Guest Column | November 10, 2014

Companion Diagnostics: Why Medical Device Manufacturers Should Care

By Michael Drues, Ph.D., President, Vascular Sciences

Michael Drues - Guerrilla Regulatory Strategy

Why should we have to wait until a patient swallows a pill to find out if it works on them?

This is something that’s always bothered me about the way we practice medicine. If you think about it, it really makes no sense. I would like to be able to know, to a very high degree of certainty, whether or not that pill will work in that patient before they put it in their body. If it's not going to work, I'm not going to give it to them — I'm going to give them something else.

Herein lies the promise of companion diagnostics.

A companion diagnostic is a type of in vitro diagnostic (IVD) that allows us to try to predict whether or not a patient will respond to a particular drug before they take it. Usually, companion diagnostics are designed from either a molecular biology perspective (testing for a particular sequence of A’s, T’s, G’s, and C’s in the patient’s individual genome) or from a biochemical perspective (looking for the presence of certain enzymes that are be produced by the liver, for example, and might metabolize these drugs inappropriately).

We actually have a growing number of companion diagnostics on the market today. Perhaps the best known example is for a drug called Plavix, a commonly used anti-coagulant. In other words, it prevents blood from clotting or thrombosing. Like many drugs, Plavix works very well in certain patients, but not so well in other patients — and in some patients, it's flat-out dangerous. We now have tools that will allow us to predict, before the patient takes the Plavix, how they are likely to respond to it.

What’s In It For Medical Device Makers?
Although they are used in conjunction with drugs, companion diagnostics are medical devices. IVDs are regulated by the FDA’s Center for Devices and Radiological Health (CDRH) as medical devices, and companion diagnostics can be regulated by CDRH as either a medical device or, in some cases, as a combination product.

No matter how you slice it, this is an area that should be very important to the medical device industry. A recent report published by Transparency Market Research projected the global market for companion diagnostics to reach $5.6 billion by 2019, and I’ve seen other projections as high as $26 billion. About 18 percent of new drugs coming onto the market have an associated companion diagnostic. And from an economic perspective, we can now sequence individual patients' genomes for $1,000 apiece, so the cost of supporting technology is dropping quickly.

Europe represents a particularly good opportunity for companion diagnostics today. Medical device manufacturers are rushing to get companion diagnostics approved as quickly as possible, to take advantage of a bit of a regulatory loophole in the medical device directives. In the EU classification system, noninvasive devices — of course, a companion diagnostic is totally non-invasive — are considered low-risk and, as a result, Class I devices.

When you think about it, just because something is noninvasive doesn’t necessarily mean it’s low-risk. Take, for example, an in vitro diagnostic to diagnose cancer. Even though the IVD never comes into direct contact with the patient, if it’s inaccurate, then it can cause great harm to the patient — if we tell the patient they do not have cancer, when in fact, they do.

In any case, for all these reasons as well as others, medical device manufacturers should wake up to the tremendous opportunity to bring new companion diagnostics onto the market.

Partnering With Pharma Companies
Medical device companies don't have to sell pharma companies on the idea of companion diagnostics — pharma companies realize the importance of this technology already. For instance, drug makers have found that they can make clinical trials much smaller, more effective, and less costly by restricting them to patients who are most likely to benefit from the particular drug under investigation. In addition, regulators and insurers are encouraging pharma companies to develop tests to pinpoint which patients are most likely to benefit from these drugs, to spare them from the needless side effects and the expense of using a drug that doesn't work in them.

The main challenge for medical device makers when approaching drug companies about companion diagnostics is convincing them to partner with them rather than the multitude of other companies that are trying to do the same thing. One piece of advice I can give you is to learn as much as you can about the pharma and biotech side of the world, so you can demonstrate to potential partners that you speak their language. In the past, medical devices have been separated from drugs and biologics, and companion diagnostics are one way where we're breaking down those barriers.

Regulation Of Companion Diagnostics
As I mentioned previously, IVDs are considered medical devices in U.S. regulations, though this is mostly a historical artifact. (When FDA started regulating medical devices back in the 1970s, it just didn’t have a more suitable bucket to put IVDs in.) One could easily argue that IVDs are not medical devices, and they should not be regulated as such, but nonetheless, they are.

An additional problem is that even though IVDs are regulated under CDRH rules, those rules are often being read, interpreted, and enforced by the Center for Biologics Evaluation and Research (CBER), not CDRH. Suffice it to say, CBER reviewers are not engineers — they are molecular biologists and cell biologists — and a molecular biologist might read exactly the same set of rules as an engineer and come to a drastically different interpretation.

I can't tell you how many times I’ve gotten panicked calls from companies that have a lot of experience developing medical devices but are now trying to develop IVDs and companion diagnostics. They say, “Hey, we thought we understood these medical device rules. We've been following them for a long time. Now, all of a sudden, we're not talking to engineers at FDA anymore. We're talking to molecular biologists, and they're asking us to do all kinds of things that we've never had to do before.” And when it comes to making a substantial equivalence argument [a key component of the 510(k)] for a molecular diagnostic using sequences of A’s, T’s, G’s, and C’s, welcome to the Wild West of medical device regulation!

Bottom line, there is a tremendous discontinuity here, in terms of how IVDs are regulated, specifically with regard to companion diagnostics. In some parts of the world, they are regulated as cross-labeled combination products. These involve two products produced by two companies in two separate packages — for example, a drug by one company in one package and a companion diagnostic by another company in another package — but the labels point to one another. One says, “Use this drug with that companion diagnostic,” and the other says, “Use this companion diagnostic with that drug.” It's not a simple regulatory situation.

Scope Creep At FDA
Just a few weeks ago, FDA issued two new draft guidance documents in the area of laboratory-developed tests (LDTs): Framework for Regulatory Oversight of Laboratory Developed Tests [PDF] and FDA Notification and Medical Device Reporting for Laboratory Developed Tests [PDF].

An LDT is a test developed by a lab for its own use. LDTs can be used to test for electrolytes — something as simple as sodium — or for something a little more complicated biochemically, like a protein. However, they can also be used as molecular diagnostics, to test for the presence of nucleic acids. Sometimes, labs will develop their own LDTs even if there is a commercially available IVD on the market that does the same thing, for a variety of reasons.

Historically, FDA has not regulated LDTs. You could easily argue that LDTs are the practice of medicine — like pharmaceutical compounding, pharmacogenomics (a.k.a. personalized medicine of drugs), 3D printing of medical devices, and so on — and the FDA does not regulate the practice of medicine. In other words, FDA cannot tell physicians or pharmacists or other practitioners what to do; they can only tell industry what to do.

So this is a very new area for FDA to inject itself into. Some people refer to it as regulatory expansion, but I like to call it the CDRH Big Bang. The FDA started regulating medical devices, then IVDs, then companion diagnostics, and now LDTs. What's next?

I'm not necessarily saying that it's a bad thing for FDA to regulate LDTs. (There are advantages and disadvantages to everything.) However, it is a major expansion into an area of medicine that FDA has never previously been involved with. Therefore, I do think it's appropriate for us to have a debate — not just within the medical or medical device community, but in the general community at large — as to whether or not we want the FDA to take on this job or not. It's a very fluid environment, and we all have a stake in the result — both professionally and personally!

Editor's Note: Dr. Drues will be teaching a 90-minute online course titled Companion Diagnostics – Opportunities, Challenges, & Rewards on November 11, 2014 at 1:00 pm EST. In it, he will demonstrate important regulatory requirements and concepts using case study discussions of real products from a variety of clinical specialties.