Personalized Medicine at Medco

In a recent press release, Medco Health Solutions announced that it is partnering with the FDA to study the applicability of personalized medicine methodologies to prescription drug treatment. Medco is the nation’s leading pharmacy benefit manager and the announcement signals the continued mainstreaming of pharmacogenomics in healthcare.

Medco and the FDA will jointly develop research projects, programs and strategies in the area of pharmacogenomics, the science of using a patient’s genotype to predict their response to drug treatments.

Medco’s objective is to advance pharmacy care and take some of the guesswork out of the prescription process. Specifically, the objectives of the program are to address:

Safety of prescription drugs
Physician participation in pharmacogenomic testing
Usefulness of tests in prescribing
Quantifying prescription information about drugs

Central to the research studies will be Medco’s extensive database of pharmacy claims. Medco is already involved with pharmacogenomic studies including Warfarin at the Mayo Clinic and tamoxifen with LabCorp.

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.

Money Back Guarantee

Well Nordstrom does it, so why not Johnson & Johnson? If a pharmaceutical company expects a patient, or the patient's healthcare payer, to pony up some $48,000 for a cancer drug shouldn't they have assurance that the drug will provide some benefit?

The British National Health Service, the healthcare provider/payer in the U.K., determines which drug treatments they will reimburse. The NHS had been struggling to justify approving the reimbursement of the drug, Velcade, because of its high price. Then the manufacturer, Janssen-Cilag/Johnson & Johnson, approached the NHS with its novel pricing experiment: pay for the drug only if it does its job.

Although the drug development/approval process is intended to reduce the risk and prove the efficacy of a new drug, in reality not all patients will benefit from a particular drug. Whether this is due to genetics of the patient, disease sub-type, co-morbidity or any number of factors is not usually well understood. Despite this knowledge, the pharmaceutical manufacturers still charge all patients the same; the ones that improve as well as those that do not.

With the new pricing model, however, the risk is shared between the payer and the drug manufacturer: the payer only pays when the drug works. Velcade is ideal drug for this model; its efficacy is easily monitored, proven and is known fairly soon after the treatment has begun.

Is this a new paradigm that will soon be sweeping through healthcare? Pay for performance is attractive to consumers but performance is difficult to measure in many cases. Even the case of Velcade is up for debate with Janssen-Cilag calling a tumor reduction of 25% proof of efficacy and the NHS requiring a 50% reduction.

This is certainly an interesting trend and one which could change the pharmaceutical industry; satisfying the FDA is no longer sufficient for drug success, it must benefit the individual patient as well.

FDA Reclassifies IVDMIA

After much consternation on the part of the nascent genomic profiling industry, the FDA has (re)classified a gene expression test system for breast cancer prognosis from a Class III to a Class II medical device. When the Dutch company Agendia first applied to the FDA for approval of their MammaPrint test, they received a Class III designation by default. Class III requires premarket approval which would significantly increase the costs of developing these systems. Agendia petitioned the FDA for a lower classification and the FDA came back last week with the lower Class II designation. Class II requires the developer to file a 510(k) premarket notification that complies with the FDA's special controls guidance document.

MammaPrint is the first In Vitro Diagnostic Multivariate Integrating Assay (IVDMIA) to be approved by the FDA for the prognosis of breast cancer. These are a new breed of genomic profiling assays that offer the promise of personalized medicine and improvements in diagnosis and treatment.

Designation of these tests as Class III devices would seriously hamper the progress of this industry by increasing the regulatory costs. As a Class II device however, the FDA has reduced the regulatory burden but has still retained certain special controls such as a description of the algorithm used to analyze the results as well as a description of how the algorithm was derived.

This is critical since the algorithms are both the key ingredient in the tests and are proprietary. Without this control, there is no way of asserting the validity of the tests.

Although the FDA has indicated that a number of tests have been cleared as Class II devices for other tumors, this guidance has only been extended to IVDMIAs that apply to breast cancer prognostic tests. This may serve as a model for other IVDMIAs to be developed for other diseases in the future.

Gateway to the FDA

The FDA launched a new initiative in May 2006 called the Electronics Submission Gateway (ESG) which lets pharmaceutical companies make regulatory submissions electronically. Although a modest step into the digital era, by all indications it appears to be a success. Before the ESG, drug companies were required to deliver the information in some kind of physical form, be it paper, CD-ROM, or digital tape. In the case of paper, the deliverable could be truckloads. The ESG allows for huge amounts of information, up to 100 Gb, but now it takes only minutes to upload, not days to ship.

Not only is transit time reduced, but the sender also receives a reliable acknowledgement of receipt; confirmation that the submission is in process. With the physical media there was always some question as to whether the documents made it to the right place or not.

Currently the FDA accepts submissions to CBER, CDER and CDRH. They also support receipt of Adverse Event Reporting System (AERS) reports. The next phase of the ESG will support submissions to the Center for Veterinary Medicine (CVM), Center for Food Safety and Nutrition (CFSN) and the Office of Orphan Product Designations (OOPD).

AERS reports topped 12,000 for March 2007, by far the largest percentage of submissions. These tend to be much shorter than the other submissions which have been growing steadily since launch. Users appear satisfied with the system and there are now between 150 and 200 registered users of the system.

Each of the above centers has its own set of requirements for submission, however, documents are free text which requires manual processing. Although delivery time of the documents has been reduced from days to minutes, the bulk of the regulatory work will proceed at the same pace as it had before. This can certainly be streamlined, as it has been in many other agencies, but this will require quite a significant investment, one which carries far more risk than what has been done so far.

Aversion to Adverse Events

The Wall Street Journal reported on Saturday on a report commissioned by the FDA regarding their development of a next generation Adverse Event Reporting System for the tracking of dangerous side effects associated with drugs on the market. The report was prepared by the Breckenridge Institute and delivered to the FDA in November 2006 but has not been released to the public. Although we don't know what it says specifically, "highly critical" is probably putting it lightly. No wonder the FDA is keeping it under wraps.

But reading between the lines, is the FDA really making major managerial mistakes here? The report contends that the FDA could have purchased an off-the-shelf software product in 2004 and have it up and running by 2005 for around $4.5 million. This would have only covered drugs and not medical devices which are also regulated by the agency. The FDA would then have to come up with another system, perhaps a custom built one, to cover medical devices and then integrate it with the off-the-shelf system.

If you put a conservative safety factor of two to the off-the-shelf system, double that for the medical device system and then throw in another $10 million to integrate them we're talking $40 million not including maintenance, support and training. The Breckenridge report states that the off-the-shelf software was a "one-time cost"? Wasn't the theory of "one-time cost" software thrown out with OS/2?

The FDA is making due with an existing "dysfunctional" system; their original AERS which results in a loss of 45 minutes per day per FDA employee because of inefficiencies and snags in the system. Presumably better software would solve that problem but it is a difficult call. Ideally the entire process could be automated resulting in the loss of the FDA employee, which is highly unlikely.

What the FDA needs now is a study to analyze why they gave the contract to the Breckenridge Institute in the first place.

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.

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.