An open-label extension study is one that will lie between a double-blind, randomized controlled drug trial (the parent trial) and the request for FDA approval. Jigna Parekh, a senior study manager for inVentiv Health Clinical, has been working in the clinical field for more than 10 years and is currently embedded with Sanofi performing extension studies. She notes in an open-label study, the primary objective tends to be very different from a typical Phase 3 study.
“An open-label study is still technically a Phase 3 study, but the focus is on collecting more rigorous information on the long-term safety and tolerability of a new drug,” says Parekh. “One of these studies would typically follow one or more randomized, double-blind clinical trials once the patient has completed treatments. We often have patients coming to the end of these studies and wanting to continue on the open-label study.”
Is there a reason for collecting more rigorous safety data? Sometimes the goal is to ensure that nothing was missed. That longer span of patient data can also be helpful when seeking regulatory approval. Either way, Parekh notes it is always better to have more data.
Extension trials tend to have a slightly different study design. Two or more protocols feed into one extension study and sponsors often have more than one Phase 3 trial taking place for a new drug. Each of those trials will have different inclusion and exclusion criteria. A well-designed study that includes all important elements from the parent trial is needed to avoid excluding potential subjects from the trial and further protocol amendments. For the study Parekh is currently assigned to, four different protocols have been incorporated.
“Although the same sites participate in an extension study, it is still a new study and a start-up process must be initiated,” she states. “IRB approval is needed and site contracts have to be signed. Most importantly, the patient dosing schedule cannot be interrupted, which means there is no drug holiday. Once a patient completes the treatment period on the parent trial and consents to participate in the extension study, the next investigational drug dose they receive is from the extension study.”
Selection Criteria And Contracts Are Challenges
Parekh notes this tight schedule puts a lot of pressure on study startup timelines because not all parent studies take a year or more to complete. Some can take just 10 to 12 weeks. Since the sites in a parent trial are still screening/recruiting patients, they may not agree to the extension study start-up process until they have randomized their first patient. All of this means the site initiation for extension studies has to happen very quickly.
As noted earlier, one of the greatest challenges of an open-label extension study is the protocol. In these studies, Parekh stresses the importance of having good inclusion and exclusion criteria in place (covering everything included in the parent trials) without excluding too many patients.
“We once had two critical amendments because exclusion criteria were well written but not properly followed,” notes Parekh. “At the beginning of the trial we had to exclude some patients who completed their treatments in one of the parent studies but could not rollover into the extension study. For this reason, it is important for the protocol to be well prepared.”
The new contract negotiations are also a challenge. Many sites will quickly realize the extension study involves the same vendors, sponsors, and patients, and has a protocol similar to the old one. For that reason they may not realize there are differences in the protocol, and that some tasks will need to be performed differently. She notes it can be challenging to get staff to understand this is an entirely new study. In some instances, the only solution is to go in and actually retrain site personnel.
Speed Is Essential
In any extension study, contract negotiations must happen in a timely manner since dosing has to continue on a set schedule. Therefore, it is necessary to get the site up-and-running as quickly as possible before the first-patient-in date. “Timelines are critical, and we cannot miss even one deadline,” says Parekh. “Adhering to these timelines can become tedious and even cumbersome at times.”
Unfortunately, these tight timelines can sometimes prevent a patient from participating in an extension study. If they miss the date of the first dosing requirement because of a delay in the startup process, they must be excluded from the study due to a protocol deviation as there may not be protocol waivers.
“If they fall outside that window by a few days, we can still accept them, but this exception is made on a case-by-case basis,” states Parekh. “Unfortunately, if we cannot enroll the patient in the extension study, they complete the parent trial and that is the end of their treatment and study visits.”
In an extension study, recruitment is not an issue since patients are pulled from the prior randomized clinical studies. However, timely rollover to the extension study and retention of those patients can still be an issue. A rollover and retention plan is developed to ensure these patients remain in the study. That plan will generally revolve around sites performing follow-up and remaining in close contact with patients.
Since the sites in parent and extension studies are the same, there is a possibility of staffs being the same for both studies. Some investigators will have different clinical research coordinators while others will not. In the event that the interim analysis for both studies occur at the same time, it can pose a challenge for both the site and study team to enter data and resolve data queries on time. A detailed and well-organized plan should be implemented in order to overcome such obstacles. Since the study is an extension of the parent trial, the interim analysis and data extraction timelines will coincide 90 percent of the time. This is due to both studies being part of the same NDA application.
It’s A Big Job
Extension studies are usually global and have a global leader. Below that person is a team of managers who interact with and manage vendors. They also oversee regional managers involved in the study, such as Parekh. In her position as senior study manager for the U.S., Parekh and her team members spend most of their time interacting with CRAs at study sites. She is also the individual in the U.S. who reports to the global leader.
“In this position, I am essentially a clinical project leader,” states Parekh. “I work on site start-up, ongoing activities, and close-out of sites. The study technically does not have a CRO since my team and I perform the CRO activities. When interacting with the CRAs, I make sure they are going through the right steps during site visits and are adequately communicating with them and conducting study training. I also interact with the sites to answer questions they might have. I primarily deal with medical directors to answer medical- or patient-related questions they might have.”
With the number of patients taking part in an extension study, data becomes a great concern. As with other studies, CRAs will visit sites to ensure data is correctly entered in the system from source data. As the project lead, Parekh provides oversight for the process to ensure discrepancies and queries are handled and resolved correctly. With this many sites, patients, and CRAs taking part in the study, Parekh notes keeping track of all the data can be pretty intense.
“Thus far, the results have been great,” adds Parekh. “We have patients in the study who are already benefiting from the investigational drug.”