Operational strategies for faster, more efficient pivotal NSCLC trials

Non-small-cell lung cancer (NSCLC) exemplifies personalized medicine: many clinical trials target patients with specific genetic markers and prior treatment regimens. Phase II and III trials are thus operationally complex and fiercely competitive. Increasing molecular segmentation, the rapid evolution of first-line standards of care (SOC), and competition among trial sponsors for a dwindling pool of eligible patients are three significant challenges to patient enrollment. 

Recruiting patients with advanced or metastatic disease who have failed prior therapies is especially difficult because these patients often have poor performance status scores, making travel to sites difficult, and they may have rapidly progressive disease, which requires fast and efficient eligibility testing.

Despite the challenges, sponsors can quickly recruit enough patients by focusing on data-driven site selection, careful protocol optimization, efficient eligibility screening, and ongoing patient and site engagement. At Parexel, we have conducted more than 150 NSCLC trials in the past five years. We have found that successfully delivering later-phase trials depends on discarding traditional assumptions and managing foreseeable challenges.

1.    Choose sites based on performance data 

Traditionally, sponsors choose trial sites after reviewing self-reported enrollment projections. These are usually based on data from standard questionnaires (10-15 pages!) filled out by site coordinators who must estimate patient accrual, even if a site has never run a study in a similar patient group. Often, the projections rely on guesswork. A site coordinator cannot accurately predict how many patients will meet the trial inclusion criteria and agree to participate.

At Parexel, we verify sites' data with a feasibility analysis, examining startup times, contract negotiations, IRB decisions, and patient metrics using our internal data, the medical literature, and benchmarking databases. 

Investigative sites for targeted NSCLC therapies must have qualified researchers and advanced facilities. We maintain a comprehensive profile of the interests, geographies, capabilities, patient populations, and principal investigators (PIs) of more than 300 oncology sites in our Site Alliance Oncology Network. We also have additional data on more than 8,400 sites where we have conducted NSCLC trials. 
Strategic site selection can identify sites that are well qualified to run trials. However, in an NSCLC trial spanning dozens of countries, patient accrual may vary widely.

For example, if an NSCLC study requires eligible patients to have had prior treatment with a PD-1/PD(L)-1 inhibitor, that could slow or even halt recruitment in India and Latin America, where advanced NSCLC is prevalent, but checkpoint inhibitors are not routinely used because of their high cost and lack of reimbursement. In one recent Phase III NSCLC trial we conducted in 22 countries, patient enrollment ranged from 100 in one European country to four in another. Knowledge of each country’s standard of care (SOC) is essential to accurately project enrollment for a multinational study. 

At Parexel, we recommend sponsors select a diverse mix of sites to balance risk and reward, similar to how a financial advisor builds an investment portfolio. An ideal site portfolio should include sites with smooth, non-bureaucratic activation processes that can quickly achieve key study milestones such as first site initiated (FSI) and first patient in (FPI). We call these ‘rapid responder’ sites because FSI and FPI milestones generate momentum and enthusiasm. However, such sites don’t always recruit the highest volume of patients; sites with slower start-up times may ultimately enroll the most patients. 

Recently, a biotech company asked us to review its site list for an NSCLC trial, which included KOL sites involved in preclinical studies. While enthusiastic, these KOLs had a poor accrual record. We advised broadening the site and KOL list to meet timelines and enable a faster start. 

2.    Simplify protocols to get the data you need

New products need a comprehensive data package to communicate value to multiple stakeholders. However, sponsors commonly present us with protocols to collect much more data than they will need. We have reviewed some that include more than 30 secondary endpoints, each of which requires procedures, monitoring, and data collection, which increases time and costs.
We advise sponsors to limit data collection to the smallest necessary number of endpoints that will demonstrate sufficient clinical activity, meet regulatory requirements, and support reimbursement. An optimized protocol includes one or two primary endpoints, a highly relevant subset of secondary endpoints (five to ten at most), and a limited number of patient-reported outcomes (PROs), with clarity on what is collected and why.

Recently, we conducted a trial where many patients did not finish their electronic PRO (ePRO) diary entries. Sick and elderly NSCLC patients were not familiar with the technology, the study protocol did not allow a caretaker or monitor to document their status for them, and the lengthy questionnaire was too time-consuming. Clinical research associates (CRAs) spent many unproductive hours tracking non-completion of the ePROs, even though the data was neither for primary nor secondary endpoints and would not impact the trial’s results. 

PROs can be incorporated into the evidence generation plan, but collection must be appropriate to the patient population. For example, electronic diary entry can be more user-friendly and intuitive if the app is available on patients’ existing personal devices, such as their smartphones. 

Emerging companies need data that builds investor confidence as quickly as possible. At Parexel, we've helped small to mid-sized companies modify their data collection plans, sometimes increasing or decreasing the number of data points, thereby improving fundraising rounds. A limited budget can even be advantageous if it forces more efficient, cost-effective protocol design. 

3.    Streamline screening to avoid delays

Screening patients for an NSCLC clinical trial, particularly one requiring biomarker profiling, involves submitting slides of their formalin-fixed paraffin-embedded (FFPE) tumor tissue in sufficient quality and volume to establish eligibility. In the second- or third-line treatment setting, patients have already provided a biopsy sample and often have very little tissue left, so they may need to undergo more than one biopsy to ensure sample quality. The availability and scope of next-generation sequencing (NGS) mutation testing vary by site, country, and region: in some localities, only EGFR and ALK testing is standard, whereas in others, a standard NGS panel will include many other mutations. Higher-than-anticipated screen failure rates can delay development timelines. 

We recently conducted a global Phase III trial that required up to 20 slides of tumor tissue from patients who had endured multiple therapies and whose condition was deteriorating. Concerns about the 28-day screening process and test turnaround times caused some sites to deprioritize the study. Many patients lacked high-quality biopsy samples that met slide criteria and were screened out, doubling the expected screen failure rate. To address the problem, we implemented a case-by-case review for patients with fewer slides but adequate biopsies, which allowed some to enroll. If tissue sample collection requirements are excessive and primarily used for exploratory analyses—such as future biomarker discovery, rather than as a primary or secondary endpoint—they should be reexamined. Sponsors can reduce screening times by expediting biopsy and lab procedures. For example, extended wait times for biopsy transport in parts of Europe can be prevented by submitting customs and import paperwork early, assisting time-sensitive patients. 

When different vendors handle biopsy and blood sample testing, samples can be shipped to the wrong location, delaying results for sites. Some vendors have limited legal approval and can only perform tests at a single facility. In a recent multinational NSCLC trial, all sites outside the EU, including the UK, Serbia, Australia, Korea, and Japan, had to send their biopsy samples to the United States for testing. As a result, only two central labs—one in the U.S. and one in the EU—received samples from every site for biopsy testing. Many sites considered the centralized process too slow, given the severity of the patients’ disease. 

At Parexel, we tackle screening challenges with clear instructions and a sample tracking system that helps sites send the correct samples to the appropriate vendor. We also provide additional biopsy testing locations whenever possible. Our project teams train site personnel on the study protocol and the inclusion/exclusion criteria before starting screening. Medical monitors make booster calls to the PIs and clarify screening best practices.

4.    Anticipate concerns about the comparator arm

The SOC comparator arm for second-line treatment of advanced or metastatic NSCLC trials is typically docetaxel, which has been used since its approval around 1999. Patients and PIs perceive it as having limited efficacy and significant toxicity, leading to a perceived lack of clinical balance. The same perception exists for other SOC arms used in NSCLC studies. For randomized open-label studies, negative perceptions of the SOC arm have serious consequences: PIs may be hesitant to offer the trial to their patients; patients may be reluctant to enroll and may drop out of the trial post-randomization after they learn they have been assigned to the SOC arm. 

At Parexel, we approach this challenge proactively. For example, we consistently communicate to PIs that docetaxel remains the established benchmark and that genuine equipoise exists, as many new agents have failed to outperform it. This makes participation an ethical choice. We produce educational videos for the main investigator meeting, in which the coordinating PI explains the trial's significance and how post-randomization dropouts can jeopardize results. This recording can be reused when onboarding new site staff.

We also prioritize regular PI engagement. We flag underperforming sites using predetermined triggers and implement high-impact interventions like booster visits or direct calls between our MDs, the sponsor, and the site PI. In a recent trial, some of these calls addressed PI concerns about the inclusion/exclusion criteria and directly led to new patient screenings. Although these outreach activities require significant resources, they pay back by helping reach key milestones. A regional PI meeting is a less costly, though possibly less effective, alternative.

Allowing patients to cross from the SOC arm to the investigational arm on progression can help with recruitment. However, it can complicate the overall survival (OS) endpoint, as "salvaged" patients in the control arm hide the true survival benefit of the new agent, which is a major issue for regulatory bodies.

The strategies outlined here—from data-driven site selection to efficient protocol design and proactive engagement with sites and patients—are not just responses to current challenges but a blueprint for the future of oncology clinical trials. As personalized medicine advances, with increasingly complex and segmented patient populations, the ability to rapidly adapt and implement intelligent, flexible operational models will be the key to accelerating the delivery of life-changing therapies to patients. The era of static, one-size-fits-all clinical research is over; success now hinges on discarding old assumptions in favor of dynamic, responsive, and patient-centric approaches.

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