Medical Device Link.

Originally Published IVD Technology November/December 2001

In Person

Integrating technology

Visible Genetics uses its technological expertise to develop an innovative molecular diagnostics device

The Trugene HIV-1 genotyping kit and OpenGene sequencing system is intended for use in detecting HIV genomic mutations that confer resistance to specific types of antiretroviral drugs, as an aid in monitoring and treating HIV.

IVD Technology: How did VGI get started, and what have the company’s product development efforts been up to this point?

Richard T. Daly: The company was started in 1994 by a very small group of scientists who had some experience in the design and manufacture of liquid-crystal flat-panel displays. They used this flat-panel technology to figure out how to do sequencing a little bit differently: by making an ultrathin gel so they could use a higher electric current, propagate the DNA through the gel more rapidly, and therefore build a smaller, faster sequencer. Having made that technological advance, these scientists tried to figure out where they could apply it. They realized that a very small, fast sequencer would be ideal in the clinical diagnostic area, so they began working on some applications in clinical diagnostics.

At that point, I became involved with VGI. I’d been the CEO of a company called Clinical Partners, which was a managed-care organization that was an early pioneer in HIV disease management. Our relationship with VGI grew out of our belief that physicians needed tools to better select drugs and drug therapy. So we’d been working together, and I was on VGI’s board of directors.

I took over as CEO in July 1999 and have focused the company on getting its first product through FDA and building out the manufacturing, marketing, and financial infrastructure to do a global business launch.

Did the company’s focus on HIV come largely from your experience in that field?

No, that predated me. The company had already been focused on HIV as one of numerous avenues it was pursuing. As in any entrepreneurial-type company with many initiatives, though, the business reality is that we can only pursue a small number. HIV seemed one of the most promising, so we really focused our resources on that.

When you say “most promising,” is that largely because there were therapeutics available where the diagnostic information would make a difference?

That’s right. That’s one of the key elements in our technology. We’re a companion technology to therapeutic intervention. So we become of value only if the physician has a number of legitimate therapeutic options to pursue and he or she is trying to determine which therapeutic option to use for a specific patient.

And you have some interest then in hepatitis C, hepatitis B, and cancer for the same reason—because there are therapeutics available?

That’s right. The virology of HCV, HBV, and HIV all present similar problems. In those groups, there are viruses that are mutating in response to treatment or certain subtypes that are either responsive or nonresponsive to existing treatments, and physicians need to know exactly what they’re treating in any individual patient.

In all three of those key virology targets, there are different levels of therapeutic interventions available right now. In HIV, there are 20 major drugs. In HBV there is a smaller number, and in HCV there is really one major category of intervention. But all of those require some direction, and in the case of HCV, it seems very clear that within two or three years, there will be many antiretroviral drugs that will force resistance patterns in the virus very similar to what happened in HIV.

Oncology of course is the same issue. Physicians are trying to predict the tumor response and the survival of the patient, so that’s a similar clinical problem.

The Technological Edge


This is very much the cutting edge of pharmacogenomics. How much of a lead in time or technology do you think VGI has in that field?

We have a big lead on the technology end. What we’ve done is to combine several novel technologies and make them work together. These include the basic sequencing technology, which is difficult in itself to master. The chemistry around any individual target is unique. Each virus or tumor presents a unique set of chemistry problems related to the elements that go into an amplification and sequencing reaction.

Then there is the interpretive software that takes from the sequencer a complex string of data, which is the decoded gene structure, and runs that information through a series of programs. Those programs predict how the functionality of the virus or tumor is going to change based on certain mutations and turns that result into a very simple and easy-to-use report for the physician.

It is complicated to get all of that into one box and make it sing together. That’s not something that’s easy to duplicate, and we don’t see anybody on the horizon that has been able to get all of those elements working together. There are companies that have one or more of those components put together, but in our particular area, we think we’ve got a substantial lead.

More importantly strategically is the concept of having a sequencing platform that can run a number of tests. The HIV product is really the first product in the wedge that will allow us to disseminate sequencing technology quite broadly in the key clinical diagnostic markets worldwide.

Is molecular diagnostics as a field more likely to be driven by the traditional targets like infectious or sexually transmitted diseases, or is the field going to start to look more toward genetic mutations as a basis for disease?

What will really direct and pace the growth of the field is what therapeutic interventions are available.

The reason that virology and oncology are key targets for us is that there are many therapeutic interventions where it’s quite clear that the ability to tailor them to the individual can make a dramatic improvement in their effectiveness.

So phase 1 would be companion technology where there exists therapeutic intervention. Phase 2, which will be perhaps three years out and continue strongly beyond that, is understanding genetic variations in the individual and the accompanying therapeutic interventions.

VGI has a genotyping database that your customers can use. How does that work?

One of the most fascinating by-products of what we’ve been doing, as customers run samples on a worldwide basis, is building up an extensive and detailed library of sequence data. In the case of HIV, it’s mutations and subtypes, so that where the virus seems to be heading can be tracked on a worldwide basis. For instance, Portugal predominantly has a subtype G, while North America predominately has a subtype B. And, fascinatingly enough, the migration of mutations and subtypes can be seen to match the patterns of international travel and commerce. That gives us a leg up on understanding where the assay and the software need to go in order to follow the virus.

Working with FDA


You mentioned the regulatory issues related to product development. How long did it take for clearance of the Trugene system, and what problems or issues did FDA raise for you?

The process from the submission of the file to clearance took about 12 months, and I would say that’s a pretty strong performance on the part of FDA. We feel FDA moved quite rapidly on this. The reviewers had to digest a submission that was many thousands of pages, and it covered the basic chemistry of sequencing, the sequencer itself, and the issue of software interpretation, all of which was new ground for them. And the agency actually took a fairly innovative step halfway through the process, having us install sequencers at FDA so that their technicians could work with the technology and become familiar with it.

So I think FDA was very helpful to us and moved through quite briskly. The process could have taken not one year but at least three years if we had followed the original path we were on, through Class III premarket approval (PMA). But early in the process, FDA had a panel meeting in which the panel recommended downclassifying the product and then invited us to use the de novo process, which has only been used about a dozen times in this area and only about half of those have made it through. So this was a fairly rapid and unusual product clearance. But no real issues popped up in the middle of the review, except just the complexity of the technology and the need to work through its details.

How were you able to cooperate with FDA in advancing its learning curve on a technology like this?

The key is frequency of contact and having a very open dialogue. It’s understanding the problems and issues that FDA is facing. The agency’s issues in looking at the submission were not unlike our own in putting it together. Different departments of VGI each worked on parts of the submission—software, instrumentation, manufacturing, chemistry, and so on—and FDA mirrored that. The agency had about seven reviewers working on different parts, so it was critical for us to make sure that we understood the issues that were coming up for those subreviewers, to know how they were being coordinated, and to address questions early so that we could have a working dialogue. It was very much an interactive process.

A part of that was that FDA recognized it was plowing some new ground, and it legitimately wanted to make sure that the reviewers were up to speed technically. We held several training sessions for reviewers and technicians at FDA, and we supplied contacts and other information. FDA also relied on its own outside sources and clinicians to understand certain points. So it was a very complex and detailed process.

The review was conducted by the Center for Biologics Evaluation and Research (CBER). Do you think that’s the right place for IVDs to be reviewed?

In this case, that’s where the HIV knowledge resided. But CBER itself pulled together a diverse team from the Center for Devices and Radiological Health (CDRH) and also the Center for Drug Evaluation and Research (CDER). The review team reached out to the other divisions, so it was really a review that cut across many areas in FDA. The agency was pretty thorough about pulling in the expertise where they needed it. It relied on CDER, for example, to evaluate certain elements in the software that looked a lot like a drug review. And there were certain elements about the regulatory process that CDRH provided.

The review process for the Trugene system was relatively complicated. Is it a model that you think FDA is going to replicate for other assays submitted in the future, or will the agency try to find a way to simplify it?

I would think that if there were another technology that was as new as this one, FDA would replicate it. In this particular technology area, FDA has now established some tough guidelines that mirror those that were in our submission. So we’ve now become the predicate device in this area.

Were there any areas in which you felt that differences in the review process or in the approach of the reviewers made things more difficult than they might have been?

I wouldn’t say any more difficult than they might have been. One of the early discussions we had is how FDA was going to regulate the software, and that broke some new ground because it was either the first time or one of the first times FDA had taken a look at software that produces, from a certain point of view, treatment guidelines and recommendations. There was a lot of discussion back and forth on how to do that.

At the end of the day, we created a very constructive process for how FDA would look at and update our current algorithms, so that the agency would not become a gating factor to getting out updated clinical information to clinicians. I thought that was a legitimately tough issue that we wrestled with, and I think we came up with a good answer.

Looking Toward the Future


How quickly do you think that your investors will support your moving into other areas, such as HBV and HCV?

We’ve got enough cash on board to move into HBV and HCV and get our first oncology product out. But clearly what people are looking for is the strength of the pipeline, and those products, plus the recent acquisition of a key science team that was formerly with a company called Virco (Cambridge, UK), are providing a lot of confidence in the product pipeline.

What is the expansion beyond HCV, HBV, and oncology? What’s on the horizon?

That’s plenty for now, and that should take us out a few years. But beyond that, we’re obviously looking for additional clinical targets potentially in the area of single nucleotide polymorphism (SNP) detection and additional sequencing/ SNP detection platforms, so that’s a longer-range technical vision of the company.

Richard T. Daly is president and chief executive officer of Visible Genetics Inc. (Toronto). He can be reached via rtdaly@visgen.com.

Copyright ©2001 IVD Technology