IN PERSON - ONLINE EXPANDED VERSION
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Marsha Oenick, PhD, is group director, research and development, at Ortho Clinical Diagnostics (Raritan, NJ). She leads an organization responsible for designing, developing, and delivering new assay/reagent products for the company’s clinical laboratory and transfusion medicine product lines. She can be reached at moenick@its.jnj.com.
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With the introduction of new measurement technologies and sample-handling techniques, the IVD industry has been able to create highly sensitive assays to detect newly discovered biomarkers. Such ongoing advances hold the prospect of determining individual patients’ likelihood of entering a disease state or progressing rapidly from an early disease state to a full-blown one. But money for investment in assay development is limited, and should be deployed efficiently.
To learn more about approaches assay developers are taking to address unmet diagnostic needs, IVD Technology editor Richard Park spoke with Marsha Oenick, group director for assay development at Ortho Clinical Diagnostics (Rochester, NY). In this interview, Oenick talks about integrating new detection technologies into multifunctional instruments, working with scientific and clinical researchers outside the IVD company, and finding satisfaction in bettering the health prognosis of future generations.
IVD Technology: What have been the biggest technological advances in assay development during the past few years?
Marsha Oenick: There has been a lot of research activity for a number of years now—with some of the outcomes being published in your magazine—that has been focused on devising new ways to improve the capabilities of existing immunoassays—to lower limits of detection, enable multiplexing, lower sample-volume requirements, and so on.
A number of exciting new measurement technologies, sample handling, and microfluidic technologies have emerged as well as a number of new kinds of detection molecules to supplement the familiar antibodies—the aptamers of nanobodies and others.
Ortho Clinical Diagnostics’ acquisition of Amic SA and its unique microfluidic platforms is indicative of the fact that some of these technologies are beginning to move into the marketplace.
You’ve mentioned lower detection levels, measurement technologies, and improvements in sample prep. Which of these do you think have been of primary interest to IVD manufacturers recently?
IVD companies have a number of interesting scientific and engineering advances to consider to incorporate into their product lines. The challenge is making it commercially viable. We consider carefully how we will automate the technology in a way that makes it useful to the laboratory and what menu items it will enable. A single assay of a single analyte on a new technology is not going to be particularly interesting to a laboratory if it has to buy an instrument that can do only one thing. So a big challenge in moving brand new measurement technologies into the commercial marketplace is having enough menu and using it to make it an attractive enough proposition both for the manufacturer to offer it and for the laboratory to buy it.
Assay Development Trends
What current trends in assay development do you see?
The biggest trend we’re participating is in regards to providing new clinical information through diagnostic products. There is a large number of diagnostic analytes that are now offered on automated platforms by a number of IVD companies. These analytes have become progressively more automated and more reliable. But now we’re turning to the question of how we can provide new clinical information through our diagnostic products. Our rapidly expanding understanding of human biology should enable us to gather much more specific information about patients’ health. We’re interested in providing this information, preferably at a time in the progression of a disease, from relative good health to illness, such that you can make a difference, taking action that can help the patient off the path towards disease and back towards health.
There’s also much activity, with some success, involving designing diagnostic companions to drugs in order to improve the pharmaceuticals’ effectiveness—that is, putting the right drug with the right patient so that it is going to do something for them, and with minimized side effects.
Our own Veridex technologies and specifically GeneSearch help indicate very specific states of human health. For instance, the Breast Lymph Node product helps the surgeon decide whether additional surgery will be required for a breast cancer patient while the patient is still in surgery, eliminating the several day wait required when using standard methods. We are beginning some interesting collaborations with the pharmaceutical side of our own business to seek assays that can help select patients who will benefit from new drug therapies in development.
You’re touching on personalized medicine.
Absolutely. I think there are two basic trends, one surrounding the question, Can I personalize the therapy I’m going to use for this particular patient? and the second addressing another question: Can I identify patients very, very early in the disease progression in order to get them off that progression track? For the latter, the objectives are earlier diagnosis of cancer, earlier diagnosis of diabetes, earlier identification of, and differentiation of, the sort of cardiovascular disease a particular patient is beginning to develop.
What sort of collaborations are taking place in terms of linking personalized medicine and companion diagnostics with the goal of developing diagnostics for specific targeted therapies?
I won’t go into the specific compounds that we are considering, but there is definitely interest for cancer therapy to select patients who are going to respond to a particular drug because that drug will effectively stop the pathway that is active for this cancer. Both protein assays and gene expression assays are under consideration to find the right signal to pursue for the companion diagnostic. The challenge is to find that signal early and use it to support the clinical trial of the drug and simultaneously support the commercialization of the diagnostics. Certainly, there is some information starting to come out regarding how FDA would like the IVD industry to approach this but this is new territory for the agency as well.
In addition to companion diagnostics for drugs, we also see possibilities for diagnostics to help patients and their physicians identify and utilize the right medical devices and treatments. We’re particularly interested in this approach in the metabolic disease area.
Development Challenges
What are the primary challenges that IVD manufacturers encounter in designing and developing assay products?
Well, we were just talking about products that can provide new kinds of medical information to the clinician. In the end, we need to prove that the product can offer practitioners truly clinically relevant information. One big challenge is that this requires increasingly expensive clinical samples and more-complex clinical trial studies.
Obviously, we also need to be able to meet the laboratory’s expectations for analytical quality and reliability and to offer it on instrumentation that supports productivity.
More-sophisticated clinical samples and trial studies come into play in three big areas. One is in providing the data to a particular region’s regulatory body in order to gain approval for marketing the product. Regulatory requirements worldwide continue to change. Though harmonization efforts exist, frankly, there are still a lot of differences in requirements between regions. So, an IVD company has to think about where it is going to want to market a product and what each region’s regulatory agency will require for approval.
Second, the IVD company needs to be able to reach physicians in order to demonstrate the utility of the product to them, show them how they are going to use it, and explain how they will be able to manage their patients differently as a result of having this information. Third, and very importantly, the IVD manufacturer has to be able to demonstrate to payers that it is worth paying for this diagnostic product because the assay really provides a cost-effective means to improve both the health of a particular type of patient and reduce the overall delivery of healthcare.
It’s critical at the same time that the IVD company has formulated strategies to gain and retain market share, due to ongoing price pressure on diagnostic products, and since other diagnostic companies are seeking to offer similar products in the long run. Thus, it needs to figure out how it is going to preserve that market share.
Making the right decision in terms of what product to develop, and then designing sample-collection regimes and trials that can support as many regional regulatory requirements and physician and payer expectations as possible—these are the main challenges, and meeting them requires a lot of focused up-front planning about how to prove the product does what you say it does. This is the new challenge in addition to satisfying the analytical and lab productivity requirements.
IVD assay development involves a lot of challenge. On the other hand, it is so extremely rewarding to be able to provide products that, for minimal cost compared to lots of other things—and really minimal impact for the patient versus having to go through more invasive means—can deliver similar, or generally even better.
How do IVD manufacturers overcome such challenges?
Mostly, it’s about planning. It’s about thinking ahead for the long term, deciding how to approach which regions, and very, very carefully designing clinical studies. It requires substantial communication with regulatory bodies in terms of what they are looking for, with healthcare providers in terms of how they are going to use the product, and with payers with respect to whether this is something they’re going to be interested in seeing used.
And though we’ve talked primarily about new medical content—such as assays supporting cancer diagnosis or metabolic disease therapy—OCD faces the same kinds of challenges in providing diagnostic-type products for the blood donor screening community as well, like the Trypanosoma cruzi assay that went on the market a couple of years ago.
That has been extremely gratifying. We’ve seen that, just about every day, a unit of blood is removed from the supply that could have potentially infected someone had it been transfused. We conducted substantial clinical studies for this product, to convince not only FDA of what the product could do but also the blood donor centers that this is an important product that they are going to want to use.
But the effort is well worth it in the end, because we know that it is for the good of mankind. That’s what makes it easy for me to get up in the morning and go to work for this company.
Joint R&D
If one of your scientists discovers a biomarker or has an idea for a new test for a specific analyte, do people not involved in the science or R&D side of it but rather in areas such as regulatory, reimbursement, or marketing get involved in initial project planning before serious time, energy, and money are invested in the actual development of the test?
Obviously, we involve external help with this as well. We spend time talking with academic and clinical researchers to help us understand whether the product idea is something that will actually meet a need. We may need to work with folks who are trying to understand the mechanism of the particular disease in question in order to find commercial opportunities.
And we spend time discussing what sort of product a clinician would find useful in his or her practice—before we know even what it’s going to look like: How would that person use it? What difference would it make to them? How will it help their practice? The IVD manufacturer really has to make sure that there is a need for the assay before committing to its development and commercialization. As I mentioned, pretty substantial investments are necessary to move a new product into the marketplace, especially in the United States, since FDA isn’t really interested in organizations just putting out tests that can measure an analyte. FDA wants the IVD manufacturer to indicate how the physician is going to use it. This is where a lot of the expense of development lies. So, the assay developer need to know the end-user’s intended purpose so that it can provide them with the appropriate information for ensuring that they use the test correctly and in a meaningful way.
OCD spends much time in the external arena with various kinds of advisory boards—scientific, laboratory-based, or clinical-based group—to make sure that a product development opportunity is commercially viable. We use this input to determine what kind of investment profile we are going to need and what sort of regulatory challenges there will be. Also, from a marketing standpoint, these outside advisers help us see whether we would likely be successful in commercializing the product.
Specifically, then, how have IVD manufacturers been working with researchers in academia in developing assays?
OCD has gone to academia for the basic research that identifies possibilities for future products and applications. Academia is looking to understand disease mechanisms. We are in a truly fortunate new era in that our understanding is not just phenomenological but really goes to what is happening at the cellular level—what’s going on inside the cells, and which molecules are doing what.
So, we now have a much richer opportunity to find possible new analytes that may tell us important medical information. We use people like these also to provide clinical samples to help guide our analysis of whether we can actually measure a particular kind of analyte and, if we decide to bring the assay into full-blown development, to help us challenge our design to see if we can meet that clinical need.
We also work with a lot of clinical laboratories, many of which are led by academic researchers, to test the ability of our products to meet both clinical needs and the needs of the laboratory.
Do IVD companies have a relationship with academic institutions where there’s an active exchange of ideas and information between a company and a particular university or research center, or is it more free-flowing, with companies looking for new research that may offer possibilities and the academic institutions, once they’ve discovered something and announced it, waiting to talk to whomever in the industry responds first?
Both types of interactions occur. OCD has a Technology Assessment organization whose role is to follow trends in research at a variety of institutions. It looks for new possibilities emerging from basic research. We’re becoming more expert without having to do the research ourselves—and, frankly, we can’t afford to do it.
We can’t possibly afford to cover all the work that needs to be done to find pertinent analytes, so we look actively, support certain types of research collaboration, attend many conferences, and dig very deeply into specific areas of investigation.
Similarly, as it becomes known that we’re doing that, researchers with interesting ideas do bring them to us. We have a collaborative look-see at whether it’s worth moving an idea into the variety of phases that we put things through to assess the technology.
Instrument Considerations
What factors should IVD manufacturers consider when developing assays for use on their instrument systems?
The product has to meet the operational needs of the laboratory. So, in the end, the question is whether it is going to fit readily into the lab’s work flow or is going to require new sample preparation.
Certainly, the less it’s the case that the technology will require specific new sample-handling protocols, the easier it is for the laboratory to then be able to offer it among its services. That’s something we’re certainly interested in: having the ability to get our product out to as many institutions and physicians as possible.
So, there’s the sample-acquisition requirement. Then, we need to minimize the impact of the protocol for the analyte in the lab’s work flow—this is on our system. We talked already a little about sensitivity, the ability to detect lower and lower concentrations of analytes. One way of doing that is to have longer incubation times. But how does that affect the rest of the work flow for other samples and test protocols? We certainly don’t want to disrupt that, especially if the new assay is going to eventually be—we hope—an analysis that is run very frequently. We need to maintain that work flow.
And then there are the usual concerns about cross-contamination caused by the analyte itself or the reagents used with it. That’s especially so for OCD. We’re a company that seeks constantly to provide products of high quality and high reliability. We’ve developed some useful attributes for our system named Intellicheck. That system knows exactly what is supposed to be happening in the measurement process as it goes from sampling all the way to giving the user a result. It shows whether what was supposed to occur did occur.
We need to make sure that we can apply those kinds of checks to new analytes. Also, we look at whether new types of checks are available that should be added to maintain the highest levels of product quality and reliability.
You’re part of the assay development group, but OCD must also have a separate instrument group, correct?
Yes, our R&D organization has an instrument component. I would not like to use the word separate, however: we’re actually quite connected at the hip.
I have a peer who’s the group director of systems development, and there’s a lot of cross-communication between our organizations because, really, in the end, the instruments have to be able to run the assays we develop, and the assays are generally useless if they can’t work in our systems. That wonderful interplay is the source of a lot of stimulating discussions and accomplishment, as well as, ultimately, fulfillment when we get the products onto the market.
What is the working relationship between your assay development group and the instrument group like when a new assay is being developed and then launched? What are the challenges?
There’s specific work content with a new assay product, even if it’s pretty straightforward to automate, and, with our current automation system, there’s definitely work to do in terms of getting in new software and making sure all the Intellicheck functions work. That involves figuring out all the Intellicheck-specific values and all of the things the instrument is going to need to process the new analyte.
So, that’s always a critical element of the planning process, which is done at the very beginning of the project. We have instrumentation people embedded in the product delivery team because it takes the whole company to deliver a product onto the marketplace. We have teams comprising system R&D, assay R&D, regulatory, clinical, manufacturing, marketing, quality—every department is represented. It’s all planned up front, and then we manage that plan all the way through the process.
In fact, we need to plan together not only for a particular assay that we want to put on the market, but also, in general terms, for what we want to accomplish for our customers with respect to the kinds of automation systems we want to provide them in order to meet new and changing needs, and the kinds of assay products we are going to offer them. This makes for very stimulating and interesting strategic planning, including determining what kinds of capabilities the assay R&D organization and the system R&D organization need in order to accomplish our vision.
OCD recently received FDA approval for two new instrumentation systems. The assay R&D organization was very deeply involved in bringing those to market, as the assays really need to provide the same analytical performance on the new systems as they do on the systems we currently have; all the systems actually use exactly the same product. So, we are very deeply involved in the design and development of the new system as well as with brand new assays.
I tell my folks all the time that, as well as doing the standard assay development that is the job of an assay R&D organization, we are also bringing our deep understanding of measurement technologies and of OCD products themselves to the table in order to ensure the success of the whoe corporation.
Molecular Diagnostics
How have developments in molecular diagnostics affected assay development?
Well, since we have a whole new set of analytical methods for interrogating samples for the presence or absence of a single analyte or profiled analyte, that requires making those new measurement and sample prep technologies automatable. Also, there’s often not just the single analyte that you’re looking for—or looking for the absence of—but rather a profile of analytes bringing in a bioinformatics aspect.
And then there are the challenges associated with knowing how many samples are needed to design the product and how many have to be used to validate it. So, samples is an ongoing theme here, as well as the need for new capabilities in the bioinformatic technology area.
How has multiplexing influenced assay development efforts at IVD companies?
It certainly challenged us to look at the measurement technologies we have and determine which of them support multiplexing and which don’t. OCD had to consider the extent of the need we’ll have for that, how many products are going to be multiplexed and how many aren’t.
Of course, in the area of molecular diagnostics, there’s significant multiplexing, and some platforms have been built up around it. We’re asking those questions as well in the protein area. That’s one of the research areas for which we’re looking outside. We’re testing a number of technologies to see which can provide us, from the protein measurements standpoint, that necessary low level of detection—that is, high sensitivity while doing multiplexing in a short period of time with not much sample.
These are very interesting challenges, but ones that we anticipate we’re going to meet. Counterbalancing that is the question of how much that will then influence the kind of clinical studies that are necessary, which may in the end limit that development option. Also, we have to know how much more information can be provided with a panel of protein markers versus a single protein marker. It really has to be able to provide the user a lot more information to be worth the investment.
So, it definitely is influencing our appraisal of the capability of our technologies and, therefore, some of the acquisitions we’re pursuing and investments we’re making.
User Requirements
How do you find out from laboratories, physicians, and other end-users what they need most from their assays? Do you use surveys, focus groups, in-services, other methods?
We use all of those kinds of mechanisms, as well as formal advisory panels. We also send people into clinical laboratories to watch and see what they do. To observe the flow of information, the flow of samples.
We’re looking for ways we can help product users do things better, more cheaply, and more easily, which then influences our design input, because now it’s not only going to be the analytical but also the lab operational requirements that we need to satisfy. We need to learn how we can really help users in their lab productivity efforts.
If we come up with tests that are going to be difficult to perform, not many laboratories will have the trained personnel to do that. That doesn’t mean we won’t go down that avenue if it’s the path that really provides the needed medical information to somebody, but that certainly is not the preferred approach.
We also gain knowledge from direct customer interactions. OCD certainly has customers that are very willing to tell us lots of things about our products, both good and bad. We send our development projects into people’s labs to have them beat it up, see what it does or doesn’t do for them clinically, analytically, and operationally. And then, obviously, there’s always that partner involvement in final customer-focused validation of the products.
Future Challenges
What challenges in assay development do you expect to emerge during the next year or over the longer term?
I think it’s all going to revolve around making good, careful choices about where to make our investments, because providing truly new analytical information doesn’t come cheaply. So the question is, in what areas are we going to be able to get the biggest bang for the investment buck?
OCD is zeroing in on four clinical areas that we decided represent a very big global need and where we can make a difference: cardiovascular, metabolic disease, reproductive health, and oncology. We have a nice history of providing products that are very useful for lab productivity in the infectious-disease area. We expect to remain active there, and we expect other companies to remain very active, too, both in protein-based and molecular technologies for gathering diagnostic information in all of these clinical areas.
A big trend that I think we’re going to continue seeing is the use of algorithms to bring together information from a number of molecular entities to provide medical information that wouldn’t be obtainable otherwise.
Why has Ortho-Clinical chosen to focus on the four specific areas you named?
We looked at the kinds of diseases humankind is facing, and specifically at where there are unmet diagnostic needs to find patients early in the disease progression. If we can find a cancer in a patient that is still at a very early stage, we might prevent that patient having to go through some of the really devastating treatments and thus improve his or her survival chances.
Also, if we can identify people early in their progression towards diabetes, or already diabetic people early in their progression towards cardiovascular or chronic kidney disease—if we can find such patients early, we can perhaps keep them off those roads to severe disease.
We did an analysis a number of years ago of what kinds of disease areas represent real needs, and the outcomes of that are providing us with some potential opportunities to pursue. Those areas are in addition to the infectious-disease commitments that we have had over the years, and they also tie in nicely with areas that our brother and sister J&J companies are interested in as well.
What trends do you see in the future for assay development?
With respect to specific kinds of assays, many diagnostic companies are pursuing products in the reproductive health area, particularly regarding preeclampsia, and we’re very active in that area. I think companies are going to be looking at what kinds of molecules are going to help us give medical information to diagnosticians and investigating the best ways to get at them. It might be a protein measurement. Perhaps it will be a molecular diagnostic measurement. A number of analytes may have to be combined in order to finally extract useful information.
So, bioinformatics is going to be very key in helping us select possibilities and then, ultimately, in providing a product to the customer. I think we’re going to see a lot fewer single-analyte results provided to physicians and a lot more combinations. We already have some of that going on, with patients worried about not only their cholesterol but also their HDL and LDL and the ratios between them, and so on. And that’s really just a beginning.
In the molecular diagnostic area, certainly there will be more work on the gene profile—determining whether particular sets of genes have been turned on, or whether they are up-regulated or down-regulated in order to help pinpoint the kind of cancer pathway a patient might be experiencing. Much more complicated kinds of information will become accessible. But I think we have the techniques now to find it and be able to offer answers.
