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Immunotherapy has played an integral role in oncology research for more than a century, but in the last few years we’ve seen extraordinary discoveries that are transforming the way we think about cancer treatment. New advances in immunotherapies including cancer vaccines, CAR T-Cell Therapies, PD-1/PD-L1 inhibitors, and other therapies and diagnostics are transforming the standard of care and significantly improving survival rates for these patients.

This transformation is exciting for industry, but it is adding a lot of complexity to the drug development process that sponsors, CROs and investigative sites need to address. Delivering targeted immunotherapies to market requires more sophisticated site selection, and monitoring and oversight processes particularly in early phase trials in which changing standards of care and multiple arms can easily overwhelm site staff adding time, cost and risk to the trial process.

But it doesn’t have to be overwhelming. When sponsors and CROs address the following five challenges they can mitigate many of the risks that come with these trials and increase the ease with which they bring these treatments to market.

Challenge #1: The rapidly changing standard of care

Immuno-oncology research is a constantly changing science, and every new discovery has the potential to impact related ongoing trials. For example, FDA’s approval of nivolumab and pembrolizumab,  which are both PD-1 inhibitors, changed the standard of care for non-small cell lung cancer (NSCLC). If a sponsor was running a third-line study after those drugs were approved, the trial might suddenly become difficult to recruit.

To increase site’s adaptability, studies should be designed for flexibility to better enable changes midstream. This includes having pre-defined processes in place to quickly amend protocols, communicate changes to site teams, and reallocate human and capital resources as necessary. It also requires a robust education program for site monitors and investigators to keep them fully up to date on changing safety signals, including evolving toxicity management guidelines, and the importance of tracking immuno-related events as evidence of progression.

Once the trial is in operation, sponsors and CROs should pay attention to potential shifts in the research landscape, focusing not just on what is happening today, but what drugs could come to market in the next three-to-five years and how that could impact the success of their studies and eventually the successful commercialization of their products.

Challenge #2: Multi-cohort studies demand new levels of flexibility

One of the great benefits of immuno-oncology agents is that they can often be effective for multiple indications. That also drives one of the biggest complications associated with conducting these trials. In many cases arms will be added mid-research as the investigators garner new insights about how the agent works. This forces sites to rapidly adapt, adding staff and infrastructure to support new arms, often with little notice. In some cases, a single site may find itself managing 5-10 or more arms, which requires site leaders to be ready to bring on additional research nurses and sub investigators, and to manage a mélange of overlapping deadlines, changing protocols, and unique lab requirements for each patient population. This can create a catch-up environment at sites, which adds risk to the research process.

To minimize the potential for chaos and room for error, sponsors and CROs should be attuned to the capabilities of the current sites’ teams, so when they launch additional arms they know if they will need to bring in more experienced site leaders who specialize in managing multi-arm sites, and monitors who are adept at working across indications and acting as a liaison between multiple sites.

Challenge #3: Speed of enrollment

Every trial sponsor wants to see fast enrollment, indeed in some cases, strong interest in an immuno-oncology trial can lead to faster than projected enrollment rates. This flood of new patients can create a backlog of data that requires rapid data capture and management to stay on top of results. Without the right team in place, getting an analysis out-the-door can be a challenge. To prevent data jams, sponsors and CROs should do proactive planning with all of their sites d to adapt if enrollment rates surge, and set aside additional budget for bringing on extra staff to perform data entry and query resolutions if needed.

The inverse of this problem is a sudden slowdown of recruiting, which can happen when availability of new compounds shifts subject interest in participation. To avoid being blindsided by such trends, principal investigators and key opinion leaders should be tasked with keeping sponsors abreast of what is happening in the marketplace, and watching for changes in standards of care that could impact enrollment. This allows site teams to be better prepared for changes, and to adapt their enrollment strategies to pick up the slack.

In all cases, shifts in enrollment can also be more easily managed when sponsors invest in cross training key staff so they have the flexibility to move between sites, assisting teams that need additional help, and reducing overhead at sites that are slowing down.

Challenge #4 Combination therapies

Combination therapies are becoming a key aspect of immunotherapy trials, as these agents have often been found to work more effectively in tandem than they do in isolation. However, working out the ideal dosing regimen for a combination therapy can be difficult, especially in early phase studies where concurrent and sequential dosing or run-in periods are being tested. In some cases, each agent on its own will generate minimal negative effect, but together they create an unacceptable level of toxicity that will need to be addressed.

To manage these challenges, investigators need to be trained to look for immune-related adverse events as well as standard toxicities. Site teams also need to be prepared to look for early safety signals on these combination therapy trials, and ready to rapidly redesign protocols, clinical databases, electronic case report forms, and downstream biostatical analysis in response. These changes can add significant time and money to the research process, adding risks that sponsors should consider when planning their schedule and budget.

Challenge #5 Tissue samples and biomarkers

The importance of tissue samples and biomarkers in these trials cannot be overstated. These are tools that are the key to identifying whether an agent is having the desired result, and determining which populations respond to certain treatments and why. These data are crucial to supporting more efficient go/no go decision-making and to helping stratify the patient populations most likely to benefit from a new agent. But these benefits can only be achieved if sites get every sample right, every time.

This is a high-risk area of immunotherapy research that requires expert lab staff who can rapidly turnaround key analyses and decision points, and a robust tracking and coordination program to ensure that samples are properly collected, stored and shipped and that the resulting biomarker data are carefully captured. We have found the best approach to managing this critical aspect of the research is to assign a dedicated project management resource whose job is to follow up on all samples and to track collection, shipment and sample tracking. This dedicated resource will also work in close collaboration with central lab provider and analysis vendors to prevent any mistakes.


The primary lesson with all of these challenges is to plan ahead, and make sure you have processes and trained staff in place to adapt to the unexpected. Immuno-oncology trials may be a lot more complicated to deliver, but the impact of these products on patients and the business make dealing with this complexity well worth the effort.

Topics in this blog post: Biologics, Biomarkers, Clinical Trials, Genomics, Oncology