Band-Aids and Vaccines

My July 2015 article, “How to Cut Study Delays-Revisited;’ generated quite a bit of interesting feedback. However, since research has shown that 90% of all clinical trials experience significant delay, I was not surprised. Some people shared their version of one of the problems I had cited. Others called to recount their tales of clinical trials gone bad. A few offered solutions or strategies that I had not considered. What did surprise me was the concentration of troubled scenarios around one of two causes: incomplete protocol development or slow enrollment.

All clinical trials have a timeline, some more aggressive than others. However, I have yet to see one that did not increase the stress level of one or more members of the project team. When the inevitable problems occur, there is rarely enough time to pause all activities while the team determines the root cause. More often than not, a looming deadline reinforces the natural inclination to apply a Band-Aid and keep moving forward. The intention always is to revisit the situation at a later, less rushed date to develop a permanent solution — a vaccine, if you will — so that particular problem does not recur in future trials. Finding the time for that extra step in today’s pressured development environment is difficult.

The future dividends, though, make the effort a worthy investment. To further illustrate this point, I selected seven scenarios from those I received, together with the corresponding Band-Aid and my recommended vaccine.


Protocol Development

Subsequent to protocol concurrence, on the day before the investigator training meeting, it is discovered that the normal (and logical) flow of study activities at each site is inconsistent with the protocol’s schedule of activities.

Band-Aid: During the protocol training meeting, reach a consensus regarding the most efficient work flow needed to complete specific activities, document those steps, and provide a summary checklist for each investigator.

Vaccine: After the protocol has been finalized, but before it is sent for regulatory review, ask the selected investigators to review the protocol’s schedule of activities and recommend any improvements to the flow. Share these recommendations with all investigators and reach agreement on the final flow. Incorporate all changes before finalizing the protocol.


After the study is underway, it is discovered that the central laboratory does not routinely report on all analytes listed in the protocol.

Band-Aid: Determine why the analytes are not routinely reported and then revise the protocol accordingly to avoid a global protocol deviation at the end of the study. Assess the regulatory implications of this amendment and make the necessary arrangements to obtain regulatory concurrence.

Vaccine: Before the study starts, ask the chosen laboratory to run results from discarded in-house samples and report those results. Compare those results to the protocol’s required laboratory tests. Discuss discrepancies with the laboratory and revise the protocol accordingly.

Alternatively, identify another testing facility that could collaborate with the chosen central laboratory to provide the needed analyses.


Mid-way through study enrollment, it is discovered that the owner consent form does not accommodate multiple owners.

Band-Aid: Write a Note-To-File that explains why more than one owner or agent of the owner is recording study data when only one owner signed the consent form. Ask additional owners, or owner agent(s), to provide a sample signature and set of initials.

Vaccine: Design the owner consent form with spaces for the names, signatures, and initials of multiple owners or owner agents. However, for data consistency, strongly encourage the owner to designate one person as the study observer and recorder. Document on the consent form that more than one person may record observations and list the name(s) of each.


Enrollment

An investigator fell off his roof at home, taking him out of the clinic for six weeks.

Band-Aid: If available, qualify another veterinarian at the clinic to serve as investigator. If that is not feasible, refresh training for the investigator and participating site staff at one of the back-up clinics.

Vaccine: Select as study sites only those clinics that employ more than one veterinarian. Also, include personnel from each back-up clinic in the study protocol training meeting. Establish in advance the procedure for test article and supplies distribution to each back-up site.


One site’s treatment administrator resigned from the clinic.

Band-Aid: Reassign a trained study team member to the role of treatment administrator and provide training. Alternatively, qualify another member of the clinic staff to serve in this role and provide training.

Vaccine: Identify and cross-train study staff to serve as back-up in additional roles, as needed. Establish a procedure to train or refresh training for these individuals should they be delegated to a back-up role.


After several weeks of lagging enrollment, it is determined that a site’s enrollment projections were exaggerated and unrealistic given their actual patient population.

Band-Aid: Schedule a monitoring visit as soon as possible to help the clinic staff identify potential study subjects. Implement enhancement programs to boost enrollment. Prepare to add a back-up clinic and refresh training.

Vaccine: Evaluate each site’s true enrollment potential during their qualification visit. Confirm that evaluation during each site’s initiation visit. Develop an enrollment support procedure, including enhancement programs and implementation thresholds. Obtain sponsor approval of all programs and plans before the study begins.


At another clinic with slow enrollment, it is discovered that the site is participating in another study with a similar indication.

Band-Aid: Close the site and initiate a back-up clinic.

Vaccine: During each site qualification visit, determine if anyone at the clinic is currently participating in another trial. If they are, discuss the study investigator’s involvement, if any, and whether the other study is targeting a similar population. Review the clinic’s patient database to confirm the site’s enrollment potential.


There may be a certain comfort felt each time that a Band-Aid is applied. Something constructive has been done that allows us to return to the pressing matters at hand. There are, however, two problems with BandAid solutions. First, they are only a short-term fix that does nothing to prevent a future recurrence. Second, they sometimes are insufficient to treat the underlying problem, allowing it to fester and spread, then requiring a more extensive (and more expensive) fix at a later date.