Stepping Up for Specimen Standards

So how did you become a crusader for pre-analytical biospecimen quality control?

I’ve been an academic pathologist for most of my career, doing high-volume patient care, running translational research laboratories, being involved in clinical trials, and in all those capacities, I was exposed to the issue of poor specimens yielding poor data, without a solution in sight. But in 2005, I was recruited by the National Cancer Institute (NCI) to head up a new initiative in the Office of the NCI Director: the Office of Biorepositories and Biospecimen Research (OBBR). The goal of that initiative was to develop and implement evidence-based standards for biobanking to ensure that the human biospecimens used in NCI-funded research would be of uniform quality, fit for the analysis purpose for which they were intended and would produce high-quality, reliable data when analyzed. In other words, we intended to fix the “garbage in” problem in NCI-funded research. It was unthinkable that any part of the NCI budget of US$5.6 billion was funding science that was based on poor quality analytes and consequently yielding poor-quality data.

Pre-analytical variation has long been recognized as major source of laboratory error in clinical pathology and is dealt with in the laboratory accreditation process. For anatomic pathology, however, pre-analytical variation has not been widely studied, corrected or regulated. A real revolution has come to anatomic pathology in the form of new technologies. The tools that we now have to analyze specimens are spectacular, but they raise the bar for specimen quality, bringing us back to the basic need for analyte quality standards. We now have the ability to produce enormous quantities of data at such a breakneck pace that, if we’re not careful, we’ll produce bad data in unprecedented quantities. I think that we already are doing that and that it will set us back in the research setting and in clinical medicine alike. Fundamentally, the quality of an analysis can never be higher than the quality of the starting materials. Garbage in, garbage out.

What’s changed since you started working on standards for biobanking?

There was little to no data on how pre-analytical variables affected different specimens. There was no quality control of samples when they entered the bank, only when they were accessed for use. In one large flagship team science project at the NCI, for example, we found that 80 to 95 percent of banked samples didn’t meet the quality requirements for that genomic research! At OBBR, we realized we needed national, indeed international, standards for human biospecimen collection, handling, processing, storage, and distribution (shipping), and that these standards needed to be evidence-based to the greatest degree possible. I convinced the NCI to allocate millions of dollars to a scientific research program to investigate the impact of pre-analytical variation on the biology of human samples, to serve as a foundation for data-driven standard operating procedures (SOPs). We sought expert input globally to define the technical, as well as the ethical, legal and policy standards for high-quality biobanking. But this was revolutionary at the time – it threw a monkey wrench into translational research because it brought into question the quality of specimens banked around the world. Thanks to government funding during the economic stimulus, OBBR developed a standardized national biobank for translational research called CaHUB (the Cancer Human Biobank). Currently that bank serves only multi-institute supported team science projects at the NIH.

When I left the NCI in 2012, the pre-analytical variation problem was, unfortunately, still alive and well. I am now reunited with prestigious colleagues from the NCI here in Arizona where, under the leadership of Dr Anna Barker, former NCI Deputy Director, we formed the National Biomarker Development Alliance (NBDA), a nonprofit organization with close ties to government, industry, academia, clinical medicine and patient advocacy. Biospecimens are, of course, the major source of biomarkers, so it is only logical that the NBDA has a major focus on biospecimens. Under the auspices of the NBDA, a landmark step in the standardization of pre-analytical variation in human specimens was accomplished by going directly to the professionals who could lead this change: the pathologists! On behalf of the NBDA, I organized two convergence conferences that brought together a diverse group of pathologists, researchers, regulators and patient advocates to identify issues with specimen quality and propose workable solutions. We agreed on a “top 10” list of critical issues that needed to be addressed and prioritized those to the “top 5” that could be controlled through CAP’s Laboratory Accreditation Program and would yield the biggest bang for the buck. We were applying the Pareto Principle (20/80 rule) to the issue of pre-analytical variation; in short, we defined the 20 percent of pre-analytical variables that cause 80 percent of all quality compromise. When CAP enforces the control of these variables through their Laboratory Accreditation Program, it will be the first time in history that all human samples from the clinic (CAP-accredited labs) will be quality-controlled and fit for translational research. I’m ecstatic!

What are the current obstacles to improving standards?

We need more science behind biobanking. It’s very difficult to convince people that biospecimen research is worthy of funding and of publication. Pathologists and researchers alike are left to develop SOPs that lack the scientific rigor that they would desire simply because the data is non-existent or extremely difficult to find. For example, information about pre-analytical variables might be present the materials and methods section of published papers, but it is rarely regarded as worthy of publication on its own. OBBR tried to change that by creating the Biospecimen Research Network to legitimize and fund biospecimen science. We even coined the term “biospecimen science” because the concept that biospecimens themselves needed to be the object of scientific investigation didn’t really exist. Biospecimen science is now regarded as publishable, but it’s still difficult to compete for funding in this arena despite the fact that it’s vital - it’s a starting point for all other research based on human samples. Nobody wants to be a bad pathologist or a bad scientist. We all want analysis data that we can rely and build on, and that starts with reliable analytes.

I think the issue of irreproducible results caused by pre-analytical variation in samples has, in the past, been known only to pathologists who either do their own research or work in a medical laboratory. It’s routine in clinical work to discard samples that have been compromised in the pre-analytical period and will yield spurious data if they can be analyzed at all. In the clinical chemistry laboratory setting, for example, it has been estimated that pre-analytcal variables account for somewhere between a third and three-quarters of all laboratory errors. But the same issue affects samples in all areas of pathology; it just hasn’t been visible enough until recently. So I think it’s going to be a confluence of issues – patient awareness, physician motivation, push from funders and regulators, incentives through payors, and pathology leadership – that really drives the solution here.

We’re starting to realize that technology alone isn’t the answer to better medicinal science; in fact, it’ll obfuscate the truth if we pollute our results with poor data based on poor samples. We need to address this problem now so that, going forward, we can be confident that we’re doing the best things for our patients and for scientific progress. It’s a unique opportunity – there’s rarely a time when pathologists can have such a far-reaching impact on scientific quality by fixing one thing.

How important are pathologists in driving change?

They are absolutely key. I’m proud of what we’ve accomplished, but there’s still a lot of work to do. I’d like my colleagues in pathology to recognize that precision medicine won’t happen without them – that they are central to the future of precision medicine. No matter what their practice setting, they are part of the research enterprise that’s going to change medicine for the better.

I’m a dyed-in-the-wool cheerleader for pathology. We’ve had some negative publicity because of the perception that pathologists live in our own little sphere and don’t interact much with the rest of the medical world – except through our reports. But I believe this is an unprecedented moment for us. If pathology steps up to the plate and claims its rightful place in patient care as well as translational and clinical research, we can and will make a difference. We’re the ones who can be heroes for both patient care and translational research because human biospecimens are the common denominator.