Clinical Trial Agreements Evolving as Postpandemic Era Gains Traction
As the pace of nonCOVID-19 trials picks up, some contentious issues are arising in the negotiation of clinical trial agreements (CTAs), partly due to what sites were willing to agree to at the height of the pandemic when most CTAs focused on COVID vaccines or treatments.
“Now, everyone is trying to make up for lost time and there’s a big push to get a lot of CTAs done,” said Amanda Coulter, affiliate attorney at Coppersmith Brockelman.
Coulter, who represents sites — specifically, community hospitals and groups of physicians who want to be site investigators — said she noticed that during the pandemic sites often agreed to terms that were not favorable to them, simply because all the stakeholders were looking to get things done quickly.
“I’m finding that sponsors are now requiring things. For instance, they will require that a site counter-indemnify the sponsor. That’s not something that I recommend my clients agree to. I feel pretty strongly that if it’s the sponsor’s drug, device or protocol, that they should be indemnifying the site, and the most the site should agree to is to be responsible for their own actions. But sites often, in haste, just rolled over on CTAs. Now the sponsors are trying to say, ‘Well, you agreed to it before, so that’s what we’re going to offer you this time — take it or leave it.’”
The issue of indemnification has become more contentious as the pandemic wanes, Coulter said. “That’s the most important section of the CTA, and that’s where I’m seeing sponsors and CROs becoming more inflexible. It feels that they are very rigid and not very flexible to negotiating the terms.”
Attorney Sarah Ferranti of Epstein Becker & Green, who primarily advises sponsors and sites but has also represented CROs, said she frequently sees new and updated terms in CTAs, especially in the traditional contract terms on indemnification and subject injury.
“We are continuing to think through in the context of COVID-19 and on whether a clinical trial sponsor is possibly picking up the costs associated with a COVID-19 infection,” she said. “That’s where the difference in language might matter. If a sponsor is covering costs arising from participation in a clinical trial, that could pick up if a patient went to the site and got COVID-19. But if the sponsor is covering costs that were directly caused by administration of a study drug, that excludes a potential COVID-19 infection. There are also some wrinkles when the study drug itself may be something that makes the patient more susceptible to a serious infection. So these liability terms have shifted a bit.”
The postpandemic era is leading to a period that Coulter jokingly calls “spring fever plus COVID fatigue,” where sponsors, CROs and sites “are exhausted and inflexible, and the ‘let’s work together attitude’ has faded away.”
But Leanne Tran, principal at JD MD Solutions and manager of research counsel at Sinai Health Systems, said she thought both sites and sponsors were amenable to sharing data and added that sponsors don’t appear rigid on intellectual property (IP) issues. “That’s often some of the trickier language that we have to settle on.” Tran, who advises sites, said the language she frequently inserts into CTAs covers the transfer of data, data-sharing, the transfer of samples and IP ownership. “There seems to be a consensus to work together. Some parties are deciding to develop something jointly and have joint ownership, joint IP, and will figure the rest out later, rather than trying to hammer everything out and thinking of every conceivable situation and covering for that.”
Ferranti said CTAs will need to address issues surrounding data-sharing. “Both sides need to be really thoughtful about how data can be used by both the sponsor and the site. Sites want to potentially make more use of clinical trial data as the world recognizes the value of data going forward.”
She added that CTAs will also need to accommodate third parties involved in research that are independent of sites and sponsors — such as telehealth companies, pharmacies and labs. “It used to be that every piece of a trial would happen under one roof. Now a trial can occur in a patient’s home or the local lab or a variety of different locations. How we assign responsibility for oversight of various activities and how the data-flows will work has required some shifts in thinking about how we’re going to contract around a regulatory framework that isn’t perfect any more for these different ways of implementing trials.”
This increasing emphasis on remote operations and remote monitoring has changed CTAs in several ways, the most challenging of which involves enabling sponsors to be able to remotely monitor studies for source data verification (SDV) and compliance, said Katherine Leibowitz, co-founder of the Leibowitz law firm, which serves as outside counsel for sponsors of multisite studies. “I’ve seen both sides, sites and sponsors, scramble to facilitate this.” But sites need to protect their data, she said, and sponsors need to be careful about the contractual terms imposed by the site. “Sometimes there are end-user license agreements that may conflict with the CTA. Both parties need to iron all of this out.”
Some experts say they have seen changes to the force majeure clause in CTAs over the course of the past year. Force majeure (or “superior force” in French) is intended to relieve the contracting parties of their contractual obligations due to circumstances beyond their control. Prior to the COVID-19 outbreak, this would typically include things like insurrection, war, riots or power loss. Since the COVID-19 outbreak, sites have started adding some variation of the following: disease, epidemic or pandemic.
“This can cause sponsor pushback in some cases. The feedback that we have received recently is that sponsors feel that after navigating this pandemic for more than a year, the sites have the tools they need (mask mandates, cleaning protocols, etc.) to continue to conduct clinical trials … with minimal impact,” says Lindsay McCarthy, vice president of study startup and administration at WCG PharmaSeek.
CTAs are also changing to allow more flexibility for sites. “Sites had to shift their studies away from hospitals to satellite and clinic locations,” Leibowitz said. “The site needs the flexibility to be able to do that and at the same time they need to be able to be responsible for those facilities and their personnel, especially if they’re separate legal entities from the site.”
The decentralization of clinical trials has also changed the nature of CTAs, said Ferranti. “During the pandemic, we added the language to CTAs that was needed to keep people out of provider sites and to pay more attention to diversity,” said Ferranti. “Today, we have sites that want to be able to add one or two elements to the CTA, like telehealth appointments and electronic consent. We get a lot of questions about how the FDA regulations, which were designed in the context of a brick-and-mortar trial, apply in a decentralized or remote trial because the investigator may not be as able to personally conduct the study or control the study drug. Those things are all in the regulations, but they have to be implemented in a different way. Those complexities need to be worked out.”
Another trend that accelerated during the pandemic, Leibowitz said, is the growing number of electronic touchpoints between sponsors, CROs and sites, amplifying risks to sponsors and sites alike. “You don’t want to have heavy information-sharing obligations with the other side,” she said. “Also, you want to make sure the other side has cyber insurance. A lot of entities don’t and are exploring it or they’re just starting to get it. This is an issue that wasn’t caused by the pandemic, but it certainly brought it into high focus and it’s definitely not going away.”
Other new language in CTAs covers the remote aspects of clinical trials, including ensuring the technology platform used by sites has been properly vetted to address IT information security and privacy concerns, Tran said. “We often have to increase the robustness of that language around privacy and data-sharing and to include the telecommunications aspect.”
Tran said the remote platforms that proliferated during the pandemic have given hackers more opportunities to steal data, so the CTAs need to include a commensurate amount of liability coverage. “We’re looking at making sure there’s particular types of insurance that we see in our contracts,” said Tran, who mainly advises sites but has also advised medical device companies. “In addition to general liability, clinical trials insurance and product liability, we’re also looking to make sure there’s proper cyber insurance should there be a privacy breach. There’s a lot of sensitive [protected health information] moving back and forth, so we look at this a bit more now.”
Leibowitz said she has noticed that sites were charging additional fees related to the pandemic, such as additional personnel for remote monitoring or personal protective equipment. “The higher payments should exist for as long as those additional costs are being incurred,” she said. “As the pandemic subsides and those costs are no longer being incurred by the sites, for both parties it’s an opportunity to be financially transparent and to let everyone know they are paying fair market value for services rendered.”
Leibowitz said she had a conversation recently with a sponsor who thinks they may not have to worry about remote monitoring as people are vaccinated and the pandemic subsides. “That’s one perspective,” she said, “but I think that if people continue to want to work from home or have a hybrid model, some of these changes may be here for the long term.”