Consumer Genome Tests

With the U.S. Senate passing the Genetic Information Nondiscrimination Act (GINA) last week the bill now moves on to President Bush for signature into law. One more impediment to the genomics age will be removed. Does this pave the way for personal genomics companies such as 23andme and Navigenics?

The Wall Street Journal took up the issue of accuracy with these consumer products last week. As with many new (although I can't really call it disruptive) technologies, this one is somewhat of an expensive novelty. The main criticism seems to be a lack of accuracy in identifying just what genetic diseases an individual may be susceptible to. Although there are numerous tests for susceptibility to heart disease, the current genetic tests don't provide much more accuracy than can be provided by measuring blood pressure.

Some fairly rare genetic diseases do show up clearly on the tests, e.g. a condition associated with a higher instance of blood clotting: factor V Leiden. There is a gray area where the tests will indicate a higher susceptibility to a disease but don't go so far as to say you will contract it. This would be valuable to an individual by allowing them to increase their level of monitoring and taking preventative measures.

So far the insurance companies have yet to buy in on the whole genome tests although they have been covering disease specific tests such as those for breast cancer prognosis.

What the personal genomics companies are selling now is information, information in a quantity and form with which scientists and clinicians, let alone consumers, can barely get their arms around. As Howard McLeod, professor of pharmacology at the University of North Carolina, is quoted as saying "You get a lot of information but very little knowledge." The real challenge, and true value, will be to extract knowledge from these tests.

Genomic Health’s Healthy Results

Genomic Health's year end revenues for 2007 had more than doubled over 2006 it reported last Tuesday. A good 98% of that revenue was from their Oncotype DX multi-gene assay that predicts the recurrence of breast cancer in newly diagnosed patients. Both payers and physicians appear to be adopting the technology; an early entrant in the personalized medicine arena.

Genomic Health claims that health plans covering greater than 70% of the population now reimburse for Oncotype DX. Since the test provides information on which patients will benefit from chemotherapy, payers can reduce the costs of unnecessary chemotherapy treatments through the use of Oncotype DX.

Regardless of the economic benefits of the test, patients that will not benefit from chemotherapy are spared the discomfort of that treatment. Personalized medicine technologies appear to have quantifiable benefits but that alone is not sufficient to predict how well they will do in the marketplace. With these numbers however, Genomic Health sounds more confident and predicts revenues to increase to between $100 and $110 million for 2008.

Marathon Dog

A few years back I had the opportunity to take a friend's dogs out for runs. One of these dogs was a bulldog named Bandit. Bandit was a bundle of fast twitch muscle and would literally pull me for first mile. The second mile he would jog beside me contentedly, the third I would have to coax him along and by the fourth mile I would have to sling him over my shoulder if I had any chance of making it back home.

Despite this seeming lack of endurance, given enough time and doggy treats, I was confident I could train him for a marathon. Fortunately for Bandit, his owner decided that 5k's were the limit and probably spared him an early demise.

The story of my dog training came to mind at yesterday's Healthcare Heroes event sponsored by the Boulder County Business Report. A panel of healthcare experts provided their opinions on the future of healthcare and fielded questions. An audience member asked whether it was appropriate for healthcare providers and payers to incentivize healthy activities such as diet and exercise, since it would potentially lower the individual's healthcare needs. Although some payers do offer incentives to reduce harmful habits such as smoking, John Sackett, CEO of Avista Adventist Hospital, provided a warning that it would be difficult to issue these incentives across the general population. Given the wide genetic disparities in populations, Sackett said, standard incentives such as weight loss, may not be helpful and may even cause harm.

One size fits all healthcare has proven to be an inadequate model, should preventative programs prove any different? Are genetically based incentives a possibility? Navigenics has announced that it plans to launch a genetic test called Health Compass that will indicate what lifestyle changes people could make to avoid or delay disease. This test will be offered via the Internet for $2,500.

Although these types of tests are in their infancy, they may very well become a standard part of the healthcare process in years to come. Bandit didn’t need a $2,500 test to tell him to stop at 3 miles, his genotype was expressed quite clearly. With humans it's not nearly as clear and the benefits of testing my prove to be compelling.

AutoGenomics' Warfarin Panel

GenomicWeb News (sub required) reported on Harvard-Partners Center for Genetics and Genomics' completion of an evaluation of AutoGenomics' Infiniti 2C9-VKORC1 assay; a genetic test to determine correct dosing for warfarin. This announcement has come on the heels of the FDA's approval of new labeling for warfarin suggesting that an individual's response to the drug is dependent upon their genetic makeup.

HPCGG is participating in a clinical trial entitled: Creating an Optimal Warfarin Nomogram Trial (CROWN) to incorporate both clinical and genetic information in determining the correct warfarin dosing.

FDA Steps into Personalized Medicine

Last week the FDA approved new labeling on the blood thinner Coumadin and its generic form, warfarin. The new labeling suggests that an individual's response to the drug is dependent upon their genetic makeup. Not only is the FDA opening the door to personalized medicine, but they are actually taking a leadership role in doing so, a role not characteristic of the agency.

Warfarin has been in use for some 50 years during which time it was evident that individual response to the drug was widely varied. Dosing requires careful monitoring of patients who could suffer life-threatening bleeding if dosages were too high and life-threatening clotting if the dosage were too low. A number of factors such as patient size, age and other medications were attributed to the variability in results but it was obvious that these factors did not explain the entire story.

A story in the WSJ (sub required) last week pointed out that studies over the past decade have identified two genes that were tied to the variance in results: CYP2C9 and VKORC1. Variants in either or both genes lead to different drug responses in individuals. Combining size, age and an individual's genotype can increase the confidence with which a doctor can prescribe a patient's dosage.

The FDA's leadership in making this move is a direct result of its Critical Path Initiative, a broad initiative undertaken by the agency to modernize biomedical sciences with the goal of improving the nation's healthcare. A cornerstone the CRI is the improvement of evaluation tools, specifically biomarkers and disease models. By taking this step the FDA is actively encouraging the use of pharmacogenomics; the use of genetic markers to predict an individual's response to a drug.

Already a number of labs have begun offering genetic tests for CYP2C9 and VKORC1 such as the Mayo Clinic and Labcorp. Osmetech announced last Friday that they are developing a warfarin assay that they plan to have available by the first half of 2008.

This is all being done without a critical clinical trial; the trial that compares a group of patients that are treated without genetic testing against a group that are treated with genetic testing. Given the fact that the health risk to patients without genetic testing is reduced by the extensive monitoring they undergo during their initial dosing, it is questionable whether the genetically tested patients will actually have a lower health risk. However, by taking some of the guess work out of the dosage process, doctors can more quickly converge on the correct dosage, reducing the time the patient must spend in an over- or underdosed state and certainly cutting down on visits to the doctor for monitoring.

Public Policy on Genetic Tests

A story by Denise Caruso in today's New York Times highlights the wild west nature of genetic testing pitting companies that have invested millions in developing an accurate test against companies "with a couple of genes it ran on 30 samples." She reports that over the last six years there have been "numerous calls by government advisory bodies and expert committees... to develop special rules for labs conducting genetic tests" but none have been made. Last September, the Genetics and Public Policy Center at the Johns Hopkins University filed a citizens' petition with Public Citizen's Health Research Group and Genetic Alliance against the Centers for Medicare and Medicaid Services (CMS) citing the CMS's refusal to address the issue violates the law.

The GPPC comes down strongly on the side of the FDA citing that the Federal Food, Drug and Cosmetic Act (FD&C Act) grants them the authority to regulate genetic tests. According to the GPPC's analysis, the public already has the perception that genetic tests are regulated. The GPPC is advocating three components to ensure the safety and quality of genetic tests:

1. the laboratories that conduct the tests must have quality control and personnel standards in place to prevent mistakes.


2. the tests themselves must be valid and reliable - that is, detect genes that are actually related to disease or disease risk accurately over time.


3. health care providers must understand when to order the tests, how to in interpret them, and what to do with the results.

PGx Industry vs FDA: Round 1

Apparently things weren't quite as sanguine at the FDA's public hearing on IVDMIAs as they had hoped. The pharmacogenomic industry turned out to roundly criticize the FDA's draft guidance document. Comments seemed to focus on the fact that this is a fledgling industry and requires some leeway in order to grow, leeway that may be restricted should the FDA require the diagnostic tests go through a regulatory process. On the one hand, the FDA claims that although the components of the tests may all be approved, they have not been approved as a system and thus are considered a new devise. Because the tests cannot be analyzed outside of their proprietary kit, the results cannot be evaluated independently and thus are essentially black boxes; the consumer or physician using the test must rely completely on the authority of the manufacturer.

The PGx industry sees their costs sky rocketing if the FDA gets involved not to mention increasing time to market. Along with rising costs come rising risks; not only will the regulatory process cost more, there is an increased chance that the test will not be approved at the end of the process.

Some of this risk could be reduced if the FDA could streamline their process. This is a very dynamic field that could be of great help in both improving health and lowering costs in healthcare. This comes straight up against a government bureaucracy and the fear is that progress will be slowed to a crawl. The FDA has been charged with protecting the public's health but could they be hurting it in the process?

21st Century Medicine

On the eve of the FDA's public hearing on their draft guidance on in vitro diagnostic multivariate index assays (IVDMIAs) a group comprised of molecular diagnostic companies and investors known as The Coalition for 21st Century Medicine has asked the FDA to follow a more formal process in determining the future of this promising technology. What is being considered here is whether IVDMIAs may be subject to FDA regulation and if so, which ones and how much. Added regulation means added resources, resources that could be spent on further research and development and expansion of technologies that are still very much in a nascent stage. These are the early days of personalized medicine, a time in the life cycle of a technology where a significant investment is required to make headway. The added burden of regulation may present a set back to the industry just when businesses were beginning to show some returns.

Although regulation of IVDMIAs is inevitable, requiring the FDA to go through a more formal process before initiating regulation will buy some time, time to bring more products into the market, gain more credibility with the insurance companies and bring a greater return to investors before the added costs of regulation come into play.

FDA Approves Breast Cancer Test

As I was writing yesterday's blog, the FDA announced the approval of a genetic prognostic test for breast cancer recurrence. The test MammaPrint was developed by the Dutch company Agendia and is the first in vitro diagnostic multivariate index assay (IVDMIA) device to be cleared by the FDA.

MammaPrint uses a microarray chip to measure the activity of a set of 70 genes the pattern of which will predict whether the cancer will metastasize. Many women who have their tumors removed undergo chemotherapy on the theory that it will reduce their chances of recurrence. Studies have shown however, that most will not experience recurrence and don't need the chemo. However, it was unclear as to which patients would benefit from chemo and which would not forcing many women to needlessly undergo the treatment and its painful side effects. This test promises to make the decision easier and has shown to be 96.7% accurate.

Genomic Health also markets a genetic breast cancer prognosis test called Oncotype DX. Oncotype DX profiles 21 genes using RT-PCR technology. Both tests run between $3,200 and $3,500 and health insurers and Medicare are initiated coverage of Oncotype DX.

The FDA will hold a public meeting tomorrow to discuss its draft guidance describing its regulatory approach to this type of test.

Regulating Genetic Testing

Although there are around a thousand genetic diagnostic tests available in the U.S., only six are approved by the FDA. So if you want to know if you have a gene for susceptibility to a bacteria living in hot-tubs you can submit your genetic material to any one of a number of labs and have them run a test. Of course there's no guarantee of the results, either that the genes tested for are markers to indicate susceptibility or the algorithms matching the expression profiles to susceptibility are correct. Even after testing negative for the genes you may still get the dreaded hot-tub bug. For this reason, the FDA has recently announced that it will begin the public comment period regarding genetic tests. David Ewing Duncan has written an article in Technology Review on this impending arrival of personalized medicine.