Biospecimen Quality in Clinical Research

Figure: Laboratory Information Management System (LIMS) for biospecimen quality in clinical research
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Abstract

Biospecimens form an integral part of many clinical research studies. The production of valid clinical data sets depends largely upon the quality of biospecimens utilized in the study. Annotations of biospecimens help unveil information related to disease prognosis, diagnosis, and treatment. However, there are several stages including collection, processing, and storage through which a biospecimen travels before its utilization in research. Even minute mismanagement during any of these stages may lead to quality degradation of the biospecimen and thus skew the clinical data. Consequently, it may result in escalated costs. So it becomes critical to maintain scrupulous attention to ethical, legal, and social concerns related to biospecimens and to adhere to defined regulatory guidelines and bioethical standards. While it is hard to guarantee the biospecimen quality during clinical research, there are a many ways to surmount the obstacles.

Introduction

High-quality biospecimens form the core of clinical research. Clinical research involves the collection, storage, and analysis of thousands of biospecimens from several places at different time points. Analysis of biospecimens facilitates the identification of genetic and molecular biomarkers for disease prognosis and the discovery of novel drugs for therapeutic benefits. However, biospecimens are subject to various collection, processing, storage and environmental factors that may erode their molecular composition and consistency, resulting in poor and inaccurate research outcomes. The present article delineates the impact of biospecimen quality maintained by biorepositories for clinical research and the measures to obtain high-quality biospecimens that adhere to bioethical standards.

Why is Biospecimen Quality a Prime Requirement?

Quality criteria for biospecimens are not universal and vary with the type of study and biospecimen under consideration. For example, maintaining DNA integrity is a crucial factor for whole genome amplification studies while some other studies may depend on RNA integrity. In such situations, if the biospecimen integrity is altered, it may result in major changes in clinical outcomes. In most cases, the degradation in biospecimen quality occurs during the collection and processing stage. Delayed analysis of biospecimens can also be a major hindrance in achieving accurate clinical results. Mismanagement of biospecimens may lead to unorganized samples with missing data, delays in reporting results, and increased cost of clinical research. It is estimated that over $28 billion is spent each year in the United States alone on irreproducible pre-clinical research. Even minor quality degradation could potentially result in unreliable data while skewing the clinical research completely. Thus, flawless management of biospecimen quality becomes an important task for biobanks to enable a timely, cost-effective and accurate clinical research to progress and come to a substantial conclusion.

Specific conditions are required for the collection, transport, storage, and analysis of biospecimens. The influence of pre-analytical variables like warm and cold ischemia and delayed processing on biomolecules integrity is well established. Additionally, biospecimen quality also depends on a multitude of variables including the type of biospecimen being analyzed, the type of analytical method, type of study, and robustness of method against pre-analytical variations. This further makes identification and control of the pre-analytical variables a challenging and complex task.

How to Maintain the Quality of Biospecimens?

Biospecimens are integral to many successful clinical research projects. To ensure an accurate, timely and cost-effective study, it is necessary for biorepositories to process, preserve, and ship the biospecimens in a way that protects their quality and identity. To assess the global bio-molecular integrity status of the stored biospecimens, it is necessary to adopt sufficient measures to optimize the biospecimen quality and to control the pre-analytical bias.

1. Patient Interaction
It is important to have open and honest communication with patients about biospecimen collection to help patients understand the rationale for collecting biospecimens. How the biospecimen will be used and how the resulting clinical research data may help in disease prevention and cure, should be explained.

2. Informed Consent
For ethical and legal reasons, it is necessary to have informed consent from each study participant that includes sufficient information about the anticipated procedures, risks, and benefits associated with the research.

3. De-identification of Biospecimens
De-identification of biospecimens is a critical step in clinical research to safeguard patient health information and to comply with federal patient privacy regulations such as HIPAA. The biospecimens used in clinical research should have their identifiable information removed to secure patient information. However, a unique code should be provided on all the data collection forms and clinical biospecimens. This code should be stored separately with multiple safeguards within the biorepository, enabling the association of biospecimens and their clinical results, with the patient.

4. Protocol Standardization
Standardization of protocols is crucial for the collection, processing, preservation, and retrieval of each type of biospecimen. Standard operating procedures (SOPs) should be implemented to maintain biospecimen quality and to avoid any pre-analytical bias. The SOPs should be well structured and reviewed periodically for updates in protocol, technology or regulatory practices.

5. Shipping and Receiving of Biospecimens
The highest risk of contamination and degradation of biospecimens is during packaging and transport. To overcome this risk, it is advisable to adhere to defined procedures and policies for packaging, shipping and receiving of biospecimens. Transporting biospecimens under appropriate conditions, such as ambient temperature conditions; wet ice, dry ice, and liquid nitrogen handling, etc., can reduce the degradation of biospecimens.

6. The Collection, Storage, and Retrieval of Biospecimens
Proper attention to the collection, storage, retrieval, and disposition of biospecimens is imperative to avoid any pathogenic infection; especially while collecting blood samples.

7. Record-keeping
Comprehensive documentation for biospecimens is essential at all the stages of clinical research. A Laboratory Information Management System (LIMS) can manage the date and time of biospecimen collection, assay procedures, the original and the current quantity, expiration date, and storage locations of biospecimens with special attention to the biospecimen movements within or outside the laboratory. The use of a cloud based LIMS makes the maintenance and cost of such record keeping accessible to labs on tight budgets.

8. Quality Assurance
To maintain biospecimen quality, it is necessary that all the procedures of acquisition, processing, analysis, and storage of biospecimens are performed as per the quality assurance (QA) guidelines. Adhering to QA policies minimizes false positives and increases the confidence that the quality and quantity of the biospecimens are as expected. It is an essential finishing step in the processing of biospecimens that ensures that the biospecimens are accompanied by accurate data.

9. Facility Infrastructure
Regular monitoring of the equipment used for biospecimen storage and processing is necessary to ensure that the equipment is accurately calibrated, operational settings are periodically recorded, and scheduled maintenance is documented. Additionally, it is important to maintain periodic back-ups and emergency alarms to prevent biospecimen degradation.

Need for Regulatory Guidelines

Several standards have been established by international organizations to define and enforce the guidelines for maintaining biospecimen quality. It is imperative to obtain biospecimens under an approved IRB/EC protocol. To maintain the quality of biospecimens during shipment, it is essential to follow the International Society for Biological and Environmental Repositories (ISBER) and International Air Transport Association guidelines. ISBER guidelines provide standards for the collection, storage, retrieval, and distribution of biospecimens. It also includes guidelines for quality assurance, safety, tracking, and shipping of human biospecimens. Occupational Safety and Health Administration regulations (29 CFR 1910 Subpart Z) help determine if a biospecimen is toxic and requires a biohazard label. The Biospecimen Reporting for Improved Study Quality recommendations are applicable to all clinical research studies in which the human biospecimens are utilized. It requires that all the anatomic, histological and preservation parameters known to affect the biospecimen quality are sufficiently recorded. Adherence to these regulatory guidelines provides improved control over biospecimen composition and quality.

Thus, biospecimen quality is a critical factor governing the accuracy and reliability of clinical research data. Protecting biospecimens from degradation and deterioration during storage and shipping is an important requirement for a biobank. Additionally, it is important that all SOPs and associated QA measures are periodically evaluated and approved before implementation. Finally, it is necessary for all the stewards of these biospecimens to be attentive and tenacious in following defined regulatory guidelines in order to achieve high-quality biospecimens for clinical research.

References

1. Yuille, M., et al., Laboratory# Management of Samples in Biobanks: European Consensus Expert Group Report. Biopreservation and Biobanking, 2010. 8(1): p. 65-69.
2. Schroeder, A., et al., The RIN: an RNA integrity number for assigning integrity values to RNA measurements. BMC Mol Biol, 2006. 7: p. 3.
3. Freedman, L.P., I.M. Cockburn, and T.S. Simcoe, The Economics of Reproducibility in Preclinical Research. PLoS Biol, 2015. 13(6): p. e1002165.

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Shonali is the COO of CloudLIMS.com. In a career spanning over seventeen years, she has built a long and impressive track record of success in high technology software sales, marketing and professional services, developing operational strategies and directing new business initiatives from conception through execution.