Precision oncology trials face unique operational challenges in the study start-up phase because patients must be screened for an exact molecular profile. Determining eligibility typically requires advanced genetic testing and imaging. Therefore, enrollment can have long lead times, and sponsors must anticipate and solve problems early to meet development deadlines. Here are three challenges sponsors face and how they can overcome them.
1. Genetic testing capabilities and regulations vary by region.
Genetic testing infrastructure varies by country, province, and institution. One site may use next-generation sequencing (NGS) for molecular tests, while another may use polymerase chain reaction (PCR) technology. The level of analytical validation of those assays may vary. Sponsors conducting global trials must compensate for the variability to avoid lagging enrollment due to testing delays and errors.
At Parexel, we have detailed knowledge of genomic tests, costs, coverage, and utilization for many countries and institutions gleaned from hundreds of precision oncology trials. Timely enrollment depends on selecting vendors who have experience with specific tests and can turn them around efficiently. Genomic testing is specific to each kind of cancer, so sponsors must provide sites with clear, indication-specific workstreams to identify biomarker-positive patients.
This will necessitate intimate knowledge of the regulatory framework. For example, an immunohistochemistry (IHC) test in the EU must be validated and approved before it can be used in a clinical trial. In the United States, the FDA classifies IHC assays as in vitro diagnostic (IVD) medical devices and may require a pre-investigational device exemption (pre-IDE) depending on their use.
The FDA has approved several precision oncology drugs without a companion diagnostic test (CDx), requiring post-market assay development instead. However, a missing assay can negatively impact market uptake, patient safety, and access.1 Developing a novel biomarker test often requires sponsors to transition from a research-grade assay to a clinical-grade one. This is a multidisciplinary challenge because there are no validated diagnostic tests for novel biomarkers, and knowledge of their prevalence and the prognostic impact of positivity is limited.
We advise sponsors to conduct an exploratory study early to determine whether they need a biomarker. Ideally, by Phase 2, they must know whether they need a CDx to stratify patients or whether they can test efficacy in an all-comers trial. Statistical modelling can identify the optimal strategy. By Phase 3, they need a validated, clinical-grade selection tool.
The complexity of the EU’s In Vitro Diagnostic Regulation (IVDR) requires that sponsors initiate diagnostic test development simultaneously with clinical development. At Parexel, we have helped sponsors validate 14 novel biomarker tests through the IVDR process, accelerating patient selection and approval of new targeted treatments.
2. Radiopharmaceutical trials require specialized professionals and preparation.
Radiopharmaceuticals use a monoclonal antibody to target specific proteins on cancer cells and deliver a cell-killing radioisotope. First-generation products struggled commercially due to the lack of infrastructure and expertise in handling the therapies. However, second-generation products have achieved commercial success due to improvements in standard care and radioisotope stability. Interest in radiopharmaceuticals and theranostics (which combine diagnostic and therapeutic components) is thus surging.2
Developing a radiopharmaceutical remains operationally complex, requiring detailed knowledge of the regulatory landscape, proactive planning, and sites with nuclear medicine capabilities and experience. Theranostic scans and treatment steps are not usually part of standard oncology practice at sites. Nuclear physicists must be involved in the patient care pathway because they understand atomic decay processes, safe radiation dosing, and how to minimize patients’ and staff’s exposure to radiation. Theranostic scans can result in higher screening failure rates than anticipated, so sponsors should identify additional sites that can compensate.
Study design and coordination demands a detailed understanding of the IMP manufacturing trajectory and handling requirements. Sites must obtain radioactive materials (RAM) licenses with the proper certifications and approval from radiation committees for the specific isotope. The IMP is subject-specific and shipped after screening. To ensure that the appropriate treatment is delivered to the right patient at the right time, the IMP manufacturing and shipment times must align precisely with the scheduled visits of enrolled patients.
At Parexel, we have conducted 20 radiopharmaceutical trials in recent years, from Phases 1 to 3. We focus on launch excellence, including meticulous site selection (PET scanners, radiation therapy facilities, and experience with radioligand handling, administration, and disposal are critical capabilities), patient-centric trial design, thorough site engagement (including training and education on radiopharmaceuticals), vigilant supply chain management (including contingency plans for radioisotope supply disruptions), and strong collaboration among nuclear medicine physicians, oncologists, radiochemists, medical physicists, and study staff.
We assign a Launch Excellence Lead (LEL)—a specialized position we created in recent years—to every precision oncology trial we conduct. The LEL uses lessons from prior trials to optimize the study design and execution. They do this by accessing our internal precision oncology database, which contains site-specific historical data on enrollment performance, start-up cycles, and regulatory approval committee structure.
3. Precision biosimilar trials entail a global footprint and intense site training.
Precision biosimilars must be tested in Phase 3 trials to demonstrate equivalence to the reference biologic product. However, enrolling patients in these trials from Western countries where the original molecule is widely available is increasingly difficult. Studies must, therefore, be conducted in countries such as Malaysia, Thailand, Turkey, Moldova, and Mexico, where access to the reference product is limited. Equivalence trials offer patients a chance to receive advanced therapies they otherwise could not.
Companies must take precautions when conducting clinical trials in countries and institutions with less experience and infrastructure so as not to compromise data quality. For example, in Western countries, it is common to administer the Eastern Cooperative Oncology Group (ECOG) performance test to determine eligibility for cancer trials. ECOG performance scores range from 0 (normal) to 5 (dead) and strongly correlate with survival. An ECOG status of 0 or 1—which indicates at least 3 months’ life expectancy—is a common eligibility requirement. In other countries, the test, which requires subjective judgments, is often not routinely administered. Mistakenly enrolling patients with an ECOG score of 2 or more could result in excessive deaths attributed to the biosimilar. We, therefore, engage proactively with sites to thoroughly train PIs and site staff in scoring patient function via the ECOG scale.
We recently launched a scholarship program offering mentorship, infrastructure support, and guidance to emerging clinical research sites to resolve some of their challenges and better enable them to succeed. In countries with a suboptimal standard of genetic testing, sponsors must fund new or additional testing resources to ensure that patients meet precise molecular eligibility criteria. And where the local level of expertise is low, sponsors must act early to bring sites up to speed and sustain training throughout the study.
We are currently conducting a large Phase 3 trial of a biosimilar to treat a prevalent solid tumor indication. The trial requires excluding patients with a host of biomarkers, such as ALK, BRAF, and KRAS, so it entails extra layers of testing and a high screening failure rate because many patients have these biomarkers but have never been tested for the genetic profile of their tumors. It’s vital that the process is efficient; any testing delays could disqualify eligible patients through disease progression. So, during the planning phase, we identified local experts to engage the PIs and sites in each country and region. Regular personal calls to PIs and additional meetings, including social events, have successfully brought disparate sites up to speed quickly.
Launch excellence in precision oncology trials requires early engagement, proactive planning, and the willingness and ability to address challenges upfront.
Contributing Expert