Registration studies for oncology indications will likely continue to expand multi-regional enrollment, including investigational sites in new, less developed countries and centers. Some authors proposed multi-regional enrollment is caused by cost-saving for industry sponsors. However, overall cost-saving can be minimal for the conduct of complex, multi-regional trials in view of center fees, biomarker analyses, travel, monitoring, data management, inpatient requirements in some regions, and regulations requiring post-study treatment in some countries.
Even after marketing authorization, accelerated trial completion, requiring multi-regional enrollment, can be largely driven by timelines required by regulators for submission of data and reports, including results from post-approval commitments. Separate from costs, numerous factors lead to protocol conduct across multiple regions, including:
- Insufficient enrollment in some countries due to commercial availability of study drugs, or drugs prescribed on- or off-label in the same indication
- Growing competencies of investigators, support staff, and contract research organizations (CROs) to conduct complex trials in diverse regions
- Structured approaches to assure quality in study conduct and data management
- Improved understanding of between- and within-country differences in clinical care and outcomes
Patient-Focused Drug Development and Patient-Centric Values
In addition to traditional endpoints, such as response rates, progression-free survival, and adverse events, multi-regional trials have been gaining experience to identify and incorporate nontraditional outcomes which are meaningful for patients across regions. Sometimes termed “patient-centric values,” such outcomes can be immediately meaningful for study subjects as they choose to participate, consent, and comply with protocol requirements, supporting successful trial performance along with goals for extrapolation to future patient care.
Consensus ‘guiding principles’ for patient-centric values, obtained from interventional protocols, have gained increasing attention by multiple stakeholders who participate in design and conduct of multi-regional protocols. Modern approaches to clinical operations can be a foundation for traditional concepts of protocol ‘error-free’ Quality, synergistic with emerging concepts of Patient-Centric Value. Across therapeutic areas, regulatory scientists and multiple protocol sponsors, including a group organized by the Pharmaceutical Research and Manufacturers of America (PhRMA), continue to advance dialogue and learnings about Patient Focused Drug Development (PFDD). Specific to Oncology, the American Society for Clinical Oncology (ASCO) organized a working group with representatives from patient advocacy groups, the biopharma industry, academia, and published “The ASCO Value Framework” to guide concepts of value from new cancer therapies (Schnipper L. et al, 2016).
The ASCO Value Framework includes largely traditional data elements (e.g. hazard ratio; severe AE frequencies) that can be mathematically integrated into a composite “Net Health Benefit Score.” While traditional protocol endpoints continue to influence what is critical to quality, non-traditional measures of patient-centric value are emerging from thoughtful engagement by patient advocates and patients who appreciate the practical realities of clinical protocol design, operations, and analyses. In addition to the overall impact of protocol outcomes, such considerations of value in protocol design can favourably influence enrolment decisions by patients and caregivers (Bang R et al, 2018).
Operational Considerations for Multi-Regional Trials
When of clinical trials go beyond traditional endpoints, opportunities exist to manage reliable operational performance and outcomes analyses. Positive and not-so-positive experiences from digital technologies, applied in protocols to capture patient reported outcomes (PROs) and health-related quality of life (HR-QOL) measures have been previously reviewed (Rudel, 2015). For payer decisions, measurable outcomes reflecting patient-centric value continue to be considered by NICE and other health technology organizations: examples include reduction or delayed manifestation of malignant skin lesions; or organ- or procedure-sparing outcomes for indications like bladder or breast cancers, or diseases that lead to recurrent ascites.
While these approaches provide mechanisms to evaluate values of new therapies, considerations for design, analyses and clinical operations of multi-regional trials include: 1) cultural and language differences that can influence AE, PRO, or HR-QOL reporting, or consistent surgical procedures, which vary across countries or regions within countries. Another consideration includes: 2) perceptions about importance which differ for individuals within the same disease indication. For example, over 1400 women diagnosed with ovarian cancer have been surveyed about the relative importance of protocol outcomes, and the data indicate that women with more advanced disease may generally accept a different ratio of benefit-risk compared to women in first remission (Minion et al, 2016).
These latter survey results may be attributable to experiences with burdens of recurrent diseases and/or tolerance to prior treatment regimens. Taken together, these published experiences illustrate promising advances, along with the need for continued investigations and consensus about validation of patient-centric values in the context of multi-regional protocol design, conduct, analyses, and outcomes.
The Quest for Quality and the Validation of Value
Despite their complexity, successes in planning, design and conduct of multi-regional trials have led to numerous positive registrational protocols and a wide availability of immune-oncology (IO) therapies, and other important new cancer therapies. With the global impact on the future design and conduct of multi-regional protocols, the International Conference on Harmonization (ICH) has organized a multi-stakeholder program with goals to modernize key ICH Guidelines that have a major influence on the design and conduct of clinical trials. This new ICH E17 Guideline is designed to provide guidance on general principles on planning/designing Multi-Regional Clinical Trial (MRCT).
With direct relevance to clinical operations, the ICH E8 General Considerations for Clinical Trials will be renovated and then posted for public review and comment (see link below). These efforts enable near-term opportunities to share practical experiences and innovations that advance both quality and patient-centric value. Given thoughtful engagement, stakeholders who have experience in clinical operations can impact the future of protocol success across multiple regions, therapeutic platforms, and disease indications. In summary, new opportunities are emerging to both innovate and refine best practices for the quest for quality and the validation of value.
Head, Oncology Development & Scientific Initiatives
1) https://www.nice.org.uk/guidance/ng2, February 2015
4) Bangs R, Crispino T. From the other side: The patient perspective on cancer clinical trials. Urologic Oncology, 2018 (in press)
5) Minion LE et al. Endpoints in clinical trials: What do patients consider important? A survey of the Ovarian Cancer National Alliance. Gynecologic Oncology 140 (2016) 193–198
6) Rüdel, K. Challenges and Opportunities of Patient Reported Outcome Instruments in Clinical Trials: Perspectives from a PRO Scientist. June, 2015, Available on line https://bit.ly/2t27NUx.
7) Schnipper LE et al. Updating the American Society of Clinical Oncology Value Framework: Revisions and Reflections in Response to Comments Received. Journal of Clinical Oncology, Vol 34, No 24 (August 20), 2016: pp 2925-2934