Originally Published IVD Technology March 2005
In Person
Anticipating assay
development trends
IVD companies must learn to balance the needs
of traditional assay users with the potential offered
by new technologies.
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| Dan Lawson, PhD, is global director of hemostasis research and development at bioMérieux Inc. (Marcy l’Etoile, France). He can be reached at daniel.lawson@ na.biomerieux.com. |
Although the integration of molecular diagnostics into routine therapeutic solutions is still, by conservative estimates, a number of years away, the promise of theranostic breakthroughs is nonetheless changing the face of assay development today. As IVD companies look to the future they must also keep one eye focused firmly on the present. While industry continues to move forward into the molecular diagnostics age, it must also weigh the challenges of helping customers make the transition.
To learn more about how IVD companies are coping with the changes in assay development, IVD Technology editor Richard Park spoke with Dan Lawson, PhD, global director of hemostasis research and development at bioMérieux Inc. (Marcy l’Etoile, France). In this interview, Lawson also discusses possible sources for the mounting competition among assay companies, as well as the useful role academia can play in collaborative research.
IVD Technology: What have been the biggest technological advances in assay development during the past few years?
Dan Lawson: In my opinion, the biggest advancement really was the Human Genome Project, in the sense that it’s opened a lot of doors for assay development. Areas like genomics and proteomics and more recently, metabolomics, are the newest trends. Discoveries made in these techniques in turn lead to discoveries in disciplines like molecular biology genetics and immunology, the discovery of new proteins, new genes, and also point mutations involved in disease.
Does that mean that efforts in assay development are moving more toward the molecular side of things?
Yes, I think so. Certainly, molecular diagnostics has produced tests and assays more accurate and more reliable, and it also has made them more specific. Assays based on molecular diagnostics are usually able to diagnose a disease, directly allowing the physician to either administer or monitor therapy in a more timely fashion.
Has the Human Genome Project, then, led assay development into the area of theranostics and personalized medicine?
I think the Human Genome Project opened all of those doors. In my field, hemostasis, we are making some interesting discoveries related to gene therapy.
Before any of this gene-mapping occurred, we were basically looking at getting a result. But the focus now is more on getting a result that leads to a solution. This has been triggered by the fact that we have more knowledge about the human body based on the contribution of the Human Genome Project.
Trends in Assay Development
What is the metabolomics you mentioned?
Metabolomics is pretty similar to genomics in that you look for biomarkers, or in this case metabolites, and determine their role in terms of function-relative gene or organ function, or a particular disease state.
What other trends are emerging in the area of assay development?
Now we have the gene chip technology and the use of microarrays, which I think will also lead to new discoveries and new cures for disease. Everything is focused basically around molecular biology, immunology, and a part of that is the gene chip or DNA chip technology. There are a number of modifications of these technologies that provide continued improvements in terms of either accuracy or sensitivity.
What do you mean by modifications of technology here?
Well, in clinical chemistry, for example, we started with colorimetric spectrophotometric assays and then went to fluorometric, which offered a higher sensitivity with the same type of assay system. Now assays are gravitating toward the next level of sensitivity based on chemiluminescence. In this business, you’re always looking for the next technology or the next improvement over current methods.
Development Challenges
What are the primary challenges that IVD manufacturers encounter in designing and developing assay products?
The biggest challenge, I think, is finding the right product or the right assay for your particular market. It should be some kind of improvement over the existing technology. The IVD field is very competitive; therefore, it would be a big advantage for any new assay system to differentiate itself from everything else that’s out there.
Also, in many cases with the new assays, it is advantageous to have a technology that is patent protected. This is almost essential, to prevent competitors from breathing down your neck to duplicate your technology. It’s also desirable in the sense that you need some exclusivity in this business in order to recoup your investment. In diagnostics, the half-life of assays and other products is not the same as in pharmaceuticals, and manufacturers can be very sure that competitors are not far behind with their better mousetrap.
How do manufacturers overcome those challenges of finding the right assays, finding the next-generation technology, and differentiating themselves and their products?
From my perspective, that means having good internal and external resources—knowledgeable people inside the organization and also on the outside—in order to establish a very strong technology pipeline. The people inside the organization have to be aware of what’s going on in terms of technology development within the various relevant disciplines. That is, they need to form alliances or collaborative arrangements with individuals outside of the organization—with hospitals, research institutes, or academia—in order to stay abreast of advancements in the field.
Our organization, bioMérieux, has scientific advisers for each of its scientific businesses. We also have a corporate scientific advisory board that we rely on to make sure the company is headed in the right direction, with respect to technology trends.
Collaborative Research
Could you expand on this working relationship with academic researchers and other institutions outside your organization? IVDT has interviewed a number of academics for this column concerning their role in assay development and the relationships between academic researchers and private industry, so it will be good to have the IVD manufacturer’s viewpoint.
There are a number of ways to work with institutions outside the organization. It depends on what the company determines is the best way to achieve its objective.
In the case where the discovery is made at some other institution, bioMérieux will form an alliance and collaborate with that institution under some sort of legal agreement. What normally happens is that, first, the outside institution will develop the assay so as to optimize its performance within that particular laboratory. Then, at some point according to the agreement, the assay or its technology will be transferred to us. We will then further develop the technology for commercialization.
Assay development for commercial purposes must follow a number of procedures and guidelines largely dictated by FDA, but there are also internal policies that must be adhered to. When a technology is brought in-house, it is usually not ready for commercialization yet. It may need to be adapted to an instrument system, and sometimes special packaging may be required to give the assay a significant shelf life in the marketplace. The techniques for achieving these things are not generally known or performed outside the company.
Alternatively, an idea for developing a new assay may arise within the organization, but we may not want to devote resources to developing it internally. In that case, we will farm it out to academics or a research institute or a hospital and let them do the preliminary research. When it’s ready, we bring it back inside to develop it for commercialization.
So it goes both ways: the idea could originate with the academic researchers or within the company, with further development of the discovery being undertaken by the opposite party.
Yes. There are probably some other scenarios, but those two are the most common.
How do you find out about relevant academic research efforts? Do you maintain active relationships with certain institutions?
We do. We also encourage our scientists to be active in the various technical societies and to read the journals and other publications where these basic researchers publish their work. A lot of times, in reading journal articles, we’ll see something that might be of interest or have some potential and we’ll try to make contact with the inventor.
On other occasions, the inventor will contact us. Just a month ago, I was at a hematology meeting in San Diego listening to a presentation by a professor who had an idea that looked feasible for bioMérieux. We held some discussions and now are in the process of setting up negotiations for determining how to further advance the relationship.
Has this kind of exchange of ideas between bioMérieux and academic researchers produced fruitful results—that is, commercially viable assays? Is it something you plan to continue doing?
Yes to both. Success is probably a little less common than failure. The percentages might even be 40/60, but I think the success rate with internal development would be similar. It may be a little higher than that.
Any research effort is a risk. You don’t expect every project to result in commercialization, and even if it does lead to commercialization, the return may not be what was imagined because the demand for he test may have been overestimated or there may be a better technology out there.
Another risk issue with assay development is critical. This is the time that it takes from conceptualization of an idea to market launch—what is called “time to market.” That period is critical in diagnostics, because the half-life of diagnostic products is usually very short, and there’s always someone out there looking to improve on the technology even more.
But is all this risk nevertheless worthwhile?
Oh, absolutely. In any organization, some of the ideas put forth are going to be rejected because the company may consider them too risky, too large an investment. People on the outside, in academia, are less risk averse, because their primary focus is research per se, and publication. So we can get that technology from outside. In a lot of cases, it’s less costly than trying to develop it inside.
The pharmaceutical companies have been doing this for years. Recently, a lot of pharmaceutical companies that used to develop their product pipelines internally have now turned to acquisition as a means to sustain their product portfolios.
Designing for the Instrument
What factors must IVD manufacturers consider when developing assays for use on their own instrument systems?
Well, that can be looked at from two perspectives. From the customer standpoint, the main thing is ease of use. The assay has to be very easy for the customer to use, particularly a clinical lab or hospital. A company developing an assay typically wants something that’s going to consist of a minimum of maybe two or three reagents. If it’s something that requires five or six reagents, then it’s not ideal for a hospital or clinical setting.
Also, from the company’s perspective, the assay must be compatible with the instrumentation, in the sense that ideally the company wants to make minimal changes to the instrument relative to hardware and software. No changes at all would be preferable, and sometimes that’s the case, but if changes have to be made, better that they be minimal.
Throughput would be another important consideration for the customer—how many tests per hour will this assay allow? How many patient samples can be run in the clinical setting?—and then time to results—how quickly the laboratory will get a result it can report to the physician. So, the IVD company has to consider these requirements during the development process, to make sure that the assay is marketable on its system.
Another factor is stability on the system, because in the clinical setting you run 24/7. You want an assay that can sit on the instrument and not lose performance quality over a certain period of time. It should be functional over at least one shift, or eight hours, at least, but preferably more.
Of course, the system has to be compliant. And the company has to make sure to practice good design control. Because it’s a system the company is selling, the assay and instrument have to be very compatible when they are launched in the marketplace.
In another scenario, an organization that sells instruments and reagents might want to develop a closed system—that is, one in which the assays perform only on that company’s instruments. That way, a customer would have to buy the manufacturer’s system in order to run the assay. However, if you’re just a reagent or assay development company, you might want to make the assay more open so that it runs on everybody’s system in order to maximize sales. Those are the key factors.
Regarding your earlier point about minimizing changes to the instrument, did you mean that was an objective having to do with ease of use?
Yes. If you’re developing an assay for an already existing system, you already have software on that system to run other assays, as well as a certain number of spaces for assay reagents. If the assay contains too many components, then you might have to consider adding another well onto the system to hold all the components. Or, if the assay runs much differently with respect to kinetics or to sensitivity, then you would have to go back and tweak the software to accommodate that particular assay.
So, assay developers have to take into consideration the number and type of instrument changes a new product will require, because, again, this also relates to time to market. Also, they have to take into account the cost-benefit ratio if the necessary changes are extensive. Keeping changes to a minimum is ideal, but if the new assay is unique, a totally new technology, and is expected to bring a significant return on investment, then—and I’ve been involved in decisions of this type before—the organization may elect to make the changes to the instrument and introduce it as the next generation of the system.
Molecular Diagnostics
Molecular diagnostics has for several years now been thought of as the next big thing in diagnostics. It was going to revolutionize the IVD industry. But it hasn’t yet. Have you seen growth in the molecular diagnostics area in terms of assay development? When might it play a more significant role in the assay area?
What’s hindering assay development in molecular biology is, in my opinion, not the technology itself. I think that it is the leading-edge technology in a lot of disciplines because it is fast, it is quick, and it is accurate. The problem—or one of them—is the regulatory aspect. There is no real classification for some of the molecular biology tests that have been developed. As a result, some companies are reluctant to do a filing. Some of the assays are so original that there is no predicate device to compare them against. Because in a lot of cases it would be a traumatic ordeal for companies to try to get their assays through FDA, a lot of them are being marketed as “research use only.”
The other hindrance in the molecular diagnostics field right now is that, for a lot of the assays, there is no reimbursement. Hospitals and clinical labs like to be paid for their testing. If there is no reimbursement, then they are not going to run the tests on a routine basis, no matter how good they are. In addition, those tests that are being reimbursed have been pegged at the same rate as the tests they are replacing. Since the cost to develop a molecular diagnostic assay is considerably higher than that for some of the tests they are replacing, there can be very little profit.
I think that all of these things have to get resolved before molecular diagnostics can really take hold in the IVD market.
Is there a viable commercial market for molecular assays?
Yes, I think there is. We’re certainly involved in that area, and I think that’s where we’re targeted for the future. In time, all of this is going to work itself out. The important thing here is that, in terms of future trends in this area, there will be a change in what we want diagnostic assays to do. We’re looking for assays that are going to be able to predict outcomes, not just give a result, and assays where the result will provide the physician with a therapeutic solution. To get to that point we have to go through molecular diagnostics.
Biodefense
How has the emergence of biodefense and bioterrorism concerns affected assay development?
I think it’s good for assay development in the sense that bioMérieux is poised in that direction in one of its areas of microbiology. The threat has also increased the amount of competition in the field because more companies got involved and more researchers shifted their focus to it. I think that’s good, because competition is very good for any technology. You get improvements in the technology that way. What has come out of the terrorism situation is much more rapid, much more precise assays to detect bioweaponry. Obviously, in considering national security or the safety of the population, the faster we can diagnose this type of thing, the better off we are.
So, even as the attention paid to bioterrorism wanes with the passage of time, you think the market is going to still be there, that this is something in which IVD manufacturers involved in assay development will continue to invest time, money, and effort?
Yes. It’s maybe just a small piece of our own plans, but there are companies that have sprung up because of this new concern that are dedicated solely to this and continue working on it. Although the reaction from a couple of years ago has died down, the focus is still there. It’s not as widespread, but it is all some niche companies are working on. So, yes, this will continue to go forward.
Discovering User Needs
How do you find out what laboratories and laboratorians need the most from their assays? Surveys? Focus groups? In services?
A little bit of all that, plus internal and external marketing. Sometimes we go straight to the customer, or, they may come to us. I have met with a number of customers and potential customers at technical meetings, and they all have ideas on how we can do things better. So, the sources come from everywhere. In my field, hemostasis, the best input usually comes from the lab technician who is actually running the test or the instrument.
Do your R&D people in hemostasis have direct contact with these lab technician end-users?
Yes, on occasion. Mostly it’s members of our marketing and sales force that make the contacts, but sometimes they will request that someone from R&D go with them on a site visit. I think it’s a good experience for R&D staff. We can be so inwardly focused, so focused on the end product, that we sometimes forget that we’re doing this development work to satisfy a customer need. We require that customer input in order to end up with the right product.
The Future
What challenges do you foresee emerging in assay development over the next few years?
That’s a tough one. I think we’re still going to see advances in molecular diagnostics. I still think that microarrays, gene chips, and these types of things are going to become more and more important, because of where I see diagnostics headed. That is, we will start to develop assays that create solutions for physicians, that make it possible to predict outcomes, or predict the onset of a disease. The technologies we have now have to get better for us to get to that point.
I’m sure some new technology that I haven’t envisioned here will spring up, but I think these I have mentioned will probably be the basis for that.
How does a company like bioMérieux, which offers traditional assay products but also is pursuing the next technology, balance out the needs of those two areas? How do you retain a focus on the traditional assays while looking toward the future in the molecular diagnostics area?
We know we have to maintain the traditional assays because right now that’s our bread and butter. But also, we have to look to the future. So, what we normally do is to devote a certain number of dollars and a certain amount of resources within the R&D group to what we call product support. That product support effort assists in maintaining the current product line.
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