Navigating the challenges of large, international Phase III breast cancer trials

As breast cancer research advances with increasing molecular complexity and therapeutic innovation, global Phase III trials face significant logistical and clinical challenges. Sponsors and investigators must conduct large, multi-regional trials that accurately reflect real-world diversity and meet both scientific and regulatory standards. Companies that tailor their operational strategies, integrate advanced biomarker testing, and leverage local regulatory expertise can gain a competitive edge. 

The recent positive results of triple therapy for ER-positive, HER2-negative, PIK3CA-mutated breast cancer resistant to endocrine treatment highlight the growing potential but also complexity of breast cancer treatment today. Patients on a three-drug regimen lived a median of 7.3 months longer than those who received the standard two-drug treatment.¹ Subtyping patients and the increasing use of double and triple therapies have made breast cancer trials among the most competitive and complex to conduct.

The excellent prognosis for breast cancer patients today (the 15-year relative survival rate is 81 percent²) requires large Phase III trials that last for years to show that new treatments improve overall survival. In other cancers, smaller, quicker studies can show efficacy. Meeting the necessary patient numbers and trial goals demands multinational studies involving 20 to 50 countries, which involve significant complexities due to regional and cultural differences in access to care.

At Parexel, over the past five years, we have conducted more than 175 breast cancer trials, including 26 Phase III studies that generated pivotal data to support three FDA approvals. We focus on five core capabilities to mitigate the most significant risks:

1. Seamlessly integrate biomarker testing

Biomarker testing is essential in the choice of treatment for the entire spectrum of breast cancer. Advances in biomarker validation in tumors, including the discovery of cell-free DNA, suggest that monitoring biomarkers over time may improve breast cancer treatment by directing the right patients to combination treatments. However, designing trials for biomarker validation is complex because molecular targets shift constantly as disease progresses and becomes resistant.

Incorporating advanced testing, including next-generation sequencing (NGS), into large global studies can be a challenge for sites due to uneven accessibility and inconsistent practices across countries. In regions where biomarker panels are not yet routine due to their high cost, study sponsors must establish a testing infrastructure for the duration of the trial.

Since biomarker results determine treatment options, testing must be completed before randomization. Patients must provide timely tissue samples, often obtained through invasive procedures (especially for recurrent or metastatic disease), to qualify for the trial. Site staff must educate patients about the burdens of pre-testing and be sensitive to their decision-making process, addressing risks while also detailing the possible benefits of experimental treatments. To interpret efficacy data accurately and support regulatory and clinical relevance, stratification or pre-specified analysis by key molecular biomarkers, such as ESR1 and PIK3CA, is increasingly critical in HR+/HER2- breast cancer trials (Table 1). 

Table 1. Stratification or pre-specified analysis by key biomarkers is increasingly critical in HR+/HER2 breast cancer trials

Obtaining tissue samples and managing the logistics of analysis, including regulations on cross-border transfers, often presents major operational challenges. For instance, China prohibits biomarker samples from leaving the country.

At Parexel, we prioritize developing local testing capabilities in regions where they are not commonly available and in countries that restrict sample exports. We choose the most appropriate local vendors and laboratories based on trial requirements and carefully manage those relationships. In regions where advanced genetic testing and precision breast cancer treatments are not commercially available or reimbursed, clinical trials offer significant benefits by providing access for patients. We emphasize the medical value of biomarkers and precision medicine in these areas to motivate patients to enroll.

We recommend that sponsors streamline the biomarker screening process by using clinical enrollment managers for up to one year after the study starts. During this time, they visit each site roughly three times and can make extra visits for underperforming sites. Trained on study details, enrollment managers create a site-specific plan for recruitment and retention. They support patient chart reviews, handle the pre-screening requirements, and assist in identifying and enrolling more patients. Our data shows that enrollment managers can significantly increase screening and randomization rates (four-fold in one recent study), decrease screen failure rates (by 16 percent in another study), and convert non-enrolling sites into active participants.

2. Understand global variation in standards of care 

Some standard-of-care treatments, such as the CDK 4/6 inhibitors (abemaciclib, palbociclib and ribociclib), approved and widely available in Western countries, may not be reimbursed, or even registered in other regions, including Japan and Brazil. 

The FDA, EMA, and other regulators require trials to evaluate new drugs against a consistent standard of care. Adapting trial designs to account for regional differences while maintaining statistical validity and ensuring global approval is a major challenge. 

For example, U.S. investigators may prefer to treat breast cancer patients with approved standard therapies, which can result in slower enrollment at U.S. sites. However, including enough U.S. patients is important for FDA filing as the agency mandates that nearly 20 percent of patients in oncology trials receive a “U.S.-relevant” standard of care.  

While a single standard of care is generally necessary for accurate global results, it is possible to include multiple relatively equivalent standards of care in different countries within one trial arm, with explicit regulatory approval of the proportion of patients from each region.

Strong global regulatory intelligence is a crucial advantage when selecting the comparator arm and eligibility criteria. We have experienced medical monitors in China and Japan who provide us with geography-specific medical insights, helping to inform trial feasibility, address local challenges, and broaden inclusion criteria. 

We recently worked with an emerging biotech company to design a Phase II breast cancer trial in Japan. Japan has a high prevalence of hepatitis B and C, and our monitors understand that Japanese regulators require sponsors to enroll patients who are positive for hepatitis B, provided their disease is inactive. Most protocols routinely exclude such patients, so broadening the inclusion criteria made it more relevant to the patient population and improved recruitment. 

Early and transparent communication with regulatory agencies is essential for achieving consensus on the acceptable proportions of patients from various regions and differing standards of care or eligibility. With regulatory approval, trials can enroll patients in countries where the standard of care differs (but is not inferior) and maintain statistical integrity.

3. Stage disease progression accurately 

Breast cancer is a heterogeneous disease with multiple subtypes, such as hormone-receptor-positive/ HER2-negative, HER2-positive, and triple-negative, each with a different prognosis. It is increasingly complex to stage patients into high-risk versus intermediate-risk subgroups based on nodal disease (lymph node status indicates whether the axillary nodes contain cancer), disease characteristics, biomarkers, and prior treatment regimens.

Some investigators liken the process to “finding two needles in a haystack.” Sponsors must identify patients with specific genetic biomarkers at the precise point in their disease progression when the study is relevant. If pre-screening or enrollment is inefficient and takes too long, a patient may become ineligible. Differentiating between intermediate- and high-risk patients based on nodal status and genomic biomarkers for adjuvant (early-stage disease) trials is especially challenging.

Eligibility criteria are typically precise regarding allowed prior therapies and treatment duration. For example, we recently worked on a study recruiting patients with metastatic disease who had received at least 28 days of hormone therapy and received their initial diagnosis no more than five years earlier. Many women have been on hormone therapy for decades and were therefore excluded, and enrollment was complicated.

When enrollment criteria are narrow, site selection must be meticulous. Sites can gain visibility and recognition from being involved in important studies, which may prompt them to promise more than they can deliver. So, we carefully evaluate sites’ enrollment estimates during the qualification process to ensure they can produce a viable number of patients.

Staging disease progression accurately and identifying patients at the right moment requires a fine balance of protocol precision and operational flexibility. By combining real-time feasibility data, thorough chart review practices, and proactive site engagement, we help ensure eligible patients are identified and enrolled before they progress beyond inclusion criteria. Ultimately, successful staging is not only about biomarker detection — it’s about anticipating when and where patients will be most accessible and building protocols and site strategies accordingly.

4. Enroll on time in every region

Global breast cancer trials require expertise in navigating country-specific challenges and opportunities. Large trials provide patients in underserved regions with access to new drugs, advanced surveillance (such as scans), and comprehensive follow-up care that they might otherwise not be received. Clinical trials can also indirectly educate local oncologists and sites on advanced treatment approaches and biomarker testing, raising the standard of care in those regions. Providing medication and close follow-up creates expenses for sponsors which may vary among regions. In China and Turkey, sponsors and CROs must contract a vendor to perform all the administrative responsibilities of a clinical trial. The vendor serves as the study coordinator (a role typically performed by the sites), submits data from laboratory tests, schedules site visits, and reimburses patients. They also conduct some generic examinations, such as echocardiograms and general physical exams, away from the investigative sites, which adds expense to the trial for the sponsor.

Keeping trials on track requires the willingness and ability to address problems as they arise. Recently, we assisted in rescuing a large international breast cancer trial that was struggling to recruit patients at a sufficient rate to meet its development timeline. One problem was the eligibility criteria, which were very difficult to meet. We partnered with the sponsor to revise the recruitment and retention plan. 

First, we provided sites with a dedicated medical contact, available to answer questions and clarify procedures at any time. This immediately increased communication with the sites and provided an opportunity to educate staff about the trial. A medical monitor is available to sites 24 hours a day, in every time zone around the globe, for emergencies and eligibility issues. Clinical research associates (CRAs) began communicating with site staff twice a week to optimize pre-screening and monitor enrollment. Clinical operations leaders and medical monitors contacted principal investigators (PIs) to discuss enrollment issues and the overall progress of the study one-on-one. Establishing continuous communication with site staff, adding personnel, engaging PIs, and conducting global calls for the study team created a positive environment and boosted teamwork. The trial has started enrolling patients at a faster clip and is now on target. One site in Korea enrolled 24 patients within two months.

5. Ensure patients and sites stay engaged

Because the breast cancer clinical trial landscape is highly competitive, sponsors must remind sites to focus on enrolling patients in their trials through consistent communication and reminders. Sites with multiple breast cancer trials running simultaneously may require extra attention. 

Trial protocols should be simple and align with the standard of care. As breast cancer trials can involve multiple drugs with different modes of administration, sponsors must motivate patients to participate and adhere to the protocol-specified regimen for years. At Parexel, we provide comprehensive training for site staff on complex regimens and proper administration techniques. We also offer resources and support to educate patients and ensure adherence, particularly for long-term oral therapies.

Creating online sites and patient engagement portals for each study can maximize and maintain engagement with site staff and patients. The portal provides easy access to study information, including frequently asked questions, study binders, and a document library. Patients get access to study news, links to health-related websites, and visit reminders sent directly to their smartphones with visit-specific details, so they are prepared and ready for every visit. Site staff can access study-specific training modules, study-related systems, and a patient visit manager tool, among other features. 

We created and utilized an engagement portal in one recent Phase III metastatic breast cancer trial at 188 sites in 16 countries. Fifty-six percent of sites in the trial consistently utilized the portal, and 79% completed online training. Sites that used the portal had 20 percent higher enrollment rates, 50 percent lower screen failure rates, and 21 percent fewer protocol deviations compared to those that did not.

Turning challenges into opportunities

For sponsors, navigating the complexities of large, global Phase III trials is paramount for successful breast cancer drug development. The ability to select efficient regulatory pathways, address diverse standards of care, integrate complex biomarker testing, and rapidly enroll patients in multiple countries provides a critical competitive advantage. The rapid pace of medical, scientific, and technological advances in breast cancer diagnosis and treatment, including the emerging field of dynamic biomarker analysis, will continue to demand sophisticated global trial capabilities. 
 

Disclaimer: Parexel provides the information contained in this document for educational purposes only. The information does not constitute legal or regulatory advice. Readers should not act upon this information without seeking advice from professional advisers. 

Resources

1. Overall Survival with Inavolisib in PIK3CA-Mutated Advanced Breast Cancer, The New England Journal of Medicine (May 31, 2025).
2. Breast Cancer Facts & Figures 2024-2025, American Cancer Society (Accessed June 30, 2025).
    

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