Along with greater outcomes for patients, the movement now known as Personalized Medicine has also held great promise for new business.
In the winter of 2005-2006 (if we can call it winter in Silicon Valley) I was caught up in the hype and became a partner in a new start-up that was to offer all kinds of predictive genetic tests. We even secured the name ConsumerGenetics.com, a domain highly sought after at the time. There was to be a revolution in the way health was delivered to patients. In fact, we would bypass the doctor and go to the consumer with important health information. And best of all, the products weren’t regulated by the FDA. It was just a matter of setting up a lab, combing through the literature for the latest findings on specific genes which could predict the probability of certain disease, putting up a website, and we were in business.
This naivety landed me in a piece by Andrew Pollack of the New York Times entitled <a href=http://www.nytimes.com/2006/09/12/business/smallbusiness/12genetic.html?pagewanted=all" target="_blank">The Wide, Wild, World of Genetic Testing.
OK, so it turned out a bit more complicated than that.
In 2009 we got a letter from the FDA.
Consumer Genetics is offering a test that is a device under section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 321(h) because it is intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or is intended to affect the structure or function of the body. . . You should be aware that FDA does not consider your device to be a Laboratory Developed Test because the test is not developed by and used in a single laboratory . . . You should take prompt action to respond to this letter.
Now the FDA has decided to regulate LDTs as well. This was the focus of a track last week at the Molecular Medicine Tri Conference in San Francisco. Though the FDA has decided to regulate the tests, they still have no draft guidance. Others from industry were on hand to debate the direction of the industry.
Speaking for the FDA
Speaking for the FDA was Elizabeth Mansfield, Director of the Personalized Medicine Staff in the Office of In Vitro Diagnostic Devices. Her first point: there has been a ‘loophole’ for LDTs or what used to be called “home brew” tests. It will be closed.
To a pretty packed room for 8 a.m., Director Mansfield made her second point right away. The FDA hasn’t completed the guidance and there was no date when it would be available. Excusing anyone in the room who came just to hear that, she launched into an historical update on the FDA’s policy in regard to Laboratory Developed Tests. Her salient points:
1 - There is no need for new rules. The FDA already has the authority to regulate LDTs. 2 - The goal is to adopt a transparent approach and seek to avoid any surprises. 3 - FDA doesn’t want to interrupt medicine. They will be more relaxed toward rare diseases. And in the case of emergencies such as bio threats, they will issue EUAs or Emergency Use Apps. 4 - There will be some type of registration and listing. 5 - High risk tests will be evaluated first. 6 - There may be new classifications. 7 - For now the FDA is using enforcement discretion.
“We don’t want lab testing to stop,” Dr. Mansfield assured the crowd.
There was some time for Q & A.
“What about a predictive test for Alzheimer's--what’s the risk there? Is it high or low? Not sure the intended use.” A fellow from Genomic Health stepped to the mic. “Do you understand the conundrum?”
Mansfield is used to such questions. “There is no conundrum. This is science. We’ve been classifying risk since 1976,” she replied succinctly. “Furthermore, it’s not possible to classify without knowing the intended use.” Correctly sensing that the questioner wasn’t happy, she added, “did I answer your question?”
“No, but that’s ok,” he submitted.
“Sorry,” she followed up.
A second question came in. “You have a great database of adverse events. Doesn’t this help provide draft guidance for LDTs?”
Mansfield: Not many adverse events are reported for LDTs. Labs are not required to report. You’d be surprise at how few adverse events are reported.
Another question. “How is the FDA going to deal with new technology such as NGS?”
Mansfield: Not a problem. We deal with new technology all the time.
Speaking for Industry - Hologic
Mansfield was followed up by Stephen Day, Director of Medical Affairs at Hologic. Day was determined to point out the inconsistencies in the current system. The FDA regulates what are known as ASR’s or Analyte Specific Reagents which are really the components for test kits. Labs have gotten away with passing their products off as ASRs for RUO (research use only) and not submitting them as IVDs (In Vitro Diagnostic kits).
Though there are strict definitions for ASRs, there are hundreds of tests which don’t fit these definitions on the market passing off as ASRs. This is overlooked by the FDA. For example, an ASR can be a set of primers, or a single probe but not more. Many products which are on the market consist of multiple probes and targets such as those for HPV. In a random check, Dr. Day searched online for just such a test. On a site he didn’t name he found a test for HPV with multiple targets passed off as an ASR. Adding to the confusion, at the bottom of the website, the product was marked “For IVD Use.”
There are also IP issues with LDTs, Day noted. A manufacturer cannot sell its test with multiple primers to a lab, yet if the lab goes ahead and develops their own primers, there is violation of a patent. Many labs feel a “damned if you do, damned if you don’t” frustration at the present.
Dr. Day was obviously calling for more clarity, though he ended his talk with the diminutive “I just wanted to share what I’ve been thinking about.”
Speaking for Labs - ACLA
Next up was Peter Kazon who consults for the ACLA (American Clinical Laboratory Association). Kazon confronted Mansfield and the FDA directly. He went over a couple bills that are presently before congress which both propose that LTDs come under CLIA guidance rather than FDA. And that if the FDA did continue with regulation, they did, in fact, need new rule making.
“What would the FDA inspect in a lab,” he asked, “which is already inspected by CLIA?”
Under one bill before congress, HR 3207, labs would be required to register tests with CLIA. CLIA and the CMS could both prevent the tests from being offered. But, most importantly, said Kazon, there would be less impact on innovation. Companies would not be faced with the heavy regulatory burdens of the FDA.
I chatted with Dr. Stephen Little from one such company by the name of Qiagen after the session. Little and his colleagues at Qiagen know well the regulatory burden to launch tests. They go through the FDA for IVD approval. They have also found success working with pharma to offer CDx. They do not, however, offer any LDTs.
Is there an un-level playing field, I ask. “Yes,” Dr. Little replies. “We either need to see the burden lowered on the tests we’re offering, or see it come up for LDTs.”
Speaking for Industry - Asuragen
The final speaker on the track, Carol Berry, is a VP at Asuragen. Her company develops IVDs and LDTs side by side and has a CLIA certified lab. “Not all LDTs are equal,” she repeated during her presentation. Focused mainly on walking the audience through the ups and downs of developing a diagnostic, Berry didn’t offer an opinion about regulation other than to say that the CLIA process is extensive and thorough.
Will DTC (Direct to Consumer) tests be considered LDTs in future FDA guidance? Will products marked RUOs continue to be allowed on the market for clinical use? These and many other questions remain as companies continue to produce tests and hope to get around the FDA’s current policy of enforcement discretion.
Carol Berry from Asuragen urged the audience to look at the bigger picture. “According to the AACR, 3,000 biomarkers were discovered this year, but none have become tests. It should not be about safety, but about life saving improvements. After all, LTDs are driven by the acceptance of physicians and patients.”
“That’s just ridiculous,” exclaimed Little to me privately. “Just because some doctor or some group of patients thinks a test is ok, then it’s ok?”
In some form, regulation is coming for LDTs. While the FDA is clear that they don’t want to stifle innovation, the they feel that they have the authority to regulate, and it’ll take congress to stop them. A statement put out by the FDA listed on one of Peter Kazan’s slides read:
. . that the use of LDTs has contributed to enhanced standards of medical care and that significant regulatory changes in this area could have negative effects on the public health.
Though there are still many questions about the future of LTDs, Dr. Mansfield does have answers. She has agreed tentatively to give an interview at mendelspod and reply to the issues brought up by the other speakers. It was too bad that the organizers at the TriCon didn’t have a panel at the end of the discussion where the speakers could go back and forth among each other and with the audience.
Consumer Genetics, the company I co-founded in 2006, is still around offering a simple prenatal gender test. I’m no longer involved.
Watch for Dr. Mansfield’s interview among others in an upcoming series, “Commercializing Diagnostics.”