Q Ask the Experts

Take this expert's advice on improving CT negotiations

Keep a sense of humor about it

Clinical trial sites can improve their clinical trial (CT) negotiation processes and reduce misunderstandings with sponsors and clinical research organizations by being clear about objectives and desires.

An expert in these types of negotiations provides Clinical Trials Administrator with advice on how CT sites can get the most from the CT agreement process in this question-and-answer story featuring Robert L. Croog, JD, corporate counsel and associate director of legal services at PTC Therapeutics Inc. of South Plainfield, NJ.

CTA: When working with clinical trial sites during the clinical trial agreement process, what are some of the chief issues or misunderstandings that can arise, and how can these be resolved?

Croog: Misunderstandings can occasionally arise because the legal language in a proposed draft is misinterpreted. This happens more frequently in international trials when the site and sponsor speak different languages, but it can happen with domestic sites, too. Usually, speaking on the phone or communicating by email to provide an explanation of a particular sentence or paragraph can resolve the matter. Sometimes, an explanation may not be enough, and the site may request an example be inserted in the text to illustrate how a provision works in practice.

The publication section of the agreement is another area where misunderstandings can arise. The site, existing in a world of academic freedom, in which great value is placed on disseminating knowledge by publication, may not want to limit the right to publish results of the study. The sponsor, being a business heavily invested in the outcome, wants to publish results in a way that will preserve its ownership of intellectual property (IP), in due course after careful review to ensure accuracy of reported findings — and confidentiality is key until the analysis is complete. Usually it comes down to mutually agreeing on a reasonable period of time for sponsor review before publication, per standards accepted in the academic and biotech industry. If there are a number of centers in the study, it's important that the site understands, and that it's reflected in the agreement, that a multi-center publication occur before any one site's, or investigator's, publication. Again, market standards indicate reasonable periods for a site or investigator to wait for the multi-center publication to go first, and these periods will be set forth in the agreement.

Sometimes, investigators or their sites want the agreement to ensure their right to be named in any publication. The ICMJE guidelines are helpful in this regard. The important thing is that a unified approach be taken, fair to the study centers collectively.

One of the most frequently negotiated areas of the agreement is the IP section. Since the average cost of discovering, studying and bringing a drug to market in today's economy is upward of a billion dollars, you can imagine that it's a section of the agreement to which the sponsor will pay special attention. I have found that sites understand how important this is to the sponsor's business (i.e. recouping investment) and will agree, consistent with market standards, to reasonable terms relating to any inventions or discoveries made in the course of the study, or resulting from the protocol or the carrying out of the agreement. Often there will be some negotiation to find the right language that both sides are comfortable with.

CTA: What are some important areas to address in CT agreements that sponsors and/or CT sites sometimes overlook?

Croog: Sometimes overlooked is the possibility that the study protocol may be amended after the agreement is signed. If the protocol is an attachment to the agreement, language should be included in the agreement to anticipate and allow for protocol amendments, so the parties won't have to also amend the agreement later.

Another area that may be overlooked is the warranty of non-debarment. The FDA maintains a list of practitioners and institutions excluded from practice, for violations of one sort or another. The FDA can exclude study results obtained by debarred persons or institutions. Not only is it important to include a warranty by the site that none of the study personnel has been debarred, it should add that none have committed any action that could reasonably lead to debarment. Moreover, the sponsor should require the site to affirmatively alert the sponsor if any debarment-related issue arises after the agreement is signed, during the study, and even up to five years beyond its end (or if earlier, until a marketing application is filed with the FDA in connection with the study). Having this type of language in place can assist sponsors in meeting their reporting obligations to the FDA.

If the site or the sponsor is new to clinical trial practice, the other party may want to inquire to make sure both sides understand all their respective responsibilities with regard to Good Clinical Practice (GCPs), patient confidentiality requirements, record-keeping, internal procedures and policies for shipping and handling drugs, and safety. Everyone is a professional in the field, but best practice is to check if they're new.

CTA: What are some best practice strategies for making this CT agreement process go as smoothly and fairly as possible?

Croog: Channels of communication that are smooth and open (both internal and external), being organized, are key to success. Often the parties are in a rush to complete the agreement and begin the study. Legal departments may handle the agreement, but sometimes sites' technology offices may need to review the IP section, and of course the investigator must be kept closely in the loop. Clinical, regulatory and finance departments of sponsors each play critical roles and need to be questioned as appropriate and kept informed and up to date by the legal department, as issues may arise that require their input. With all these organizational stakeholders, it's important that between the site and the sponsor, there is one main point of contact at each for communication about the agreement.

Often clinical research organizations (CROs) are involved in a study. It's important to delineate their role in the agreement, as an agent of the sponsor, and provide some details of their role in the study. Will they provide monitoring services only, or also handle receipt and payment of invoices?

Professional courtesy and a sense of humor can assist in the process of working through an agreement.

It pays to show sensitivity to local culture and regulatory set-ups. This is more important in the international context. Sites outside the US will often be subject to regulatory requirements that influence the agreement in ways that US sponsors dealing with domestic sites will not be accustomed to. Inevitably, if the sponsor wants to conduct studies abroad, it will have to show greater flexibility where regulatory requirements limit what sponsors and sites can agree to. In the international arena, it helps the sponsor and the site to have a good CRO that can act as go-between, and communicate across language divides, and do so in a way that not only translates, but explains, each side's position to the other.