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.