Introduction
Lori Ball, MBA
Chief Operating Officer, BioStorage Technologies, Inc.
The rapidly accelerating transition from traditional drug discovery and development to personalized medicine is pushing researchers to understand more about their samples and to deploy them in novel ways. High-quality research samples with appropriate clinical annotations and their respective data are critical components to the discovery of personalized medicines. In order to support this research, biospecimen resources need to be developed and managed under established scientific, technical, business and ethical/legal standards. [1]
Targeted drug therapies that meet specific patient profiles have the potential to provide an array of unprecedented benefits across our industry and are less likely to produce adverse side effects. By getting the right therapy to the right patient at the right time, patients will get well quicker with more personalized therapies that are more effective. Research organizations that learn to better leverage their sample assets will benefit from reduced costs, faster speed to market and mitigation of the risk of drug side effects. Acquiring the sample is but one step in an exciting and evolving research process laden with opportunities for discovery and development – and for creating strategies that, when implemented, can result in significant cost savings, proficiency and productivity.
Progress towards innovative biopharmaceutical research methods often comes with additional costs, as technological advancements require new investments and experienced staff. Achieving a balance between advancing scientific progress and achieving cost-efficiency is an important focus of all research organizations today. As such, the services that support research progress need to be constantly evaluated and held to the highest standards of excellence and accountability to ensure the utmost level of quality, compliance and value. This means we have to be forward-looking, while staying agile and nimble enough to adapt as our industry changes, particularly with respect to the more than a billion human samples in storage worldwide today. [2].
The vast majority of samples in storage today were collected long before the era of genomic- and proteomic-based research. Utilizing those samples, which were collected for various research or clinical needs, demands specific patient consent and robust data collection in today’s environment. Moreover, the collections must be prepared for future use – for heretofore unknown research purposes by multiple research groups actively pursuing every phase of drug development, from basic research through to post-approval phase IV clinical trials.
Organizations must learn how to upgrade their traditional outsourcing of research assets and move toward more innovative smartsourcing strategies. At its core, smartsourcing moves beyond the traditional “lift and shift” philosophy to a more “value by innovating” philosophy. The real shift is convincing organizations to focus on optimizing their core competencies, outsourcing non-core competencies, and investing in technology solutions to drive innovation.
A workshop on global sample management sponsored by BioStorage Technologies, Inc. was recently held to discuss the multiple facets and features of sample management smartsourcing strategies, which provided a range of perspectives from the presenters. Each an expert from different segments of the biosciences industry, presenters discuss how their organizations have developed strategic partnerships designed to improve efficiencies and achieve sample management cost savings to support research discovery and development. The smartsourcing best practices and information that follow will be useful to research organizations who are seeking innovative sample management strategies to support their organization in meeting the global challenges of today and tomorrow.
Advancing Research Initiatives Through Global Sample Asset Consolidation Strategies
Amelia Wall Warner, Pharm.D
Head, Clinical Pharmacogenomics and Clinical Specimen Management, Merck & Co.
Once an organization perceives its samples as long-term assets for innovation, developing a sample consolidation strategy should be a team effort that requires an expert assessment of company-wide needs, resources and capabilities. To focus solely on collecting the sample, without giving adequate consideration to a methodology and mechanism for obtaining and maintaining samples collected for future use, invites risk that can and should be avoided.
Historically, global sample storage strategies developed organically in the pharmaceutical industry. Prior to the 1990s, sample storage was program or investigator specific, with samples being stored internally or externally, depending upon where or how the sample was used. In the late 1990s and into the early 2000s, however, this fragmented approach resulted in a storage “model” comprised of external and/or internal clinical laboratories without centralized planning or oversight. Many pharmaceutical companies have now invested in a prospective, centralized oversight model that is split 50:50 between internal and external storage.
It is recognized that 70% of clinical trials across all phases of research include a minimum of one sample per subject for long-term storage. This translates to collections ranging from 1,500 to Merck’s 3.5 million human samples – the world’s largest. At the higher levels, the industry began to appreciate the actual value of its specimen collections, especially its genetic specimens, and to make strategic decisions about consolidating its storage repositories. Some chose to outsource specimens to a single vendor; others to multiple vendors; and others opted to build an internal resource. The decision is neither obvious nor one-dimensional, as evidenced by the fact that virtually every company in the industry has changed sample consolidation strategies during the past 15 years.
Merck’s decision to consolidate biostorage repositories externally was made more than a decade ago as it was recognized that operating a biostorage repository is not regarded as a core Merck business function. The external option continues to offer Merck a number of advantages: an integrated and auditable set of locations that could be overseen with relative efficiency; standardized billing, paying storage fees from a centralized budget rather than maintaining clinical grants; and standardized sample handling across types of specimens.
Consolidation provides the ability to integrate data into a central source, while locating specimens around the world. Samples can be mobilized from storage sites for rapid analysis and for research that is not specific to a sample drug but to such broader issues as patient diseases or standards of care. Consolidation also enhances the efficiency of complying with audit/withdrawal requests with respect to human samples, where subjects are asking to withdraw consent for long-term use.
IT infrastructure and upgrades must be monitored and meshed with a cohesive internal strategy for locating specimens. Regardless of the model utilized, this cannot be emphasized enough: an integrated IT infrastructure is essential to locating global specimens over time.
Each model has unique features and advantages appropriate to your organization and the size and purpose of your sample collection.
Fully redundant biostorage repository. Half of every sample is stored in two locations, maximizing the opportunity to minimize the effects of a natural disaster or freezer failure and to withstand local regulatory changes. This could be important because some privacy regulations affect transfer across borders of specimens and data derived from specimens. However, this is a very expensive model to sustain which does not maximize the organization’s return on investment, especially with regard to a very large sample collection.
Single vendor, multiple sites. With an internal or external vendor, this model utilizes at least two sites – one in the United States and one in Europe or China, for example. The site best suited to your global clinical trials strategy can decrease the cost of global shipments and increase opportunities for effective oversight. It also can provide the ability to withstand some jurisdictional issues related to human specimens stored in that location. However, it can carry a greater risk if the vendor fails to adhere to your processes over time and quality declines. Moving specimens is an onerous task.
Multiple vendors, mixed model. Having biostorage repositories operated by multiple vendors, or a mix of internal and external sites, offers the greatest flexibility, but at a cost. The risk of a company or site failure due to quality, cost or stability issues is reduced. Increased oversight, in the form of more staff within the company, is required. Quality levels are not identical, vendor-to-vendor, which requires more oversight at best and remediation of conflicting or on-going issues at worst. Vendors make their own reinvestment decisions, and a business that works on relatively narrow margins is going to be inclined to cut costs, where possible, and that could have an adverse effect on quality.
Multiple vendors, consolidation. Developing a multiple vendor consolidation strategy imposes a number of considerations. The remediation of quality issues across vendors will not move at the same pace; the challenge is to maintain a high level of quality regardless. Despite having standard operating procedures (SOPs) in place, ongoing quality can vary and an active audit program with external vendors is necessary.
To outsource your biostorage repository fully, as Merck has done, it’s important to engage an expert internal team to qualify potential vendors on some special topics.
A general clinical lab qualification process probably will not be adequate because it does not track the appropriate items for biorepository evaluation. The team should examine five factors:
- Robust chain of custody – for specimens coming through
- Temperature maintenance – throughout processing
- Accessioning process – and monitor it over time
- Coding process, if applicable – industry-standard compliant
- Downstream processing capabilities – where will the work be done and will samples be returned
In developing assessment criteria, give special attention to hidden costs, which can be presented as:
- High in-fees – what costs are included to get specimens into the biorepository
- High protocol set-up fees – some vendors are accustomed to setting up protocols for clinical trials and those fees are included; bringing a large collection that has been stored for a long time, with multiple protocols, could generate unexpectedly large set-up fees
- Higher than expected project management fees – a red flag
- High destruction fees – a red flag
- Exit fees – especially important because the vendor assessed today may not have the same quality assessment in 10 years; protect your organization by agreeing to pay a smaller exit fee if the vendor’s quality declines
Every model has pros and cons and each requires an investment in oversight or in the vendor. It is fallacious to assume there is no need for internal staff if you outsource, because you must oversee each vendor; the more external vendors you opt for to minimize the risk of one vendor, the greater cost to oversee them. Oversight is a real cost requiring on-going audits, weekly reviews of arriving inventories and personal attention to projects.
An integrated, well-annotated specimen collection will significantly increase the return on your investment. Selecting the right strategy for your company and collection is essential to having robust specimens for quality research over time.
Bioprocessing of Sample Assets: Emerging Opportunities From State-of-the-Art Academic Biobanking Initiatives
Andrew Brooks, Ph.D.
Chief Operating Officer, RUCDR Infinite Biologics at Rutgers University
We are challenged today to think about how we are integrating bioprocessing methodologies with sample management logistics and repurposing samples within academia and in personalized medicine initiatives. It is also important to be current with the status of clinical trials and to be aware of ongoing developments with respect to research and discovery.
There was a time when samples were collected for an individual purpose, usually to ask a specific question and to arrive at an equally specific answer. If another question arose, the task was to get another sample and conduct another test. This process was very costly, time consuming and inefficient. More recently, sample bioprocessing methods have been developed that allow us to ask many different questions and to address the increasing stringency in regulatory hurdles with respect to drug and therapy approvals.
More importantly, this established processing methodology allows us to prepare samples to answer questions about metabolome, proteome, genome and other molecular components of interest. This presents us with a number of significant sample management challenges, starting with a frequently overlooked but important process: the critical process from sample collection through bioprocessing to placement into storage. Once the sample is in storage, the challenge is mostly to preserve its volume and integrity.
The global and logistical management of the collection process requires complete and centralized knowledge about each sample – where it was sent, how much was sent, how much remains, freeze-thaw data and other environmental factors. Tracking informed consent is required for compliant sample utilization. The future utilization of research samples is tied to the level of consent obtained from a study subject. Knowing the sample is being optimized strategically is essential. The objective is to maximize precious biological resources through the best use of primary samples and efficient bioprocessing technologies to improve yield and quality. Appropriate storage formats and temperatures ensure researchers achieve the most benefit from samples being stored for future use.
Nucleic acid amplification and cell line establishment enables us to create renewable resources that preserve the primary sample or precious collections – or both. The sample collections from 20 and 30 years ago that we are working on currently are being depleted. Researchers are requesting samples from these collections to use with new analytical technologies. By integrating technologies that create renewable resources, we can preserve these older samples and prevent them from being depleted. We can also establish appropriate distribution guidelines to preserve sample resources by defining the needs for specific downstream applications.
Over time, sample size has been decreasing, while the number of sample requests is increasing. Our goal is to withstand these demands by creating renewable resources and focus on efficient and integrated processing so we can get more out of every sample. Integrated workflows incorporate maximum use of the primary sample. Efficient bioprocessing and extraction techniques and performing analytical and functional quality control helps preserve samples.
RUCDR creates renewable resources from these limiting and labile samples. One Paxgene tube of blood collected for RNA provides a few micrograms – enough to distribute to two or three labs. We take 500 picograms of total RNA (using NuGEN Inc. technology) and can linearly amplify ten micrograms of cDNA to get enough material to distribute to hundreds of laboratories, provide more robust and reproducible gene expression data while preserving the primary sample at the same time.
BioStorage Technologies and RUCDR Infinite Biologics have developed the Bioprocessing Solutions Alliance to provide advanced, state of the art bioprocessing and biobanking solutions to the bioscience industry. The innovative, wave-of-the-future services available from the Alliance provide integrated sample management and bioprocessing capabilities at significant cost savings.
The Bioprocessing Solutions Alliance offers outsourcing of sample management and bioprocessing providers with an integrated partner. The two partners have experience in sample logistics and sample management with integrated bioprocessing and quality control that allows for greater utility from every project. The alliance leverages joint facilities, an integrated technology solution, scientific expertise and considerable economies of scale.
The most important resource any study or clinical trial has is the biological sample. Creating a centralized sample bioprocessing and storage framework can maximize the utility of each collection for current and future use. Once a project is initiated, the ability to organize and consolidate bioprocessing workflows and sample storage becomes even more challenging.
You can get more out of every study and increase the potential of what you hope to accomplish more efficiently and economically by having an integrated sample and bioprocessing plan before you start.
Attaining Efficiencies with Critical Research Assets Through Internal Consolidation and Outsourcing Partnerships
Karen McNamara, MBA
Clinical Supply Sr. Manager, Infinity Pharmaceuticals, Inc.
Our company’s leadership wanted a new perspective on attaining efficiencies with our critical research assets through internal consolidation and outsourcing partnerships. Currently, we have over 15 global studies in various stages, with more than 16,000 samples in our repository and an expected increase in sample volume.
Following an analysis of how other companies manage samples, we met with a subgroup of stakeholders in our organization that touched a sample throughout its lifecycle at Infinity. There was agreement amongst stakeholders on the inefficiencies in the current process and there was high engagement and support for the development of a more streamlined process. One key takeaway is that sample management – a shared responsibility between Clinical Operations and Molecular Pathology – was being carried out differently on each of our trials.
Process mapping enabled us to identify internal gaps in our sample management efforts. Forty identified gaps were put into one of five categories:
- Out-of-scope, such as pre-clinical sample management
- Process, including such issues as the need to return tissue samples to the site
- System, where a variety of systems contained unique but nonintegrated sample data that could not be integrated
- Data, including multiple data elements with different names 5. Vendors, with a focus on understanding and communicating vendor expectations
Our next step was to prioritize the high-risk/easy-to-implement gaps and focus on them first. Then we began to develop a plan to address other identified high priority gaps and create standardized processes to achieve further efficiencies. As we moved forward, we learned that in trying to streamline all the data, every member of our team had to fully understand the different aspects of the process we were attempting to streamline. Missing just one piece of data, or one item of information, could take us down the wrong path. For example, not understanding that a sample’s collection time point could be a critical piece of information in selecting a sample for analysis could result in the removal of the time point data element in the sample inventory system in an effort to streamline; however, removing this data element then handicaps the scientist’s ability to identify which sample to select from our inventory system.
When looking at data across studies, it is easy to leave something out or ignore it if there is not appreciation for why that piece of data is being collected. Only later in the process does it become apparent that the data is essential. To prevent that, we relied on our collaborative approach and on having subject matter experts (SMEs) on hand. Without the right SME, it is easy to overlook a vital point. Even with our SMEs involved, we learned that we could not prevent some errors, but we could achieve a workable balance that did not overwhelm the work we were doing. The key leaders within each of our company’s functional areas identified the experts within their groups who worked with us and then reported back to their respective groups. We were committed to developing standards that could be applied throughout the organization; if they did not or could not apply, we would be creating a problem. Our information technology department was heavily involved.
Some of the gaps identified in our analysis were homegrown and evolved over time. Others could be categorized as generic to any organization without the standardized system we developed. It is necessary to look across the lifecycle of the sample as it moves from collection to the lab to extracting data from it to consumption or destruction. Different vendor systems touch that sample and data, and we had to understand that process and how to manage it to ensure it was reproducible, reliable and compliant. Standardization tweaks applied to individual systems required a holistic lifecycle and systems assessment to ensure we did not hinder progress later.
Today, we have a unique partnership with BioStorage Technologies. Their on-site technician manages our inventory using their sample management technology system, ISISS®. The internal reaction to the tech’s presence has been positive. It filled system and resource gaps we were aware of across the company but did not have the resources to support. Moreover, the technician was a welcome addition to our staff that helped make our work successful and whose presence demonstrated leadership’s buy-in and active support at the same time.
With the current samples in-house and the expected increase in volume, we knew we had to build a data standard library and align our various systems to capture the appropriate data and standardize the management process for doing so. The goal is to transfer all of our sample data from various systems into our own internal integrated data system,allowing us the benefit of pooled sample data. Prior to implementing our data standards within ISISS®, we were dealing with more than 100 data elements and 1.75 million data points. Today, we have reduced those numbers to much more manageable 23 data elements and less than half a million data points. A much more scalable data set.
We are not finished, but the progress we have made to date can be attributed to four factors:
- Ownership/Accountability – one person has to be dedicated to the overall process and accountable for its success. Company leadership needs to be engaged and supportive of the effort.
- Awareness – understanding the value of our samples as future assets helped generate awareness of the need for a more sophisticated and efficient sample management process. While individual teams are doing what they think is best for the trial, a consistent, shared global view and in-depth insight of the sample lifecycle process will help avoid issues in the future.
- Consistency – we have continued to rely on a collaborative approach and we have continued to expand our educational efforts throughout the company.
- Vendor buy-in – At the onset, it was clear that expectations from both sides were not aligned, a critical gap. To address the gap, we examined our vendor relationship and a governance plan was implemented to support performance reporting. A monthly dashboard captures metrics over time and provides visibility to leadership on both sides. We revisit mutual expectations periodically to make sure metric reporting evolves as our relationship evolves.
Strategies for Achieving Regulatory Compliant Logistics and Sample Management Efficiencies in Asia-Pacific
Reynaldo Roman
Senior Manager Regulatory Compliance, Marken
As international borders and boundaries seem to disappear in a growing global economy, many companies are anxious to pursue smartsourcing opportunities available in emerging Asia-Pacific markets. However, proliferating, complex and country-specific regulatory compliance practices may challenge the capabilities of supply chains and the efficiency of global logistics strategies. Of 116 biopharmaceutical companies surveyed last year, 57% rated global logistics as a significant challenge to business, and only 8% said global logistics presented no challenge. The World Economic Forum, in a study conducted two years earlier, measured the level of government regulation and the degree of burden imposed by regulations on companies in 142 countries. Businesses in more than 120 of those nations – a robust 86% - described government regulations as “burdensome” or “extremely burdensome” [3].
As the number of clinical trials around the globe has continued to increase, dealing successfully with such regulatory burdens makes sample management a more important, precise and deliberate process. Your objectives are clear: import your sample kits and export your samples efficiently and cost-effectively. The procedures and policies that allow an organization to be successful in one country, however, do not necessarily guarantee equal success in other countries. Every country must be approached – at least initially – as a unique market, with procedures and policies aligned to its specific compliance requirements.
Many research organizations in the United States do not realize how burdensome trade regulations in emerging markets can be when compared to the United States. Although imports into the United States are highly regulated and frequently subject to the oversight of more than 40 regulatory agencies, only a small number of domestic imports require permits or licenses and most domestic exports do not require licenses. This may not be the case in emerging markets. Being aware of the inherent regulatory implications that are unique to a market or country can make a measurable difference in the time, efficiency, cost and validity of your study. Licenses and permits are often necessary and the process for acquiring them can be lengthy and frustrating.
For example, importing tissue slides into China for training or for equipment calibration requires permits from the Ministry of Health (MOH) and from the Chinese Inspection and Quarantine Service (CIQ). The process of obtaining these permits can exceed 30 days. On the other hand, importing diagnostic kits into China is a relatively straight forward process, but exporting the subsequent samples will require a new MOH permit, with approval time often exceeding two weeks. This period of time does not take into account the approval from the Human Genetics Management Office (HGRMO) which can result in an additional 90 days waiting period.
Document requirements also vary greatly depending on the type of product and country of destination. For instance, importing diagnostic kits containing a needle into India requires five different import documents and can take up to eight weeks to gain the necessary agency’s approval. In contrast, kits that do not include a needle require only a standard set of import documents and the shipment clearance can be achieved within 48 hours. In order to export the subsequent samples from India, six different export documents for permit application and five documents for export approval must be obtained. One can expect to wait approximately eight weeks in order to obtain the necessary documentation.
In order to overcome the regulatory hurdles in emerging markets, it is vital to know exactly what is being shipped, where it is going and to understand the applicable regulatory implications. A simple error in the process can result in critical clinical supply chain interruptions in patient recruitment and continued treatment; deteriorating inventory; missed production opportunities; exhausted import licenses; date and quantity expirations; and/ or additional costs incurred due to delays and unforeseen obstacles.
The following are two of the most common errors made by importers and exporters in the process of importing or exporting samples or kits.
The first is not having a contingency plan for the possibility of delayed shipments because of clearance setbacks due to country – and/or region-specific practices and procedures, especially in emerging markets. Some countries are in the early stages of strengthening or expanding their regulatory agencies and accommodating the barrage of new shipments at their borders. Considering that interagency communication can often be strained, it is not unusual for agents at different regulatory authorities to struggle with changing rules and policies which can result in clearance delays of merchandise while the proper approvals are sought. Additionally, there’s potential that an inexperienced inspecting officer may forget to sign a certificate or export document resulting in the delay or detention of a shipment containing a valuable sample.
Second, a seemingly harmless mistake or omission on a document cannot be remedied by the mere suggestion that the required information is implied, or that logic dictates understanding of the intent, if not the meaning. Document accuracy is essential in regulatory compliance. In the United States, a clerical error on an import document, such as a missing weight or quantity, can typically be corrected fairly easily. In China, however, the same mistake can result in a shipment being detained for weeks. The description on permit applications, invoices and product labels must be identical. A clerical mistake on a permit application can require the process to start from the beginning. Clearance decisions typically come down to comparing the wording on a product label to the wording on the CIQ permit. If these two do not match exactly, the inspecting officer may conclude that the documents do not pertain to the product and the shipment can be detained. Any attempt to explain that the discrepancy is the result of a harmless omission or typographical error is futile.
In order to avoid these pitfalls, the importing or exporting company must give their global logistics strategy the same high-level priority as their project planning strategy. Companies must understand the process from start to finish and communicate with the product development and support staff. Additionally, it is crucial to ensure that the information on all shipping documents must match word for word and letter for letter. Missing a number or making the slightest error on a packing list can have an adverse effect on a project of international scale, and with budgets tight and time frames condensed; global logistics are viewed sometimes as little more than a necessary evil.
While establishing a unique process for each country is not necessary, a flexible template that can be adjusted to the complexities of an individual market and consistent communications with service providers can be helpful. A process template should be designed to anticipate unique challenges that prompt to the engagement of the appropriate internal and external experts at each step. It is important to realize that, with respect to international logistics in emerging markets, change can occur quickly with a lapse in vital communications. Therefore, it is important to stay in frequent contact with service providers who have a daily presence in the marketplace and can become aware of last-minute developments and/or changes in the markets that you want to enter. If recognized as a critical component of your overall approach to the business, a carefully implemented strategy for regulatory compliant logistics and sample management efficiencies can help assure a successful trial in emerging markets.
Summary
Selecting the most effective sample management smartsourcing strategy for your organization has the potential to contribute significant long-term efficiencies and cost-savings. Each sample management model offers a unique set of risks and rewards along with a concomitant investment in the vendor or in vendor oversight. Whether your company size is large or small, a company-wide vision that perceives samples as future assets will help generate awareness of the need for a more sophisticated and efficient sample management process.
When selecting the best sample management model for your organization, it is important to assess your existing structure, resources, and supply chain to identify opportunities for improvements and costsavings. Centralized bioprocessing and storage models can offer significant advantages in quality improvement and maintenance as well as time- and cost-saving opportunities. Selecting the appropriate model, especially in a smaller organization, can help secure previously unrealized efficiencies in sample management through internal consolidation and outsourced partnerships. An integrated sample management and bioprocessing plan can maximize the potential efficiency and economic benefit of every study you conduct. Each sample management smartsourcing strategy should have a global component that addresses regulatory compliant collection, logistics, and storage efficiencies to ensure a successful trial, especially in emerging markets. Attention to every detail enables organizations to achieve a timely, cost-efficient, and successful global logistics program.
Optimizing core competencies and outsourcing non-core competencies in the management of research samples allows organizations to achieve even more opportunities for efficiencies and innovations in clinical research. Several strategic approaches exist and selecting the right organizational model is an important first step. By implementing a smartsourcing approach to sample management, organizations can better leverage their biological sample assets and this will set them up for greater success in the world of personalized medicine.
References:
- Vaught J, Rogers J, Myers K, et al. An NCI Perspective on Creating Sustainable Biospecimen Resources. J Natl Cancer Inst Monog 2011; 2011(42):1-7.
- Clement, O. Biological Sample Storage and Management. Lab Manager Magazine. Published October 7, 2009.
- Zaino, Jennifer. The State of Global Clinical Research Trials. UBM TechWeb and Wipro IT Business, 2011. Web.