The Right Investigators

Featured Blog by Denni O. Day

While every investigator is a veterinarian, not every veterinarian makes a good investigator. Good investigators are not a homogeneous group, but they do share certain characteristics, like organizations, perseverance, and integrity.

Finding Study Investigators
There are multiple ways to recruit investigators. Some sponsors compile a database of veterinarians to whom they mail or fax study invitations. This method may often generate a high number of responses, but selecting from such a pool can be time-consuming and relatively risky. Even veterinarians who appear to satisfy all of the requirements may falter under the burdens of protocols and regulatory standards.

That may be why certain sponsors rely on a roster of trusted investigators to whom they return for every study. Even if one of these investigators is not interested in participating in a particular trial, they often can refer the sponsor to one of their colleagues. Reliance on familiar investigators can yield more predictable results but, over time, may also lead to complacency. When the sponsor-investigator relationship gets too cozy, data quality usually suffers. It should never be blindly assumed that an investigator who performed well during one study will automatically deliver the same results in a subsequent trial.

Another approach is to search the summary of an approved drug that is similar to the compound being evaluated in a planned field trial. Listed investigators may be interested in participating in another trial and could bring useful experience and relevant perspective to the planned study. These summaries are available at http://www.fda.gov/ AnimalVeterinary/Products/ApprovedAnimalDrugProducts/ FOIADrugSummaries/. However, the same caution applies to these investigators. Experience in a previous trial does not guarantee superior performance in the planned study.

Clinical research organizations (CROs) are another source of experienced investigators. Many CROs have databases of investigators with clinical trial experience in one or more therapeutic areas, and large patient populations with the corresponding indications. Some CROs will identify and qualify a team of investigators for a sponsor as a stand-alone service.

Some CROs, and even some sponsors, are in perpetual recruiting mode, always searching for new and better investigators. They use a variety of techniques, from advertising to trade shows, to identify potential investigators. They then invest the time to thoroughly vet each candidate before adding them to their roster. This regular investment pays healthy dividends when future studies must get up and running quickly.

Once a potential investigator has been identified, they should be evaluated for participation in the upcoming field trial. Their file should contain a current resumé, a copy of their registration (and DEA license, if necessary for the planned trial), and information about their practice and staff. After the candidate has reviewed the protocol, the sponsor or CRO should reconfirm their interest in and availability for the trial, answer any questions they might have, and verify that they have the requisite patient population. They also should review the study’s investigator budget and get the candidate’s agreement to that.

If the potential investigator passes all of these hurdles, the next step is the site qualification visit. This inspection will determine whether the potential investigator has a modern facility, adequate and properly-calibrated equipment, secure storage, organized medical records, and a friendly and professional staff. This visit also will give the sponsor or CRO another opportunity to confirm that the clinic has enough potential study subjects to meet their enrollment target quickly. Potential investigators who meet all of the study parameters then can be formally admitted as study investigators and be invited to study training.

Training Study Investigators
The US Code of Federal Regulations (Title 21), Section 312.50, requires that study sponsors provide investigators with the information they need to conduct an investigation properly “… ensuring that the investigation(s) is conducted in accordance with the general investigational plan and protocols contained in the IND.” Like many regulations, this directive sets the objective but leaves the specifics to the regulated. Suffice it to say that, at the conclusion of study training, the investigators should know what they are required to do, how to do it, when and in what order they will do it, and what to do if something unexpected happens.

Sponsors and CROs differ on the most effective way to train investigators and, to some extent, the choice may depend on the total number of investigators and/or the complexity of the protocol. For some sponsors, budget constraints may dictate the training format. In the final analysis, though, the decision should be based on which format is expected to best prepare the investigators to produce superior results.

Training via webinar is often the least expensive and most flexible format. It allows the sponsor to train each investigator separately, small groups of investigators, or all of the investigators at once. When multiple investigators are trained in the same webinar, they have the opportunity to interact and benefit from each other’s questions and comments. If the webinar is recorded on a DVD, copies can be sent to each investigator to share with other clinic staff and to refer to whenever they have questions during the study. Webinar training also may be the only option when tight timelines necessitate rapid study initiation.

The biggest disadvantage to webinar training is the lack of a controlled environment. There is no reliable way for the sponsor to determine whether each investigator is actually watching the webinar or has muted their phone and gone back to their clinic activities. It also is difficult to assess each investigator’s absorption of the training material and virtually impossible to role-play potential study situations.

On-site training is preferred by some pharmaceutical companies because it allows the project manager to qualify the site and train all of the staff in one visit. It also is an opportunity to see the clinic in action, assess their organization and veterinary skills, and check the medical records for potential study subjects. However, since this training format is conducted in active veterinary clinics, it is subject to staff schedules and frequent interruption by pressing client issues, pet emergencies, and other clinic activities. Such distractions may hinder the investigator’s and/ or clinic staff’s understanding of important protocol details, thus compromising the overall effectiveness of training and, perhaps, site performance during the trial.

Centralized training often is touted as both the most effective and most costly method. Having all study participants – sponsor, investigators, site technicians, clinical supplies distributor, laboratory representatives, biostatisticians, medical writers, electronic data capture administrators (for EDC studies), and the CRO project team (if involved) – together in one room, away from ringing phones, office responsibilities, and other distractions facilitates better interaction among all attendees, more consistent instruction of the protocol, deeper understanding of the pharmacology, and faster problem resolution. While the upfront cost of centralized training may seem high, it is almost always offset by faster enrollment, fewer queries, and better data. The value of shorter timelines and quicker regulatory approvals is far greater than the cost of plane tickets and hotel rooms.

Whatever training method is used, it may be worthwhile to periodically review certain key elements to correct misunderstandings, catch errors, and retrain the investigator and participating site personnel as needed to ensure protocol compliance and enhance site performance.

Investigator Support
Once formal study training has been completed, initiation visits can be scheduled for each investigative site. Under certain circumstances, a site may be ready to enroll their first study subject immediately after training has been completed. As appealing as this may be to the study’s project manager, it may be advisable to delay enrollment until the study monitor can schedule a site initiation visit. This will give the monitor an opportunity to review all of the topics that were discussed during the training meeting, identify any gaps in understanding, and provide whatever refresher training may be needed. If training was conducted on-site, the study monitor can initiate the site right away and, perhaps, observe the first enrollments. If the site has not yet scheduled any subject screening visits, the monitor might advise the staff as they search the clinic’s medical records for likely candidates and also suggest various recruitment strategies.

As the study progresses, the monitor’s attention should shift to the three critical determinants of a successful study: enrollment, test article accountability, and data quality. Depending on the complexity of the protocol’s inclusion/exclusion criteria, enrollment can be relatively easy or extremely challenging. It is important to set realistic enrollment targets for each site and then to provide strong support to keep site staff focused and enthusiastic. Close tracking of each site’s progress against their target will help identify which ones need additional assistance or, in certain instances, when additional sites should be initiated to meet the overall enrollment goal.

One of the monitor’s responsibilities during each site visit is verification of each enrolled subject against the protocol’s inclusion/exclusion criteria. A frequent contributor to study budget overruns is the disqualification of completed cases that should not have been enrolled. Another important monitoring task is the reconciliation of test article inventory, which should be completed at every visit. Delaying it to the end of the study only increases the risk of discrepancies. The monitor also should confirm that test article is consistently stored in a separate, secure location, especially if the test article includes a controlled substance.

How often a monitor schedules their site visits depends on each site’s level of enrollment, number and frequency of protocol deviations, and number of queries issued and resolved. At every visit, study communication records and other site documentation should be reviewed for organization and completeness. Outstanding queries also should be addressed, and remedial training provided when warranted. And, while not every investigative site is audited by the FDA, a call announcing an audit can come at any time. Therefore, it might be advisable to prepare the site personnel for that event in advance. Monitor travel cost usually is an important consideration when scheduling site visits but, in the context of an entire study, one additional monitoring visit at the right time often can result in a significant improvement in data quality from the respective site.

Bonus: Ten Tips for Tremendous Trials

  1. Before the study starts, set clear expectations for every member of the project team, including the sponsor, investigators and other site personnel, CRO (if involved), monitors, laboratory, electronic data capture provider (if data will be collected electronically instead of on paper case report forms), biostatistician(s), and medical writer(s).
  2. Include only those investigators who are truly interested in, and committed to, the study. It is better to delay study initiation until the right investigators have been recruited than to proceed with study investigators who are not fully dedicated to a quality study.
  3. Design and execute study training so that everyone involved understands the requirements of the protocol, accepts their responsibilities, and is committed to superior results.
  4. Establish a project team communication plan, including what will be communicated to whom, by whom, when, and how.
  5. Create a study team communication plan so that personnel at each investigative site know whom to contact for questions and problems, what communications they can expect and from whom, and the frequency and format of such communications.
  6. Develop a monitoring plan and a projected site visit schedule. Regular monitoring prevents most end-of-study surprises.
  7. Assign enrollment targets to each investigative site, but do not assume that they will always be met. Prepare a contingency plan.
  8. Whether the study is paper- or EDC-based, review case report forms as quickly as possible. This will help catch errors early and indicate where remedial training might be needed or if a protocol amendment is warranted.
  9. Reconcile test article inventory frequently and resolve discrepancies as soon as possible.
  10. Don’t wait for the inevitable problems. Anticipate them and design solutions.

Our pets are not just animals. They are loyal companions, treasured members of our families, and, in certain instances, valuable assets. As such, they deserve the very best care available. That care will come from the new therapies being developed by veterinary pharmaceutical companies, and those therapies must be proven in clinical field trials. Finding, training, and motivating veterinarians to be effective investigators will help ensure the success of those trials … and the long-term health and wellbeing of our beloved pets. And that is the heart of the matter!

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