following is a list of "hidden" costs commonly encountered in clinical trials that you should discuss with the sponsor and ask to be reflected in the contract and budget:

• Additional cultures, tests, scans, etc.
• Excessive number of "screening failures"
• Unplanned hospitalizations
• Recruiting time longer than expected
• Unscheduled patient visits
• Unexpected equipment failure; service or replacement expenses
• Handling amendments to the contract
• Repeating consent procedures for already-enrolled patients if protocol is amended or risk/benefit knowledge changes
• Costs of shipping and packing materials
• Unexpected travel or other personnel expense
• Unplanned home health visits
• Lab mistakes; costs of redoing tests
• Treatment for adverse events
• Cost of tests performed to determine if adverse event is trial-related
• IRB fees
• Document preparation time (e.g., IRB application forms) or document costs (e.g. translation of consent form)
• Time to handle Case Report Forms
• Staff time spent on monitor site visits
• Time and travel expenses for investigator meetings
• Storage costs
• Costs of advertising/subject recruitment
• Early cancellation of the project
• Inflation and/or cost of living salary increases during a multi-year trial

Don't commit to a budget before you see the final version of the protocol.As long as the protocol is considered a "draft", the budget is also a "draft". Until you receive the final protocol, stamp all budgets as "draft".

Make sure all definitions are clear and understood the same way by yourself and the sponsor.What exactly does an "enrolled subject" mean? What is an "evaluable" record? How do you define a "dropped" patient? When is a protocol "completed"? What constitutes a "screened" patient? A "randomized" subject? You should have operational definitions of any such terms and those definitions should appear in your contract.

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Insist on payment for start-up costs at the beginning of the trial. If you have prepared an accurate Overall Budget, you will know exactly what those costs will be and will be able to justify them. This payment should be non-refundable if the trial is canceled (or you should have a cancellation fee written into the contract).

Include a specific payment schedule in the contract. Do not agree to such vague terms as "payment will be made upon completion". Instead make sure the contract says something like: "payment will be made within 30-45 days of receipt of invoice".

In addition, you should have a billing and payment schedule tied to calendar dates, not to protocol completion milestones. For instance, you can arrange to bill quarterly for all the milestones reached in that quarter, rather than having to wait to bill until a certain number of milestones has been reached.

Define payment milestones. If your initiation payment will be made at "start up", what does that mean? Will you be paid when the contract is signed, when the first patient is screened, when the drug is released, after the first monitor site visit? Payment for screening for the trial should be made at time of work performance, not bundled into payment for later protocol completion milestones. Protocol completion milestones need to be stated as, for instance, submission of the Case Report Form to the sponsor, not simply as "completion" of the protocol for that case. Make sure to specify when and how you will bill for, and will be reimbursed for, "hidden" costs such as patient drop-outs or screening failures.

Do not agree to excessive back-loading of payments. As a rule, no more than 20% of the total reimbursement for the study should be withheld to be paid upon completion. Make sure the end of the study is clearly defined (e.g., submission to the sponsor of the last of your patient data, with final payment to follow within 30-60 days).

Include the right to renegotiate the contract should the protocol be amended, or unanticipated costs arise, or if the trial will last more than a year.This renegotiation will be more successful, should you need to do it, if you analyze your actual costs at intervals as the trial goes on. Is the protocol requiring more staff time, more visits or more tests than you had anticipated? Carry out a reanalysis of your actual costs early in the trial, since early renegotiations are more likely to be successful than later ones, when you may have accumulated significant unreimbursed costs.

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Be willing to say no. If the trial seems not to be feasible, you can always decline. Be clear to the sponsor about why you are declining, and leave open the door for participation in future trials which better meet your goals.

Other contractual issues: Proprietary information & restrictions on publication. Sponsors often want to control the flow of information about the product being tested or about the results of the testing. Sometimes they will ask the principal investigator to sign an agreement not to disclose proprietary information from the trial, or will include a clauses in the contract that limit the investigator to publishing only reports approved by the sponsor.

Most academic medical centers which perform clinical trials under contract do not agree to such contractual restrictions on publication. Instead they recommend clauses allowing the sponsor prior review of publications with a set time limit (usually 30 days) to review and respond to manuscripts and to make appropriate patent applications as needed. These institutions do not as a rule agree to the sponsor's having any veto power over the publication.

On the other hand, most academic medical centers do allow investigators to agree to reasonable restrictions on divulging proprietary information about the product being tested, in recognition of the sponsor's investment in that product. This means that sponsor-provided privileged information would be excluded from any publications. A reasonable restriction on divulging privileged information would be one that is specific about what information is restricted, that covers only one particular trial or product, and has a clearly delimited end point to the restriction.

Model contracts. A number of academic medical centers provide model clinical trials contracts on-line for their investigators. A very thorough model contract that addresses most of the issues discussed above is offered by the Baylor College of Medicine at http://www.bcm.edu/blg/blg_news_fall2003.html.

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