Precision medicine represents a paradigm shift in the life science and pharmaceutical industry.
An estimated 73% of oncology drugs and 42% of all drugs in development follow the precision medicine paradigm.1 Whereas the traditional model of drug development focuses on primary protocol endpoints, the precision medicine model further emphasizes exploratory endpoints and collection of separately consented “future use specimens,” resulting in the need for far more sophisticated specimen collection regimens and complex operational plans.
Instead of the traditional approach of conducting analyses at the end of trial, precision medicine trials include ongoing analysis to support critical trial functions, such as segmentation of study cohorts or enabling interim analysis in adaptive trials. These analyses require access to high-quality specimens while the trial is in flight. As a result, trials that do not effectively track and manage specimen collections risk raising regulatory compliance issues and delaying key execution milestones.
In addition, lack of ready access to structured specimen-level consent parameters (e.g., storage duration, allowable use) limits the value of specimens in supporting future research. Thus, subject consent collection, tracking, and management are key enablers of success in precision medicine trials.
Letting the Trends Lead the Way
Responding to these developments, a recently published International Council for Harmonization (ICH) guideline strongly encourages that genomic specimen collection be conducted “in all phases and studies of clinical development” and that chain of custody be documented.2 Correspondingly, specimens need to be collected, tracked, and properly stored for long-term use. Large-scale biobanking efforts such as the UK Biobank provide an effective roadmap for creating a valuable specimen resource for biomedical research.3,4
Meanwhile, clinical trial monitoring is undergoing its own paradigm shift to risk-based monitoring (RBM), which dynamically adjusts the distribution of monitoring resources to areas with the greatest impact on patient safety and data quality. The concept of RBM has evolved over the past decade and more, culminating in guidance documents from both the U.S. Food and Drug Administration5 and the European Medicines Agency6 in late 2013. Since then, adoption for RBM has been rapid. However, minimal effort has been made to ensure that RBM principles are expanded to reflect specimen- and content-related needs of precision medicine and companion diagnostic trials.
Traditionally, clinical trial monitoring has not focused on specimen-related issues, which is notable, given the heavy (and ever-increasing) reliance of specimen-based testing to generate clinical trial data.7 This is an even more significant problem given the importance and growing sophistication of specimen collection regimens and test plans designed into precision medicine trials.
Consent management support for specimen future use is an important factor to consider when monitoring study site performance. The trend toward clinical monitoring practice toward RBM presents an opportunity to improve trial monitoring to better support precision medicine needs.
Focusing in on Specimen and Consent Key Risk Indicators
A well-conceived RBM plan should account for the full spectrum of study risks, and therefore must include well-developed specimen- and consentcentric components, but currently RBM plans are lacking when it comes to supporting precision medicine trials. Although some examples of risks related to study subject specimen management have been identified as part of critical clinical trial processes,8 the list is far from complete. Further, those factors already identified have not generally been monitored operationally as key risk indicators (KRIs). Out of the 141 KRIs compiled by TransCelerate BioPharma in 2015, which represents industry practice at the time, none directly reflect specimen-related risk.9
We propose that precision medicine trials would be better supported in terms of RBM plans by adding “Specimen and Specimen Consent Management” as a new KRI category that focuses on critical processes and data from a “specimen-centric” perspective. We propose that this information be incorporated into the integrated quality risk management plan (IQRMP), and be assessed by specifically defined risk indicators.
In order to support this new category, clinical trial specimen and specimen consent information must be collected systematically with a verifiable provenance; tracking via Microsoft Excel spreadsheets, the status quo for most study teams, is an inadequate tool to perform this task. While most clinical trial stakeholders who manage subject specimens can track them within their organizational boundaries (e.g., within a central lab), specimen lifecycle tracking across the clinical trial ecosystem of sites, central labs, testing labs, and biorepositories is typically limited or omitted altogether.
Bridging the specimen management and tracking gap with new processes and technology will allow access to relevant operational data (consent, collection, tracking) that, in turn, will enable a more comprehensive RBM plan, including monitoring of additional specimen-centric KRIs. KRI deviations that exceed predefined thresholds from expected value ranges would trigger corresponding remediation plans and allow continuous improvement with regard to collection of consent information and handling of specimens.
Addressing the Risks
Some specimen-related risks can be addressed by expanding the scope of existing KRIs; others require defining new risk indicators that are unique to clinical trial specimens. Some example areas of specimen-centric KRIs would cover:
- Rate of overall specimen-related issues
- Missing/wrong specimen collection
- Specimen shipment delays
- Specimens lost due to quality issues
- Sample collection without proper patient consent, especially for optional collections
- Chain-of-custody deviations
Together, the authors would like to issue a call to action that the clinical trial community embrace the opportunity to make RBM even more valuable by incorporating specimen and specimen consent– related risks that reflect the needs of precision medicine trials. Specifically, we recommend:
- formation of a group of stakeholders to evaluate specimen-oriented RBM needs, perhaps as a subgroup within TransCelerate, the Clinical Trials Transformation Initiative (CTTI), or other existing industry consortiums;
- publication of a whitepaper on specimen and specimen consent considerations within RBM, including recommended best practices;
- creation of a set of tools (such as standard data transfer specifications) to facilitate specimen tracking data exchanges among the clinical trial stakeholders; and
- delivery of conference sessions to spread awareness about the opportunity and recommended approaches for RBM to improve coverage of specimen-related risk factors.
RBM is an exciting innovation in clinical trial operations aimed at achieving both cost savings and improved trial integrity. For precision medicine and companion diagnostics trials, RBM requires enhanced visibility into specimen operations, resulting in not only risk reduction, but also operational efficiency gains. Thoughtful inclusion of specimenand consent-related risk factors will significantly increase the value of RBM, especially for precision medicine biomarker-based clinical trials.
- Schneider D, et al. 2016. Accelerating the development and validation of new valuebased diagnostics by leveraging biobanks. Pub Hlth Genoms 19(3):160–9. doi:10.1159/000446534
Jian Wang, PhD, (firstname.lastname@example.org) is CEO of BioFortis, Inc.
Maureen Cronin, PhD, is executive director for knowledge management and utilization with Celgene Corporation.
Daniel Joelsson is director of global business planning and operations with MedImmune.
Rebecca Simamora is vice president of clinical operations with Regenxbio, Inc.
Michael Tanen is director of clinical biomarker specimen management with Merck Research Laboratories.
Kenneth Wilke is a principal with BioStrategy Solutions, LLC.
Brenda Yanak is global head of specimen strategy and innovation with Q2 Solutions (a Quintiles/Quest joint venture).