By Ed Miseta, Chief Editor, Clinical Leader
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Leesa Gentry has conducted many clinical trials in her 20+ years in pharma, half of which have been with Otsuka Pharmaceutical Co. While every study is challenging in one way or another, a recent trial tested her ability to coordinate with sites to ensure they were properly equipped and trained to pull off a study.
Gentry, who currently serves as director of Global Clinical Management for Otsuka Novel Products, is accountable for the implementation of multiple global trials for products relating to MDR-TB (multidrug-resistant tuberculosis), imaging, and oncology.
Otsuka has been working on new TB medicines for over 30 years and is now the largest private funder of TB drug development in the world. As such, the majority of Gentry’s time has been spent working on trials for MDR-TB, defined by its resistance to two main drugs currently used to treat TB — isoniazid (INH) and rifampicin (RMP). Patients can become resistant to these drugs if they are not administered correctly or are not given with the appropriate companion drugs.
When launching a new Phase 3 trial for MDR-TB, Otsuka wanted to recruit as many global patients as possible. Sites were set up in South America, Asia, Southeast Asia, and in the Baltic countries in Europe. Patients were even recruited in the U.S. and Egypt. South Africa was originally not included due to concerns over patients co-infected with HIV, but was included in later studies.
LOW RESOURCE SETTINGS POSE CHALLENGES
Although Otsuka had patients on almost every continent, the facilities that existed varied greatly from one location to the next. In fact, Gentry uses the term “low resource settings” to refer to what existed in many areas.
“Low resource settings are really denoted by inconsistent access to international healthcare standards in that region,” notes Gentry. “Patients may experience stock-outs of medication or the country might be utilizing some sort of global granted funds to procure second-line drugs. The facilities may lack necessary infrastructure or be located in areas where transportation, electricity, or other essential services are difficult to maintain. Many of the facilities will oftentimes have fewer personnel as well. They have trained personnel at the site, but they don’t have extra personnel available to perform clinical trial work on top of the daily tasks they are already required to perform.”
In some locations Gentry notes there is limited access to specific types of equipment. For example, in the MDR-TB trial, Otsuka wanted to be able to compare data across several different regions. An automated system would be used to check sputum from patients’ lungs to see if bacteria were growing. Many of the sites did not have the equipment necessary to do so.
With the extensive experience Otsuka has in TB, Gentry knew before the trials started that the company would be working in low resource settings. As a result, a highly qualified team was put together consisting of individuals with medical or epidemiologic experience working in this field, in MDR-TB, or perhaps at the CDC or other global organizations.
Gentry knew it would be important to have individuals managing the study that understood the resource environments Otsuka would be working in. Therefore, she included individuals who could understand what would be required to get all of those sites up to applicable standards. Since each site was very different in terms of infrastructure, a very individualized approach was used. “There were certainly similar themes across several of the regions,” she says. “For example, we knew these sites were doing really good work, but they were resource strapped, especially in terms of highly trained staff. In many locations, we had to add staff and train them on trial requirements. There was also a lot of equipment that had to be purchased, particularly in the lab, but that was different in every case and often depended on the region.”
The trial required eight or more in-patient treatments simultaneously, making it a bit more cumbersome than some previous MDR-TB studies. While some regions were used to that kind of regimen, there were many that were not. In a few areas, Otsuka actually had to create a site where patients could be treated for 56 days in more of a hospital-type setting.
"[The face time required by site staff] was really unheard of in any trial I had worked on previously."
Director of Global Clinical Management, Otsuka Novel Products
SITE VISITS WERE MANDATORY
Otsuka enrolled 481 patients across approximately 20 sites. “We tried to focus on sites that had demonstrated good treatment in the past and had access to quantified, eligible patients,” says Gentry. “For that reason, we deliberately tried to limit the number of sites that would be treating patients.”
Since it was impossible to determine exactly what the equipment and infrastructure needs were at each site, Gentry and her team took the time to visit each one. She believes one of the most valuable lessons learned from the trial was the amount of time and face-to-face interaction required by her team.
“It was really unheard of in any trial I had worked on previously,” she says. “We just decided that, in order to make this work, we were going to have to ensure our team was extremely well-connected to each site. This was accomplished by having team members make multiple visits to each site. We did use CRO partners and also hired local clinicians in each of the regions where we worked. To ensure everything flowed smoothly, we created a paradigm where those individuals worked as a part of our team. At the same time, our employees working on the project were just as involved locally as any of the CROs. At one point we attempted to track our flight miles and found that five members on our team could have gone to the moon and back. That’s a lot of travel.”
At the beginning of the study, the team included just Gentry and a medical monitor. Later, Otsuka created a position referred to as regional lead and added three CRAs (clinical research associates) to the team. Each one was put in charge of a different region and had local CRO personnel working under them. An internal SOP required the team to perform 5 percent oversight of all sites, which was later increased to 20 percent. That equated to someone having to be at the site about every other month. To ensure everyone on the team was on the same page, the initiation visit, which generally takes around four hours, was extended to two or three days.
The extension of the initiation visit allowed teams to review all of the presentations that would be used for training and to ensure that clinic nurses and lab technicians received the training. To avoid confusion, a CRO team that spoke the local language was also brought in to help with the training. The additional time also afforded teams the opportunity to re-verify facilities and equipment and review a few patient charts with staff to help them identify patients who would be eligible for the trial.
FINDING AND TRAINING PERSONNEL
Even though Gentry knew from the outset that additional personnel would have to be hired at each site, finding qualified individuals was still quite difficult. An even bigger problem had to do with several of the sites (such as those in the Baltics) being government entities. At those sites, the ability to hire additional staff was very limited due to funding constraints. Otsuka resorted to having its CRO partners hire the additional staff.
The individuals hired were generally study coordinators. If there were not enough government personnel available, the company would partner with nongovernmental organizations to provide qualified workers. Generally these were entry-level CRAs who were placed at the site as study coordinators. They were managed by the site staff but paid by the CRO.
It was important to Otsuka that all sites follow ICH (International Conference on Harmonization) good clinical practices (GCP). Naturally, there were some sites where Gentry knew some additional work would be required. The standards dealt with the way the site was documenting information, which had not been performed correctly in the past.
“For example, one of our sites had a very good clinical practice and kept a logbook of the vital signs for each of their patients, but they were kept in conjunction with all the other patients,” she says. “There wasn’t an individual patient chart that could be reviewed by an external third-party audit. Therefore, we had to change the way they were documenting information and then train personnel on how to do it correctly.”
Physicians also required some training. Gentry notes the doctors were very talented and passionate about treating TB. However, some were not used to managing and documenting adverse events as required for a clinical trial.
“These investigators deal with MDR-TB in multiple patients on a daily basis,” says Gentry. “They are not necessarily thinking about whether a particular side effect is common with many of the second-line drugs. Some of these drugs can cause nausea or other symptoms more difficult to detect, such as hearing loss. The physicians were not used to documenting such things as adverse events. So, we had to provide some training.”
Doctors also were accustomed to providing data in multiple formats, depending on the task. Otsuka needed to have them focus on creating a source document that would be the single place for information to be housed. Many were also not used to transcribing that information into a second location, such as an electronic data capture (EDC) system.
Reflecting back on the process, Gentry notes it was a big deal. With MDR-TB, patients have to be directly observed during dosing. This is to make sure the patients are adhering to the requirements. That process is sometimes at odds with what is required for ICH GCP, and was one of the biggest hurdles that needed to be overcome.
“I did not expect this to be an issue,” she says. “Generally, the doctor is not responsible for patients maintaining their medication and taking it every day. But in a clinical trial, control of the drug is important and medication must only be dispensed to the patient who has consented. Some of these sites had to be deprogrammed from what they were used to doing regarding dispensation, documentation, and adverse-event reporting and taught how to perform tasks in a way that would meet ICH GCP requirements.”
PURCHASE NEEDED EQUIPMENT
When it came to making sure every site had the equipment needed, there were a few themes that emerged, although the needs still varied by location. Appropriate infection controls (environmental controls, personal respiratory protections, and administrative controls such as limiting staff contact with infected patients) also had to be in place at each location for both the safety of the patient and to ensure patients weren’t being double-infected, which would cloud the data.
Most of the equipment required was needed in the labs. Almost every site required a mycobacteria growth indicator tube (MGIT), an automated device necessary to evaluate sputum cultures while controlling for local/regional bias. In most sites, the equipment was rented. Even if a site had an MGIT, it generally wasn’t large enough to analyze the large number of samples collected. In those locations, a second unit was rented. Additional lab equipment, such as refrigerated centrifuges and microscopes, were also needed at some sites.
A reliable Internet connection with sufficient capacity was required to perform the EDC requirements of the trial. To increase the Internet capacity in many locations required switching to a different service provider.
There were other various equipment needs, such as lockable storage cabinets that would hold collected samples, as well as desks and chairs in those locations that did not normally have regular CRA visits.
“Overall, I would say we were pretty lucky to find most of the equipment we needed locally,” says Gentry. “Importing equipment from another country would have made the effort a lot more difficult. When it came to locating the equipment and supplies we needed, our CRO partners were extremely helpful.”
COMPARABLE RESULTS ARE CRITICAL
Prior to this study, the trial sites had only ever measured results against themselves; collecting data that would be measured across multiple regions was also new to them. But comparability of data was a major goal of this study for Otsuka.
“To make sure everyone was doing this correctly, we created a standard lab manual,” states Gentry. “This ensured the same procedures were followed exactly in every lab. In addition to the normal clinical monitoring that is performed, we added another layer of monitoring specifically for the lab. Lab personnel were trained in microbiology and responsible for ensuring processes were performed according to the lab manual.”
The results of the trial show the efforts of Gentry and her team were worthwhile. Otsuka was able to obtain data on 421 of the 481 patients, across every site, despite the fact that patient adherence to this type of regimen is very difficult. The lab manual Otsuka developed and utilized for this study was later endorsed by the Global Laboratory Initiative of the Stop TB Partnership, providing third-party endorsement of the standard processes used in the lab. The treatment has been approved in the EU, Japan, and South Korea, with registrations and access initiatives ongoing in other countries.
“Our data was incredibly consistent,” adds Gentry. “It has been analyzed many times and in many different ways, and it has always been consistent. I think that consistency, as well as patient retention, are very good measures of quality.”