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Working with Study Directors
Industry tips for successful outsourcing experiences
By Steve Snyder
What is a “Study Director?” It is a term that is defined in the FDA’s Good Laboratory Practice (GLP) regulations as described below:
FDA 21 CFR Part 58 Subpart B
§58.33 For each nonclinical laboratory study, a scientist or other professional of appropriate education, training, and experience, or combination thereof, shall be identified as the study director.
§58.33 The study director has overall responsibility for the technical conduct of the study, as well as for the interpretation, analysis, documentation and reporting of results, and represents the single point of control.
§58.33 The study director shall assure that:
a) The protocol, including any change, is approved as provided by §58.120 and is followed.
b) All experimental data, including observations of unanticipated responses of the test system, are accurately recorded and verified.
c) Unforeseen circumstances that may affect the quality and integrity of the nonclinical laboratory study are noted when they occur, and corrective action is taken and documented.
d) Test systems are as specified in the protocol.
e) All applicable good laboratory regulations are followed.
f) All raw data, documentation, protocols, specimens, and final reports are transferred to the archives during or at the close of the study.
In other words, the study director is ultimately responsible for all aspects of preclinical toxicology studies. The challenge for study directors is that they are responsible for multiple studies that are in different phases. Study directors routinely are involved in developing protocols for some studies, managing the in-life portion for other studies, evaluating data for other studies, and writing reports for other studies . . . all at the same time! The number of studies in any one phase may shift frequently, depending on the type and duration of the study. On top of these regulatory responsibilities, CRO study directors may have to manage internal meetings, client visits, training sessions, integration initiatives, email, telephone calls, and much more. In short, clients expect study directors to do everything and are generally not sympathetic to the fact that they have other job responsibilities or are managing studies for multiple clients. Clients want their studies conducted with no issues and they expect their e-mails or voice-mails to be answered promptly.
Because study directors have so many responsibilities, I enlisted the assistance of several industry veterans to provide advice so that clients can optimize their relationships with CRO study directors and improve the likelihood of a successful outsourcing experience. Here is what they suggest:
Study Director Challenges and What Sponsors Can Do To Alleviate Them
Let the CRO know what your expectations are regarding communication, both frequency and mode. Some folks prefer e-mail and never answer their phone, while others prefer talking on the phone, so let your CRO know what works for you. Let them know what you want in your protocol, your general expectations on treating animals if they have a non-test article related health issue, and if you have special reporting requirement. This should be done upfront, rather than after a problem arises. If you as a sponsor don’t like what you are seeing, let the study director know so that it can be changed. Open communication between the study director and the study monitor, in both directions, is critical.
Share information regarding findings from previous studies.
Provide information on therapeutic class and indication.
Provide timely delivery of all vehicle and test articles prior to study initiation and provide for any further deliveries of additional material in a timely manner.
Provide timely delivery of all required test article information, such as Certificate of Analysis, stability and homogeneity documentation, MSDS, and expiration or retest dates.
Provide storage requirements for all materials prior to shipping so the CRO can be prepared to meet these requirements.
If you don’t have a formulation, you don’t have a study. Scaling your formulation up from discovery to a large toxicology study may not be as straightforward as you think. Test articles can and frequently do perform differently when formulated in large batches. Make sure you have sufficient time prior to starting a study to do the prestudy formulation and analytical work, so you aren’t surprised on Day 1 of a study.
Make sure that the analytical and bioanalytical methods are validated prior to starting your study. If the methods aren’t validated prior to study initiation, and you run into issues, you then have stability issues to contend with as well. Different matrices can act differently, and study validity is questionable if the exposure can’t be determined. With the complex molecules/formulations we are working with today, this is becoming more and more of an issue.
Let the CRO determine the appropriate wording in the protocol to ensure that the technical staff completely understands what needs to be done. Every institution has its own language, so when a sponsor insists on using their own wording in a protocol, it has to be interpreted for every technician who is working on the study. This leads to errors being made on a study.
Approve and sign the study protocol in a timely manner and certainly before animal receipt. Ensure that the protocol accurately reflects the intended study design, to avoid last-minute changes that can lead to study deviations.
Approve and sign all protocol amendments in a timely manner and understand that sponsor-directed changes in the original study design can lead to increased costs and timeline changes.
Respond to all Study Director inquiries in a consistent and timely manner as you would expect them to respond to your inquiries.
Avoid last-minute decisions and changes. CROs are committed to working with you to make the necessary changes but “haste makes waste.”
Communicate your expectations of the type of frequency of study updates (including data receipt) with the Study Director prior to study initiation.
Be flexible in your technical expectations. The CRO strives to be an extension of your facility, but it cannot duplicate it. Most technical procedures can be conducted successfully and with high quality in several different ways, so let the technical staff at the CRO do it the way they were trained and know best.
If the sponsor has some study aspects being conducted in-house or at a third-party facility, ensure delivery of these reports to the Study Director in a timely manner. This remains a significant issue for the CRO in meeting report timelines.
Recognize time zone differences: a west coast sponsor calling an east coast CRO at 3:00 PM PST will make it very difficult if not impossible for a change to be made immediately on the same day.
Document a backup decision-maker for the Study Director to contact if the primary contact will be out of the office, and/or always provide the cell phone number of the primary contact.
Have a clear agenda of what you want to accomplish when visiting the CRO to monitor a study and provide this information to the Study Director at least several days prior to the visit so that your agenda can be accomplished.
Remember that a study’s success may well depend upon good lines of communications between the sponsor and the CRO but communication is a two-way street.
Regarding report finalization: if a sponsor knows when it is filing its IND, it is prudent to tell the study director. The study director can help track the date, and ensure that the timeline is met. If you are using draft report for the filing, tell the study director, and keep track of the filing date, so that when you get close to the 120-day mark, you have a finalized report to submit to the FDA. Sometimes the finalization and archiving can take some time; the CRO wants to help you but can’t if it isn’t fully informed.
Reports must be finalized, regardless of the status of the test article (progressing through development or dead). The longer it takes to finalize the report, the more work it is to get it finalized. Some sponsors will let a report sit unfinalized at the CRO for (literally) years, because it is no longer a high priority. This puts the CRO in jeopardy of receiving a FDA 483 citation, and it is much more work in the long run to get the report finalized; SOPs may have changed, there are new interpretations to the regulations, critical staff (study director, pathologists, toxicokineticists) may have left the company and the report needs to be reassigned, etc. It may be preferable to finalize the report, and amend it later if changes need to be made.
Being a CRO study director is a very tough job. Sponsors need to appreciate the responsibilities of study directors and help them to be successful. Make your study director successful and you’ll improve the likelihood of having a successful outsourcing experience. A number of suggestions have been provided to help guide sponsors to achieve this goal. I would like to thank Dr. David Serota of MPI Research and all of the other industry veterans for their contributions to this article.
