The convergence of instrumentation and assay technology will help IVD manufacturers meet customer expectations.
Richard Creager, PhD, is the corporate vice president of the Immunoassay Business Center at Beckman Coulter Inc. (Fullerton, CA). He can be reached at rcreager@
In the search to build a more efficient and cost-effective assay system, IVD manufacturers must learn to look beyond the traditional clinical platform. Smaller sample sizes, signal amplification technology, and intra-agency cooperation will improve clinical data understanding and guide assay development strategies.
To learn how various innovative factors affect assay development, IVD Technology editor Richard Park spoke with Richard Creager, PhD, corporate vice president of the Immunoassay Business Center at Beckman Coulter Inc. (Fullerton, CA). In this interview, Creager discusses the importance of synergy in instrumentation and assay technology, as well as how current industry trends affect product discovery, development, and execution. He also talks about the advantages of developing immunoassays in-house, how simpler instrumentation can help laboratories meet customer expectations, and the role of molecular diagnostics in the future of assay discovery.
IVD Technology: What have been the biggest technological advances in assay development during the past few years?
Richard Creager: I think the most significant advance in the last decade has been the discovery and advancement of signal amplification technology. For example, enzyme-mediated chemiluminescence, compared with the fluorimetric or the colorimetric systems, added two key areas to the industry. Chemiluminescence signal amplification provides improved assay sensitivity (lowered detection limits) and the ability to achieve larger dynamic ranges, up to six orders of magnitude. As a result, almost every major IVD manufacturer has developed to chemiluminescence-based immunoassay systems since the 1990s.
What were the driving factors that led to the development of amplification technologies such as chemiluminescence?
In the mid- to late 1980s, IVD companies were looking for ways to amplify their technologies. The thought was to use immunoassay detection and pursue chemiluminescence, which provided the ability to increase signal production. In medicine, chemiluminescence-based immunoassay technologies allowed clinicians to identify the significance of low-concentration circulating analytes, which was not possible with the older systems.
Evolving with the Market
What are the latest trends in assay development?
I see three broad trends occurring in the industry right now: the continuing development of more-efficient and reliable assay systems; new biomarkers that improve patient health and reduce the cost of care such as reducing hospital stays or monitoring the effectiveness of therapy; and the increasing use of multiple analytes in various mathematical algorithms to drive results that offer additional clinical information.
The first trend is being driven in part by the shortage of skilled laboratory personnel and ongoing efforts to reduce healthcare costs. More-efficient and reliable immunoassay systems will be necessary as hospitals merge, laboratories grow larger, and workloads increase. Further, I see a definite push toward full laboratory automation and complementary information systems in response to the shortage of skilled technologists.
As chemistry and immunochemistry systems are combined into work cells, IVD manufacturers will incorporate features of total lab automation into more-compact units. These systems will automatically label, sort, store, and transport tubes to immunoassay analyzers; pierce the cap to improve laboratory personnel safety; perform the analysis; verify the data; and send the results to physicians when the process is complete. It is a convergence of instrumentation and information technology (IT).
The second trend in assay development results from the revolution in genomics and proteomics. We are seeing a host of new biomarkers that significantly improve patient care. For example, certain markers, called companion diagnostics, help predict or monitor the effects of a prescribed therapeutic drug on a patient. These markers could help stratify patients that may be harmed by certain therapies. I see the continued emergence of new biomarker targets on the horizon.
The third trend is the evolution of mathematical analysis and bioinformatics. The convergence of immunoassays with IT provides additional information that will assist clinicians and their diagnostic decisions. For example, the free PSA to total PSA ratio is a simpler version of bioinformatics. This ratio provides a risk profile regarding the likelihood of a man with a high PSA value actually having prostate cancer, helping a physician determine the need to perform a biopsy. New prostate cancer biomarkers and algorithms are being developed which may provide additional specificity for determining the aggressiveness of prostate cancer.
In the cardiovascular area, IVD developers are researching combinations of biochemical markers, along with patient history and demographic data, to provide more information to physicians. As the number of variables increase, more-complex mathematical algorithms may be needed to provide physicians a better ability to analyze a multitude of variables that the human brain just cannot examine alone.
Improvements in assay systems, new biomarkers and bioinformatics should improve the contribution that laboratory testing plays in improving patient health and reducing the cost of care.
How do IVD manufacturers overcome the challenges of designing and developing their assay products?
During the last 20 years, IVD manufacturers focused on developing instrument systems; essentially the same assays were available on all systems. During that time, very few new biomarkers were released into the routine testing market. Typical development times were one to three years. However, the discovery of new biomarkers and introduction of these into routine clinical practice is changing that paradigm. With new biomarkers, the product development process from discovery to routine clinical practice may now take eight to 10 years to complete.
In addition, governments, regulatory agencies, and payers are interested in improving test safety and efficacy, as well as decreasing the cost of care. As a consequence, IVD manufacturers will be required to perform more clinical studies that demonstrate improved patient outcomes and better economic benefits, such as reduced hospital stays, using targeted therapies.
In the United States, IVD companies classically worked with FDA for approval. However, with new biomarkers and bioinformatics, IVD manufacturers also should consider how to work with payers to achieve favorable reimbursement. The same is true in Europe. For reimbursement, IVD companies will need to perform different types of clinical studies that assess economic outcomes in addition to safety and efficacy. Overcoming these challenges will also take lobbying efforts by industry associations to help educate government officials, regulators, and payers about the benefits of new types of diagnostics that will improve patient care and reduce healthcare costs.
How have IVD manufacturers been working with academic researchers in developing assays?
The IVD industry has moved from simply developing assays to discovering new biomarkers, and some of the initial clinical feasibility studies of such biomarkers show that they provide additional valuable clinical information. The days when IVD manufacturers develop new immunoassays without collaborating with clinicians, academicians, educators, and payers are gone. Academic researchers also provide independent and peer-reviewed studies, which demonstrate the benefits of such new tests.
In the past, we identified key opinion leaders, known for conducting extensive research in a particular area, and we reached out to them to set up collaborations. These partnerships will continue to be important. Such relationships are instrumental in identifying new biomarker discoveries, whether they are protein markers or molecular markers in a specific disease area. IVD manufacturers will not be successful in the marketplace unless the key opinion leaders are aware of their companies' technology.
What factors led to IVD companies no longer developing immunoassays in-house?
To clarify, years ago, most of the clinical validation was completed in-house using frozen samples. Now, many IVD companies perform validation externally. As far as discovery, the challenge becomes one of focus and cost. We prefer to focus our basic research on a couple of areas. To do the process justice, developers have to dive deep. Manufacturers have to choose specific areas to concentrate their research, because it is prohibitively expensive to cover the whole field. So reaching out to academicians provides more extended opportunities. I think it is beneficial for the academicians as well because industry collaborations provide sources of funding other than just government grants. National Institutes of Health funding has decreased over the years, and diagnostic companies provide additional sources of funding for academic research. Overall, it is a mutually beneficial relationship.
What factors must IVD manufacturers consider when developing assays that are used on their instrument systems?
Each instrument system provides immunoassay developers with different constraints. Manufacturers should have a comprehensive understanding of the overall biocompatibility with instrument components, as well as management of external environmental factors, such as temperature, humidity, and personnel, and their impact on antibodies, binding reactions, solid phases, attachment chemistries, matrix effects, buffers, and additives.
Reagent and assay developers need a thorough understanding of the mechanical and electrical software and physical limitations that instrument systems present, which will allow IVD companies to design assays that minimize the constraints. Assay system manufacturers that have in-house engineers and scientists have a competitive advantage over companies that outsource some of this activity because they have the capability to understand and integrate all of that research information throughout the design process.
Gathering Customer Feedback
How can IVD companies balance instruments with assay systems in order to design a test that is effective, yet still comply with such constraints and limitations?
We use a combination of customer feedback and Six Sigma design methodology to get the best product that meets customer expectations. We typically talk to a large number of customers around the world to fully understand their requirements, and then condense their feedback to produce key user requirements. From there, we have that information documented in design specifications and test our hypothesis against an even larger number of customers.
In the first round, we might talk to 100 customers to develop our hypothesis; in the second round, we might survey 1000 customers to validate it. Once we understand the variables involved, we use Six Sigma statistical methodologies to design our models and, ultimately, test those designs.
How do IVD companies find out what laboratories and laboratorians need most from their assays?
IVD manufacturers have to be in constant contact with their customers around the world. Different markets present different constraints. Once manufacturers have a test on the market, companies have to maintain contact with customers for feedback on how that test or product is performing and whether it is meeting customer needs and expectations.
How do IVD companies gauge what various markets and customers in different global markets need in terms of assay development?
We are starting to see a globalization and synergy of expectations. Years ago, emerging markets didn't have the capital to buy state-of-the-art automation, instrumentation, and assay technology. Today, we see that changing. Now, we are developing essentially the same products for all markets
Meeting Future Challenges
How have developments in molecular diagnostics affected assay development?
Molecular diagnostics has made it easier to design antibodies and other ligands than was possible 15 to 20 years ago. In the case of antibodies, IVD companies can pursue recombinant antibody development. In the case of proteins, manufacturers can develop molecular models to help conjugation chemistries, and develop and manufacture antigens for calibrators, controls, and immunogens.
We are using molecular biology to better understand the presentation of various target antigens in different physiological states, such as whether they are free, complex, or breakdown products. Molecular biology is used in all aspects of the assay design.
Will molecular diagnostics continue to play an increasing role in assay development and remain beneficial in assay design in the future?
I see molecular diagnostics and immunodiagnostics as excellent companion products. However, I do not see molecular diagnostics replacing immunoassays. Molecular diagnostics will continue to provide additional information to the laboratory and physician.
In the case of infectious disease, a combination of DNA and RNA detection along with antigen detection adds more clarity to a number of infectious diseases. In the case of cancer and cardiovascular disease, molecular diagnostic information adds a greater understanding of a patient's condition.
What future challenges will emerge in assay development? What new trends can the IVD industry expect to see this year and in the future in assay development?
The assay development market tends to move slowly. Not much has changed over the last 20 to 30 years, other than a few additional biomarkers. Due to the challenges in both regulatory and reimbursement, I think it will continue to be a gradual process.
As stated earlier, we will see the emergence of new biomarkers and bioinformatics. We also may see a drive to use smaller sample sizes. Another trend may be to move testing away from the central laboratory and closer to the patient. In the future, there will be a demand for assays to be faster and more compact, so they can be used in intensive care units, emergency rooms, chest pain clinics, delivery wards, and other areas where laboratorians can test a biological sample and receive results within minutes. I see many new biomarkers coming out that are more critical-care driven, where physicians need fast answers to give effective treatments.
What sorts of technological challenges do such trends pose to IVD companies to create products in the assay field where nonprofessional laboratorians will be required to operate them?
I expect IVD manufacturers to create simpler instrumentation, less-complex assays, and, to some extent, more multiplexing devices. Whether they involve one tube or several, multiple tests will help the industry meet these new technical challenges.