There is no doubt that clinical trials, in general, need to improve. They take a long time, cost a lot, and are increasingly complex with multiple endpoints. Usually patient recruitment/retention is targeted as the biggest area in need of improvement. But what about the study protocol itself?
According to Victoria DiBiaso, global head of clinical operations strategy and collaboration at Sanofi, “When it comes to improving trials, you have to look at protocol optimization. For us, that is where it all begins. You can’t get good data without a successful trial, and you can’t have a successful trial without the right protocol.” She adds that communicating better with patients and sites is also an important part of the company’s current strategy to make its clinical trials more efficient.
COMPLEX TRIALS REQUIRE NEW SOLUTIONS
The complexity of today’s clinical trials is best exemplified by an increase in patient visits and the number of procedures required — two factors that are negatively affecting the time and cost of conducting trials. About six years ago, Sanofi undertook a concerted effort to reverse this trend by understanding why trials were getting more complex. The result is a model that has allowed the company to see a yearly decrease in timelines, as well as other dramatic improvements.
When it comes to protocol design, Sanofi is looking at improving the process from two aspects. The first is considering the complexity of the design to see whether it can be optimized and simplified. The second focuses on feasibility planning and recruitment, which DiBiaso notes is essential to a quick study start-up. She believes the industry has inadvertently shifted too much of that burden onto sites.
To address the problem of recruitment, Sanofi first turned to patients and sites to get both more involved at the protocol-drafting stage. Patients certainly need to be aware of trials and the benefits they provide. But sites are equally important. Patients must qualify for a trial and be willing to participate, and sites can be instrumental in making that happen. Sites also know what the sponsor is hoping to achieve from a scientific perspective, and they understand the requirements from a real-world, practical viewpoint.
Front and center in both the protocol design and patient recruitment efforts were digital technologies. A recent wave of new technology and innovation that simply did not exist in the past is presenting options for improving trials. This is also one of the critical areas where Sanofi knew technology could come into play. The company is now working with TriNetX, a global health research network, and another EHR (electronic health record) provider in the EU to assist with the difficult task of feasibility planning. For Sanofi, that planning entails influencing protocol design via external advice and technology, geographical strategy, site, and patient input, and estimating the probability of hitting enrollment targets. By connecting with patient populations in real time using EHRs, Sanofi is able to see data on patients and compare those live data sets to the targeted patient population.
“This allows us to make sure the patient population we are targeting truly does exist,” says DiBiaso. “We also can determine if the patients at a particular site are representative of the characteristics being sought for the study. TriNetX allows us to instantly see a list of sites that match specified criteria. We’re able to enter the inclusion/exclusion criteria and, because it’s a live EHR data set, run an analysis or simulation based on certain characteristics. For example, we can see whether an anonymous cohort of patients has a certain disease, is on a certain background medication, or has lab values that fall within a given range.”
The EHR system also will notify users if they might be inadvertently excluding individuals who should be eligible for a trial. Analysis will reveal where patient eligibility is being restricted. “All of that intelligence is moved up to a much earlier stage, prior to the protocol being finalized,” states DiBiaso. “Now, when we actually approach a clinical trial site about participating in a study, we have access to generalized, anonymous patient information that neither we nor the site had available in the past. The information allows us to fix problems before we get too far along in the protocol design.”
"The information allows us to fix problems before we get too far along in the protocol design."
Global head of clinical operations strategy and collaboration, Sanofi
CONNECT PROCEDURES TO ENDPOINTS
Patient retention plays a key role in a trial’s success. Therefore, making sure patients are able to abide by the study protocol is something Sanofi is also closely examining. First, the company is examining trial protocols to ensure they are patient-centric. A key point of that examination is ensuring the number of visits and procedures in the protocol are all connected to trial endpoints.
“Via a thorough review of our protocols, we are now able to quantify every visit, every procedure, and every aspect of the study to make sure it ties back to something that we need to measure as part of our regulatory and strategic pathway,” states DiBiaso. “This can play a huge role in reducing the complexity of a study, which also will reduce the burden on our patients and sites. If we find a procedure that does not tie back to a specified endpoint, it is removed from the protocol.”
Even after reducing the complexity of a study, there is no guarantee patients will be able to abide by the numerous requirements, such as clinical visits and medical procedures. Therefore, the number of procedures and visits will still need to be discussed with patients and advisory groups, who will then provide feedback on whether it is conceivable for patients to perform the required tasks.
Typical questions might include:
- Could a patient conceivably make the required number of visits to the clinic?
- Would a patient likely be able to spend the required time at the clinic?
- Would a patient likely be able to fill out the patient diaries using a specific technology?
- What information would patients need to make an informed decision about participating in a clinical trial?
If patients indicate that a trial is asking too much of them, Sanofi will simplify the trial requirements. The goal is to lessen the overall emotional or physical burden on patients so as to increase the probability that they will opt in to the trial.
ELIMINATE SITE VISITS
Making patients aware of clinical trials and simplifying your protocol are good initial steps to increasing recruitment rates. But getting more patients to take part in clinical research will generally entail breaking down additional barriers to participation. Those barriers often can be jobs and families that limit someone’s ability to get to the clinic. Therefore, removing the need for patients to visit a clinical site was still a concern for DiBiaso.
To overcome that hurdle, Sanofi formed a partnership with Science 37, a company that brings clinical trials into patients’ homes via telemedicine. This enables Sanofi to leverage services, such as home nurses, so patients are able to schedule visits at home in the evening or on the weekend.
“Science 37 is a unique model,” says DiBiaso. “They have something called a ‘meta site.’ A primary investigator is based at their clinical trial site and works remotely in a distributed fashion through the use of telemedicine. This enables patients to be located in various states and towns across the country.”
The result is that rather than having to go to a brick-and-mortar facility to be part of a trial, nurses can go into a patient’s house to discuss how they are feeling, collect vital signs, or even change the investigational product if necessary. Skype also can be used to have conversations with patients.
“One of our primary frustrations is finding the right patients and knowing they want to participate but finding out they can’t participate because of work or family,” says DiBiaso. “Taking three hours out of your day to visit a clinic can be a difficult task for any patient. By fitting that visit into a patient’s home life, we can easily eradicate that situation.”
She notes this model is especially helpful when dealing with patients with rare diseases because, traditionally, they often have to travel (sometimes via flying) the farthest distances to trial sites. In these cases, treatment can be administered at a local infusion center using remote capabilities and telemedicine options.
"Via a thorough review of our protocols, we are now able to quantify every visit, every procedure, and every aspect of the study to make sure it ties back to something that we need to measure as part of our regulatory and strategic pathway.
VICTORIA DIBIASO Global head of clinical operations strategy and collaboration, Sanofi
Wearable devices certainly play a role as well. Live data from patients experiencing symptoms can be automatically entered into data centers where they can be reviewed by researchers. In diabetes research, DiBiaso notes data on patient glucose levels can go directly to clinical trial sites, where the data and monitoring are performed in real time.
“We know that sites are dealing with multiple vendors for their data collection and trial management systems, so looking at technologies that simplify their daily tasks is another goal,” states DiBiaso. “There are technologies that now enable sites to use one universal sign on and have one place to go to access all the information housed in a trial. Some day we also hope to see predominant use of eSource, where data captured from a patient can be input and directly moved into a clinical trial database, avoiding some of the manual administrative work that many sites are required to perform.”
Simply making patients aware that trials exist is a final goal that Sanofi is pursuing. In the past year, the company created The Clinical Study Guide website that explains why trials matter, how they work, what a patient can expect from participating, and even facts to debunk many of the myths about trials. The site was developed in partnership with patients and sites. Social media channels also are being used to help patients locate trials that may be a fit. Since patients do not spend a lot of time online looking for studies, Sanofi is making the process of locating a trial easier for them.
“We participate in industry benchmarking such as CMR (Centre for Medicines Research),” says DiBiaso. “Based on last year’s numbers, our cycle time is faster than the industry median. We are seeing improved results from our efforts, and we are not letting up. We have a mandate to continue to evolve and make the process even more efficient. Like others in the industry, we had been struggling with protocol amendments, but in the last six years we have been able to cut them in half. We are seeing improvement in site performance and a reduction in screen-failure rates. We are seeing a reversal in all of the complexity around performing clinical trials, and that has us feeling very optimistic.”