Precision medicine is a rapidly evolving field in which physicians may use diagnostic tests to identify specific biological markers, often genetic, in an effort to help determine which treatment may be most effective for each individual patient. Precision medicine includes a reactive approach to disease treatment, but an emphasis on the use of biomarkers in preventive measures and early intervention, is possible for diagnostics that measure disease risk before the onset of clinical manifestation. 

Based on a report from the Tufts Center for the Study of Drug Development, 42 percent of new medicines in drug development have the potential to become precision medicines, with an anticipated 69 percent increase in the number of personalized medicines in development over the next five years. These statistics, along with continuing advancements in science and technology clearly highlight opportunities to completely transform the way that our industry currently treats patients. With these incredible opportunities, however, come many challenges in regulatory policy, adoption, and clinical trial monitoring and operations.  

An Added Complexity to the Drug Development Process

Clinical trials play a critical role in the development of breakthrough diagnostics for precision medicine. New diagnostic tests are typically “clinically validated,” a necessary regulatory step, within the context of a clinical trial. Advances in personalized medicine initiatives have led to a pronounced increase in the number of biomarker-driven research objectives being incorporated into recent clinical trials. The addition of complex biomarker strategies to clinical trials adds a new level of complexity to the overall drug development process that increases overall risk of failures, and will need to be closely managed.

Whereas traditional trials focus on standard protocol endpoints, precision medicine trials emphasize stratification of such endpoints by a biomarker. Furthermore, the research required to get to that point often entails conducting “exploratory” biomarker research in earlier trials to test the hypothesis that biomarkers actually stratify response. Such strategies require incorporation of complex biomarker specimen collection, resulting in the need for increased specimen-centric monitoring plans. Not only do the traditional trial risks need to be monitored, but the additional collection of biomarker specimens necessitates that the integrity of the biomarker specimen will need to be monitored and tracked throughout the lifecycle of the study and the larger development program. This requires two key strategic elements: 1) to develop robust IT systems that associate and integrate data, and 2) the need to elevate biomarker specimen collection as an increasingly important component of an effective risk-based monitoring (RBM) program. 

Integration of Patient and Specimen Biomarker Data

As defined in more detail in a previous article, our data systems must able to integrate subject informed consent with all specimens collected in an executed clinical trial. Furthermore, they must also correlate permissions (or restrictions) data with individual specimens in a fluid, continual way to ensure compliant use of specimens at all times. It is of extreme importance that we protect a patient’s rights related to data and privacy while also remaining compliant with global laws and regulations in the utilization of collected specimens. 

In addition, we also acknowledge the requirement to associate specimen metadata (records of origin, collection, processing, storage, and quantity and quality measures) with descriptions that bring context to biomarker specimens collected in the course of a study. Additionally, there’s a need to associate standard clinical data (age, gender, and ethnicity), disease status, treatment, potential response/resistance to treatment and biomarker status. This type of data integration is particularly critical for precision medicine trials that may include ongoing analysis of specimens to support critical trial functions, such as segmentation of study cohorts or facilitating interim analysis in adaptive trial designs. It also supports the idea of a “bedside to bench” approach where diagnostic development in complex biomarker clinical trials is actually driven by the patient and patient specimens.

Risk Based Monitoring Plans for Precision Medicine Trials

As biomarker data continues to drive an increasing number of trial decisions and clinical endpoints, making patient specimens even more significant and valuable, a specimen-centric focus needs to become an integral part the clinical trial monitoring process. Clinical trials play a central role in the development and delivery of breakthrough diagnostics for precision medicine. 

The trials facilitate evaluation of which drugs, devices, and treatments are safe and effective for targeted patient populations. Clinical trial monitoring has undergone a shift in recent years to a more modernized method of monitoring, such as RBM. This monitoring approach adapts the distribution of monitoring resources in each study tothose areas critical to patient safety and data quality. 

Adoption of RBM has been widespread, and has been advanced by groups like TransCelerate Biopharma Inc. The U.S. Food and Drug Administration (FDA) have supported RBM by providing published guidance documents for industry. Unfortunately, while these efforts to advance and modernize the way we monitor clinical trials has had a positive impact on the safety and quality of trials, there has been a serious lack of focus on specimen-centric issues and risks. Of the 141 key risk indicators (KRIs), compiled by TransCelerate BioPharma in 20154, there was no risk indicators that directly addressed the risks associated with collection, storage, processing, or shipping of specimens collected during a clinical trial.

Some have stated that, “in biomarker-driven clinical trials, patient specimens are as important as the patients themselves,” especially when there is an interaction of trial deliverables with biomarkers that associate with clinical endpoints. With the growing number and complexity of clinical specimens collected and biomarker assays deployed in precision medicine trials, it is time to open the dialogue to focus on specimen-centric risks. As such, it’s essential to expand the scope of the existing 141 KRIs, as well as introduce and define new KRIs that specifically target the risks associated with clinical trial specimens. In a recent publication, a call to action for the clinical trial community included biomarker subgroups to industry consortiums, a specimen-centric monitoring whitepaper, standardization of data transfer specifications, and a concerted effort to spread awareness about improving how specimen-centric risks are monitored in precision medicine trials. 

Here it is proposed that such trials be supported by RBM plans that account for specimen-centric risks, including full chain-of-custody for the specimens collected, linked consent management, and data quality. The clinical specimens ultimately have a significant impact on clinical decisions and the development of high quality diagnostic tests that determine the best course of treatment for the patient.


With the increasing number of scientific tools available and an improved adoption by the pharmaceutical industry, the promise of precision medicine is being realized. Along with this, RBM is an important advancement in clinical trial operations achieving improvements in clinical trial management and patient safety. We now have the opportunity to look ahead and expand the efforts in RBM to tackle specimen-centric risks. As the number of precision medicine trials continues to grow, we need to drive new initiatives to assure full chain-of-custody for clinical specimens, and the quality of specimens and data collected.


Michael Tanen

Director, Clinical Biomarker Specimen Management

MRL, Merck & Co., Inc., Translational Medicine

Rahway, NJ USA



1) Management of specimens collected in biomarker-driven Clinical Trials: Integration of datasets to drive Translational Science, Michael Tanen, Clinical Trials Arena, Jan 31, 2017 –

2) TransCelerate RBM interactive guide –

3) FDA guidance for industry, Oversight of Clinical Investigations – A Risk-Based Approach to Monitoring (OMB 0910-0733) –

4) Transcelerate: Risk Indicator Library –

5) Improving Precision Medicine Trials by Extending RBM Principles to Include Specimen and Consent KRIs, Wang J, Cronin M, Joelsson D, Simamora R, Tanen M, Wilke K, Yanak B, 26-27 June 2017 –