Principal Scientist Regulatory Operations, Q² Solutions

Viren Patel, PhD

In February 2021 we published an article in 

 entitled, “Self-collection of Blood Specimens in Clinical Trials."

 The article described how the pandemic accelerated interest in decentralized clinical trial (DCT) approaches, including the use of blood self-collection devices to enable a clinical trial participant to collect their own blood without having to visit an investigator site or have a healthcare worker visit them at home. We went on to describe innovative self-collection devices and the operational and patient burden considerations associated with such an approach.

From an operational perspective, we reviewed the various collection approaches, the need for assay development (since the devices collect capillary blood vs. venous blood, which is typically used for laboratory safety testing), the device regulatory framework, kit building, centrifugation, and direct to and from participant processes. As for patient burden, we discussed considerations around study design, tests required, pain tolerance, collection time and complexity requirements, participant use of collection devices and centrifuges, participant logistics considerations, and participant support needs. Finally, we described a correlation feasibility study we conducted, which demonstrated good correlation between venous and capillary blood specimens for a 12-analyte chemistry panel using a Tasso-SST (serum separator tube) self-collection device and a Sandstone Diagnostics portable centrifuge.

Since then, we have continued to perform scientific and operational feasibility studies to determine how we could make a safety testing panel available in clinical trials via at-home self-collection of blood specimens. While a finger prick via a lancet and dripping blood into a tube may be technically possible for at home collection, participant feedback indicated that this approach was less preferred and more painful than venous phlebotomy and the shoulder based innovative blood collection devices, like those produced by Tasso, therefore we focused our research on the Tasso+ device.

Most safety lab tests require venous blood specimens to be centrifuged within one hour after specimen collection and prior to shipment to the laboratory for testing. Fortunately, there are small portable centrifuges on the market and others under development, which are designed for at-home use. Clinical trial laboratories can develop robust processes to enable shipment of centrifuges to participants, clear participant instructions, and shipment of centrifuges back to labs. And labs can develop centrifuge reutilization programs, so that the right number of centrifuges are available at the right time for a study, to optimize cost and simplify logistics.

With the intention of reducing patient burden and operational complexity regarding centrifugation, we wondered if it would be possible to generate test results that correlate, if participants ship specimens to the lab without centrifugation, and have the lab staff perform the centrifugation, versus the standard process of investigator site staff performing centrifugation prior to specimen shipment to the lab. While we assumed this would not work for all analytes, the team felt it would be worthwhile to determine feasibility.

As such, we embarked upon a feasibility study to compare the results from three specimen collection approaches to help determine if lab centrifugation of specimens for safety (chemistry) testing is feasible. Approach 1 utilized venous blood centrifuged immediately, approach 2 utilized capillary blood, obtained via the Tasso+ SST device centrifuged within one hour of collection, and approach 3 also utilized capillary blood, via the Tasso+ SST device, but it was not centrifuged and instead shipped to the Q2 Solutions laboratory, where the specimens were centrifuged. The specimen sets were tested on the Roche Cobas 8000/c702 for a 15-analyte chemistry panel, including: Alanine transaminase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP), Total bilirubin, Direct bilirubin, Total protein, Albumin, Glucose, Sodium, Potassium, Chloride, Magnesium, Calcium, Phosphorus, Enzymatic Creatinine.

Process optimization—refrigerated shipments

We observed good correlation between the venous and Tasso SST capillary specimens that were centrifuged immediately at the investigator site. However, some capillary specimens that were not centrifuged at the investigator site arrived at the laboratory hemolyzed, which for some analytes (e.g. AST and ALT) would result in result cancellation. Through experimentation, we found that refrigerated shipment of specimens enabled the non-centrifuged specimens to arrive in an acceptable condition for testing. Upon testing the specimens, the results also showed acceptable correlation with results from the other two approaches (routine venipuncture and centrifuging Tasso SST samples at site) for most analytes studied.

With the success of the feasibility study, we conducted a validation study with a similar design around the three specimen types, but this time with 25 different analytes. At the time of publication, we have successfully completed the validation report for a 7-analyte liver safety panel, including Total Protein, Albumin, Alkaline phosphatase (ALP), Alanine transaminase (ALT), Aspartate transaminase (AST), Direct Bilirubin, and Total Bilirubin. The results for the 7-analyte liver safety panel showed good correlation and good sample stability to provide enough time to ship samples from a participant’s home to the laboratory. Details are available upon request. The report for the other 18-analytes is under development. It is important to note that the validation report is based on an alternate sample type validation performed according to industry guidelines such as Clinical and Laboratory Standards Institute (CLSI) EP35 (Assessment of Equivalence or Suitability of Specimen Types for Medical Laboratory Measurement Procedures). We encourage clinical trial sponsors to discuss the approach, and share the validation report, with regulators prior to using for diagnostic and patient care purposes.

The term “Liver function tests,” is a historical misnomer to describe Liver Chemistry Testing, as the assays performed not only access the function of the liver (synthetic function) but also hepatocellular injury and the hepatobiliary tract conditions. Testing and monitoring of the various proteins made by the liver is important for determining hepatic health, especially in subjects enrolled in clinical trials.

 Most drugs are metabolized by the liver and monitoring early damage is essential in preventing Drug Induced Liver Injury which may lead to liver transplant or even death.

 Levels that are higher or lower than normal can indicate liver problems. Some common liver chemistry tests include:

Alanine transaminase (ALT). ALT is an enzyme found in the liver cells and convert alanine into pyruvate to provide energy for the liver cells. When the liver is damaged, ALT is released into the bloodstream and levels increase.

Aspartate transaminase (AST). AST is an enzyme that is involved in gluconeogenesis in the liver Like ALT, AST is normally present in blood at low levels. An increase in AST levels may indicate liver damage, disease, or muscle damage.

Alkaline phosphatase (ALP). ALP is an enzyme found in the liver and bone and is important for breaking down proteins. ALP made in the liver, bone, kidney, small intestine, and other organs of the body and thus is non-specific; however elevated levels may indicate liver damage or cholestasis or certain bone diseases.

Albumin and total protein are proteins used to measure function of the liver. These are produced in the liver to be secreted into the plasma. Albumin is the major protein in the blood and helps transport many important molecules the body needs to regulate metabolic processes. Lower-than-normal levels of albumin and total protein may indicate the failure of the liver to produce these important proteins, thus liver damage or disease.

Bilirubin, is a byproduct of the normal breakdown of red blood cells. Bilirubin normally is processed in the liver and is excreted in stool. Elevated levels of bilirubin (jaundice) indicate liver damage of the hepatobiliary tract or disease or certain types of anemia.

Measuring the transaminases (ALT/AST) and bilirubin are critically important in determining if a drug is responsible for causing Drug Induced Liver Injury (DILI). DILI is responsible for the majority of liver transplants, thus being able to assess liver chemistries before DILI occurs is critical in pharmaceutical trials.

Operational and patient-burden oriented processes

At the same time as investigating analyte correlation feasibility and validation, we examined operational and patient burden-oriented processes. As with the scientific work, our operational work began with a feasibility study to work through how a self-collection visit would impact clinical trial laboratory processes, investigator site processes, and most importantly patient burden. After the feasibility work, we formalized the processes as described below.

: Based on information in the validation report and the specimen collection instructions a test code was created to enable the laboratory systems to generate lab reports and reference range alerts.

The Tasso direct to participant (DtP) investigator kit ordering portal

: The Tasso kit ordering portal was enhanced to enable a clinical trial investigator to order a kit and send it directly to a study participant, while capturing the necessary details for a clinical trial laboratory to accession samples. The portal is required to be compliant with regulations and assure that the laboratory and many study team personnel do not have access to personally identifiable information (PII).

: Information from the portal is printed onto paper requisitions which are included in the kits that are sent to study participants. In addition, unique bar codes are printed onto tube labels. These steps enable the laboratory to accession samples according to standard procedures. Electronic approaches to this process are also under consideration.

: Participants are provided with written and video instructions for use regarding the proper way to prepare for the specimen collection, the use of the Tasso+ device, packaging, and shipping instructions. Some study teams may require that investigator site personnel provide training on site or via video call to assure proper collection, packaging, and shipment and to help participants become confident with the process.

: Two options are available to mitigate the risk of participants not being able to collect a specimen via a potential device failure. First, it is possible to ship out a new device within 24 hours of receipt of an order for a replacement from an investigator site. Second, it is possible to include two devices in the original kit order.

: To minimize patient burden, we chose not to require participants to register devices via a web portal, but instead they are provided with pre-printed patient-specific requisitions and tubes. Beyond self-specimen collection and shipment, the only other requirement is for the participant to enter the time and date of collection on the requisition form.

: Shipping specimens in a cool refrigerated state, via a commercially available packaging solution, reduces patient burden by eliminating the need for at home centrifugation for the liver panel analytes above.

: Prior to specimen collection participants are asked to schedule their specimen pick up with the courier to occur on the same day as specimen collection. It is recommended that pickups be scheduled between Monday and Thursday only when the participant is available to give the sample directly to the courier.

: The blood specimens arrive at the laboratory in a 0.6 mL SST Tube where they are accessioned into the laboratory information system and sent to the lab for centrifugation and then testing. Lab reports, alerts, queries, and data transfers are managed via standard processes.

: The role of the clinical trial investigator remains unchanged. The investigator remains accountable for specimen collection, as well as patient care and support, including questions about how to utilize the device or ship the samples. Lab reports and alerts are provided to investigators just like any other lab test and investigators remain accountable for queries.

: Currently the offering is only available in the United States of America, but plans are in place to expand geographically.

: The table below compares the fee structure of an investigator site specimen collection, home healthcare specimen collection, and self-collection. The table assumes a single specimen collection visit for a liver panel. The fees for the self-collection liver panel process are far less, at least an order of magnitude less, than a nurse visit to a participant’s home. In the US there are some phlebotomist networks, and the fee for a phlebotomist visit with courier fees and testing are similar to the overall fees for the self-collection liver panel.

: Identity verification is available by having investigator site staff observe a patient via video conference. In addition, digital identity verification solutions, some of which have grown out of a need to manage COVID-19 testing, have become available. Finally, colleagues have opined about the concept of genetic identity verification as well as advanced analytics.

: Since the Tasso system can capture a participant’s email address or mobile phone number, it is possible for the system to send reminders to participants. Alternatively, Decentralized Clinical Trial (DCT) suppliers may manage patient reminders.

Laboratory scientists and operations teams around the world continue to collaborate to find ways to drive increased utilization of the self-collection of blood specimens for laboratory testing in clinical trials and diagnostics. Further innovation, including in the areas below, may help to drive adoption.

: Clinical trial protocols may require many tubes of blood and a dozen or more panels and tests per visit. How could this be accomplished via self-collection devices, which collect relatively small volumes of blood? Would a participant have to use a dozen or more devices and manage a convoluted specimen processing and shipping process?This doesn’t seem practical. A significant reason why the self-collection liver panel has become a reality relates to the work that Roche Diagnostics has done to minimize the sample volume requirements for their automated chemistry analyzers. It’s also why we were able to test 25 analytes using as little as about 600 µL of whole blood (200-300 µL serum). If Roche Diagnostics and other instrument manufacturers can continue to innovate by reducing sample volume requirements while maintaining automated approaches, the chances of expanding the self-collection test menu, to meet the needs of clinical trial protocols, will be improved.

: Some tests that require immediate centrifugation may not correlate to centrifugation at the laboratory, so the operational and patient burden considerations around the distribution of small portable centrifuges to trial participants, use, and return of centrifuges to the laboratory will have to be addressed.

 Some sample types have very limited stability and require freezing soon after specimen collection. Today, in many jurisdictions, it is possible for a courier to bring dry ice to a participant’s home to pick up specimens, however, to date the authors are unaware of instances in which this has been attempted in a self-collection process utilized for data reported in a clinical trial.

: Tasso, along with other innovative device suppliers like Neoteryx and Drawbridge Health, offer solutions that collect blood onto porous material, and others provide participant oriented dried blood cards and lancets. These dried blood approaches enable improved sample stability. There has been some success with this approach regarding Pharmacokinetics (PK),

Can self-collection of blood in clinical trials improve patient recruitment and retention?

 That’s exactly what the non-profit Patient Centric Sampling Interest Group (PCSIG) is trying to determine via a carefully constructed clinical trial.

While the creation of the first ever self-collection 7-analyte liver safety panel for clinical trials via the Tasso+ device is a considerable achievement, it is recognized that for the use of self-collection of blood in clinical trials to gain further acceptance a much broader test menu is required. Many clinical trial testing and commercial diagnostic testing colleagues are performing feasibility studies related to many kinds of tests with the aim of making additional tests available via self-collection approaches in clinical trials and healthcare.

, Vice President, Strategy & Corporate Development, 

, Global Director, Scientific Harmonization, 

, PhD, Decentralized Trials Solutions Manger, 

, Director, Decentralized Trial Solutions, 

, PhD, D-ABMLI, MBA, FACB, Senior Laboratory Director, 

, PhD, Principal Scientist Regulatory Operations; all with Q² Solutions

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https://www.appliedclinicaltrialsonline.com/view/self-collection-of-blood-specimens-in-clinical-trials

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https://academic.oup.com/jalm/advance-article/doi/10.1093/jalm/jfac127/6931879

M Ammar Kalas, Luis Chavez, Monica Leon, Pahnwat Tonya Taweesedt, Salim Surani. World Journal of Hepatology (2021) 13:1688-1698

Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation. U.S. Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER). Center for Biologics Evaluation and Research (CBER). July 2009

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https://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0255841

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At-home Self-collection of Blood Specimens for Safety Lab Testing in Clinical Trials via the Tasso+ Device