Practical examples of why this needs to be a continuous process

Hot on the heels of the publication of PSI’s article in International Biopharmaceutical Industry, we present best practices and practical examples for employing continuous feasibility in pivotal studies in oncology.

Executive summary

  • Ongoing feasibility assessment plans for operational, regulatory, site, and patient challenges that will happen during the course of a clinical trial
  • Three factors that influence the ongoing feasibility of oncology clinical trials are:
    • Rapid evolution of standard of care
      • New approvals and updated treatment guidelines influence oncology trials more than other trials, partly due to their longer durations; development of newer therapies (ADCs, radiopharmaceuticals, and cell and gene therapies) are transforming the landscape
    • Global variability in drug availability
      • Regional differences in regulatory approval and patient access to therapies inform clinical trial design, and procurement and supply of new standard of care (i.e., control arms)
    • Changing site profiles
      • Sites overloaded with numerous trials struggle with effective recruitment – ongoing site evaluations, adaptive sponsor support, and building new relationships with sites are expensive
  • Three practical considerations to operationalize continuous feasibility are:
    • Capitalize on knowledge
      • Early collaboration with KOLs harnesses regional experience, and a decentralized feasibility approach means critical insights into trial design and local needs
    • Select sites in the context of new drugs
      • It is important to understand current site capabilities, and their ability to anticipate and deal with change. Early feasibility questionnaires, consistent site communication during trials, and using readiness scoring models can help ensure the right sites remain the right sites
    • Use data-driven feasibility tools, including AI
      • While more data sources can complicate analyses, AI can enhance trial feasibility – identifying protocol overlaps is one use – however, human decision-making remains critical
  • More than in other therapeutic areas, continuous feasibility assessment in oncology is crucial due to rapid innovations and evolving challenges

Why is it essential for oncology clinical trial feasibility to adapt continuously, rather than remain a one-time assessment?

Feasibility is one of the most important aspects of clinical trials, as it evaluates whether and how a trial can be successfully conducted. However, sponsors should not expect the set of conditions present at the start of the trial to persist. Looking ahead – drawing on data, industry news, and modeling – is essential to understand and prepare for future conditions.

  • Early feasibility is crucial for identifying challenges from every angle – patient, site, sponsor, CRO, SoC, and regulators.
  • Ongoing feasibility focuses on gauging study interest, site resources, capacity, capability, and evolving SoC during the trial.

At all levels, feasibility must be redefined as a continuous assessment of a trial’s ability to be successful across operational, regulatory, site, and patient aspects.

As standards of care and drug availability evolve, so do the operational demands of clinical trials, especially in complex, pivotal oncology studies. The continued emergence of new treatment modalities, such as multi-specific antibody-drug conjugates, cell and gene therapies, and radiopharmaceuticals, necessitates an evolution in the approach to oncology feasibility.

This white paper focuses on the most critical factors affecting oncology trial feasibility and provides practical recommendations for operationalizing ongoing assessments.

katarzyna moscicka profile

Continuous feasibility ensures adaptability to shifting operational demands, regulatory landscapes, and treatment modalities. It is the gold standard of feasibility that all trials, not just oncology trials, should be aiming for.

Kasia Moscicka, Head of Feasibility and Site ID, PSI

The three key factors that influence ongoing feasibility in oncology

Focusing on these key factors, with an experienced CRO partner, can reveal the most relevant influences for your clinical trial.

(1) Evolution of standard of care

In oncology trials, there is a frequent need for mid-study protocol amendments and revisions due to the development of newer therapies, new approvals and updated treatment guidelines. Protocol amendments occur more often (91.1% compared with 72.1%) and at a higher average number (4.0 compared with 3.0) than in non-oncology trials [1] (compounded by the typically longer duration of oncology trials compared to other trials, which increases the possibility of a change occurring during the study period [2]). New treatment modalities or methods, such as those below, are part of a paradigm shift moving oncology from broader, systemic interventions, towards complex, personalized, mechanism-driven strategies.

  • Antibody-drug conjugates (ADCs) offer the potential for precision targeting of a drug to a specific cell or tissue. However, this can limit patient access. Many ADCs target the same antigens, resulting in strict trial eligibility constraints, competition for patients among similar treatments, and challenges for oncologists and clinical trial design. To date, almost 30 HER2-targeted ADCs have been developed, with positive results in 23 clinical trials, and two FDA approvals [3]
  • Trials with radiopharmaceuticals require meticulous coordination in the face of challenges such as discrepancies in imaging capabilities, regulatory approval delays, and supply chain limitations of critical nuclear materials [4]. More than 1,350 clinical trials for cancer treatments using radioisotopes are underway [5], with technical challenges and the requirement for specialists with backgrounds in nuclear medicine and dosimetry the only limitations to this revolutionary therapeutic avenue
  • Cell and gene therapies also contend with strict patient eligibility criteria and the complexity of manufacturing and administration. They demand top-tier medical facilities and experienced teams of multidisciplinary staff with experience in high-dose chemotherapies, as well as the capacity for potential ICU admission and monitoring. Over 5,000 clinical trials are listed with the NIH [6], with oncology being the leading area of investigation (accounting for 80% of gene and nearly 70% of cell therapy trials) [7, 8]

The PSI example – diffuse large B-cell lymphoma

In Q1 2023, PSI enrolled its last patient in a study of a monoclonal antibody for the treatment of diffuse large B-cell lymphoma (DLBCL). Towards the end of the two-year enrollment period, the ADC polatuzumab vedotin-piiq was approved by the FDA, changing the standard of care. The feasibility of this study was due in no small part to its timing at this pivotal point in the evolution of the standard of care for DLBCL. If polatuzumab vedotin-piiq had been available, according to PSI’s landscape analysis this study simply wouldn’t have been feasible – the sponsor wouldn’t have achieved their milestones.

The PSI example – melanoma

Traditionally, cell therapy in cancer was focused almost exclusively on treating hematological malignancies 9. Now, there is a definitive shift to targeting other types of cancer, including solid tumors. PSI was approached by a global sponsor looking to run an innovative trial of their cell therapy in melanoma. Promising results in other types of solid tumors were a great starting point, however site selection was crucial if the therapy could be proven to work in melanoma. Sites needed dermatology/oncology experience, PIs with melanoma experience, cell therapies capabilities, and a limited number of competing trials. Choosing the right sites is critical – site selection and patient enrollment are currently underway.

The PSI example – solid tumors

PSI are currently running an ADC trial in patients with solid tumors; as with many ADC trials, additional and specific safety and PK monitoring is required (especially during the first few hours post-administration). Close safety monitoring ensures early detection and prompt management of adverse events, whilst maintaining the validity of any data generated. However, this results in an increased workload for sites (requiring real-time safety data review, and additional patient education and safety review committees). CRAs are able to collaborate and contribute, allowing sites to focus on treating patients; and data monitoring teams have experience and capacity working quickly and with large quantities of data.

(2) Changes in drug availability

Delays in regulatory approval (“drug lag”) and fragmented access to approved therapies lead to regional differences in standards of care, which in turn impact the design of clinical trials. Even after a drug is approved, differences in patient access can complicate the sourcing of trial control arms and comparators. Drug lag varies widely, ranging from 128 to 723 days in Europe to over 2000 days in some Asian countries [10-12].

These regional variations affect all stakeholders; PIs may hesitate to join new trials if established therapies show superior efficacy, especially in trials with placebo comparators. If a new standard of care is essential for a trial (per regulatory instruction), but is unavailable due to costs or logistics, sponsors must handle procurement and supply (increasing logistical challenges and expenditure). Furthermore, many trials have prior therapy components clearly defined as part of entry criteria. Country selection therefore must be based on SoC availability.

The PSI example – multiple myeloma

A phase 3 study of patients with multiple myeloma was initially enrolling well across Europe. However, midway through the enrollment period, the enrollment curve unexpectedly flattened. The cause? The approval of daratumumab, a monoclonal antibody, with reimbursement, that was quickly adopted as the new SoC. This trial, which had previously excelled at enrollment, now faced a 30% drop in interest among potential trial participants, with the sponsor at risk of missing its enrollment targets.

The PSI feasibility team proactively monitored the approval of emerging therapies and had prepared a contingency plan from the outset. Enrollment was opened in countries and sites that did not (yet) have access to daratumumab; in one month, approximately 15 new sites were activated. Ultimately, enrollment of more than 450 patients was completed on time.

The PSI example: metastatic castration-resistant prostate cancer

On behalf of a sponsor, PSI ran a radiopharmaceutical trial for patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). Despite the hard work by the sponsor and PSI to get the drug approved within four years (from initial award to PSI, enrolling over 850 patients to surpass the sponsor’s recruitment goal four months ahead of schedule), due to drug lag the treatment is not yet fully available worldwide, almost three years later.

(3) Changing site profiles

Sites support multiple trials simultaneously; all at different stages of completion. When sites are overloaded with a high number of trials (and running multiple EDC systems at once [13]), it can impact their ability (both in terms of capacity and capability) to recruit effectively, especially if multiple trials are started at the same time. Matching a trial to a site isn’t a one-time evaluation – it is an ongoing process to make sure everything continues to run smoothly and successfully. Sites should also be chosen in the context of familiarity with handling predicted toxicities [14]. Even if the chosen team has experience with dosing strategies and the protocol has comprehensive early detection and management of toxicities within, challenges may still present for sites already running at capacity [15]. Site feasibility assessment in oncology can be estimated to cost approximately $10,000 per year per site [16], and the changing nature of site profiles makes this an important investment. Building relationships with sites new to a particular CRO or research area (or, indeed, research altogether) is an invaluable strategy for a sponsor to not only ensure adequate numbers of trial participants, but also as a safety net for changes in site situation.

Offering ongoing and adaptable support is essential for all sites during a trial. Specialized site support teams and companies like MilestoneOne provides site support, strengthening their inherent capabilities through access to experience and expertise – making sure patients are able to continue trial participation and have access to life-changing treatments [17].

jennifer zalud profile

Oncology trial feasibility hinges on the interactions between evolving standards of care, global drug access disparity, innovations with therapy and toxicology, and how sites change over time. Proactive, adaptive approaches ensure the success of our oncology trials.

Jenna Zalud, Manager, Feasibility, PSI

The 3 important considerations to operationalize continuous feasibility in oncology

Reactively addressing challenges that arise during a clinical trial can lead to fragmented solutions and isolated processes. Having a unified, comprehensive strategy that addresses various factors over time helps to keep trials on track. Important considerations include:

(1) Capitalize on site networks, KOL and local input, and decentralized feasibility

Early outreach to key opinion leaders (including active, patient-facing physicians) and sites helps ensure an accurate understanding of the protocol’s appeal to sites and potential benefits to patients. They can provide expert input on trial design, considerations for recruitment and retention, and alignment with current clinical practice. These relationships often provide a perspective that can be initially overlooked until after the study begins, and they possess the expertise to understand, as the study progresses, the shifting needs of their locality. A CRO with global presence has access to KOL input from various regions to understand the variability and perception of trials. This decentralized feasibility approach uses insights from a broader network of investigators and sites, enabling sponsors to adapt to local challenges and opportunities in real-time.

The PSI example – endometrial cancer

Advisors on a recent cell therapy study in advanced endometrial cancer recommended expanding the inclusion and exclusion criteria to allow up to three lines of prior chemotherapy rather than one, as patients with recurrent disease after first-line treatment often receive either another line of platinum-based chemotherapy or a non-platinum regimen; thus, relaxing this restriction would broaden eligibility. As a result, enrollment was completed nearly a month ahead of initial projections.

The PSI example – radiopharmaceuticals

The growing demand for specialized expertise, for example, in radiopharmaceutical trials, poses new challenges to even experienced clinical research sites, making the role of research-naïve sites even more critical. Sponsors can collaborate with skilled nuclear medicine teams who lack familiarity with the clinical research process to initiate these sites and implement the protocols needed to maintain quality and efficiency.

Localized feasibility teams offer valuable, firsthand insights during trials, and can deliver real-time knowledge of local standards of care. This active, ongoing information can highlight current treatment trends and enable proactive adjustments as needed.

The PSI example – GEP-NETs in China

China is an important and emerging radiopharmaceutical market; a relatively untouched patient population is advantageous for sponsors [18]. However, the regulatory landscape in China presents significant challenges compared to that in Europe or North America, including longer overall timelines and more complex regulatory frameworks.

The sponsor of a radiopharmaceutical trial for patients with somatostatin receptor-positive neuroendocrine tumors of gastroenteric or pancreatic origin (GEP-NETs) decided to recruit in China towards the end of the enrollment period of their trial (having already had success across Europe, North America, and in India and Australia). To mitigate the difficulties that can be faced when enrolling in China, from the start, PSI sought local expertise and APAC knowledge from the PSI teams in China and from PSI’s APAC KOL network.

(2) Select sites in the context of new drugs

The increasing availability of PD-1 inhibitors and the rise of radioligand therapies, like Lutetium 177Lu vipivotide tetraxetan, will undoubtedly influence clinical trial feasibility in the coming years. Site outreach needs to take the form not only of understanding a site’s current capabilities, but also of anticipating the impact of changes to the site throughout the trial period. Early feasibility questionnaires, featuring concise and targeted questions, can effectively gauge the capabilities of sites to perform initially. Repeating such questionnaires, combined with thorough landscaping, projections, and local know-how, can help gauge the ongoing feasibility of a trial.

CROs routinely gather important information during site selection; however, it’s important to take it further. Through the database of global sites and capabilities, CROs can minimize the presence of outdated information by maintaining constant communication with sites and understanding their current capacity.

The initial considerations in a feasibility questionnaire for a radiopharmaceutical study might include:

  • Does the center have enough nuclear pharmacists on site?
  • Does the nuclear medicine department have clinical research experience?
    • If not, who will provide the training or on-site support?
  • Which radiopharmaceutical license is required, and is it active?
  • Which isotopes are listed, and what are the quantities permitted?
  • What is the site’s approval process?
  • Does the site have the appropriate equipment and capabilities?

Even experienced sites require regular check-ins to help them convey their need for additional support through timely and appropriate questioning. While past data serves as a valuable resource, it doesn’t always reflect the current status of a site. Using a combination of internal and external data sources, a readiness scoring model enables sponsors to identify high-performing centers, thereby contributing to a comprehensive global dataset for future studies.

The PSI example – tumor-agnostic study

Specific country knowledge is required to acquire or ensure a site has an active radioactive materials (RAM) license, which allows the site to use RAM for research and development, diagnostics, and treatment. PSI maintains a database of RAM licenses per site/local authority/country. Regulations and the licenses themselves vary between settings, with some broad licenses covering many isotopes. PSI’s site technology specialist team worked with a site in France for a radiopharmaceutical trial for patients with advanced solid tumors. Upon receiving the site’s RAM license, they discovered that it wasn’t licensed for clinical intervention with the particular isotope in human subjects.

The site was immediately contacted to request a license amendment. On the same day, PSI reached out to the French Nuclear Safety Authority (ASN) to verify any changes in ruling. The license amendment was required and was received in under 3 months.

(3) Use data-driven feasibility tools, including AI and machine learning

Simply adding more data sources and datapoints doesn’t guarantee better results – insights can still remain hidden, and the increased volume may create analysis challenges that require AI to solve. The strategic use of generative and agentic AI and machine learning can transform feasibility throughout study durations. An AI similarity search could enable sponsors to quickly identify similar protocols, highlighting potential trial overlaps. Instead of depending on high-level or unreliable industry benchmarks, these systems can present data in a reliable and clear way, allowing feasibility and operational teams to have greater oversight than ever before.

The PSI example – breast cancer

A large biopharma sponsor requested that PSI perform a feasibility analysis for their trial in patients with breast cancer. It was crucial that the trial enrolled effectively, as the breast cancer landscape is highly competitive and constantly evolving [19]. During the course of the trial, various relevant treatment options for the patient population were approved (PI3K/mTOR inhibitors), which meant amendments to the protocol’s exclusion criteria about prior treatments were needed. Using PSI’s established breast cancer network, and VISIONALTM, the control arms of the trial could be quickly re-evaluated. The data subsequently generated meant the trial population was more robust, and that findings were relevant to the real world.

profile picture for Jessica Phillips

These practical and pragmatic approaches are the first steps towards operationalizing continuous feasibility. While it is always necessary to have humans making the final decisions, AI is transforming how we view and review site selection. AI is helping to streamline workflows, cut costs, and leads to better quality data.

Jessica Phillips, Associate Director, Feasibility, PSI

Feasibility in oncology, redefined

The three key factors and the three key considerations are not exhaustive – other issues not covered here, such as addressing the gap between KOL feedback and regulatory guidance, and determining when and how to implement NGS testing, should also be considered (and will be considered by the right CRO partner). However, we are seeing immense change. The dynamic oncology field is constantly being reshaped by revolutionary innovations, accompanied by new challenges and new questions for/from sponsors.

Despite these innovations, progress in oncology is often slow (as among other specialties – the “bench to bedside” lag is approximately 17 years [20]). Every delay doesn’t just slow innovation; it means that patients lose out on potentially life-saving treatments. Continuous feasibility isn’t a theoretical strategy – it is an essential strategy for sponsors and CROs alike. While many requirements for feasibility assessment emerge at the start of a trial and aim to preempt future challenges, as oncology research rapidly advances and standards change, ongoing operational, regulatory, site, and patient feasibility evaluations are vital.

Adopting this mindset and investing in decentralized feasibility, networks of PIs, KOLs, and sites, as well as in AI, allows sponsors to expedite the approval of their innovations, accelerate market entry, and meet patient needs.

Learn more about how PSI's feasibility team can create a tailored feasibility plan for your upcoming pivotal oncology study

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Abbreviations

ADC, antibody-drug conjugate;
AE, adverse event;
AI, artificial intelligence;
ASN, French Nuclear Safety Authority;
APAC, Asian-Pacific (region);
CRO, Contract Research Organization;
CTR, Clinical Trials Regulation
DLBCL, diffuse large B-cell lymphoma;
FDA, Food and Drug Administration;
GEP-NETs, neuroendocrine tumors of gastroenteric or pancreatic origin;
HER2, human epidermal growth factor receptor 2;
ICU, Intensive Care Unit;
KOL, Key Opinion Leader;
mCRPC, castration-resistant metastatic prostate cancer;
NGS, next-generation sequencing;
NIH, National Institute of Health;
NMIBC, non-muscle invasive bladder cancer;
PD-1, Programmed Cell Death Protein-1;
PI, Principal Investigator;
RAM, radioactive materials;
SoC, standard of care.

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