Stop the poll, I want to get off

Genetic Engineering and Biotechnology News have just published the first survey conducted by their Science Advisory Board, a project called SciPulse Perspectives which aims “to take the “pulse” of scientific minds all over the world”. The survey asked 500 US members “ to share their views on the direct-to-consumer (DTC) testing industry, specifically in the context of the FDA’s warning letter to 23andMe back in November of 2013.”

You can read the results of the poll, yourself, and I won’t bother to comment on them. What concerns me is the way the poll has been framed suggests a fundamental misunderstanding of the FDA’s action. The poll infographic states that the FDA’s position is that “there is a potential for harm when genetic testing results are presented without the counsel of a physician” and that the FDA decided “to stop 23andme from providing genetic interpretations directly to individuals without involving an intermediary physician for counsel.” This is a serious misrepresentation of the FDA’s action, which, as I stated in a previous post, is more concerned with the failure of 23andme to provide the Agency with data about the safety and effectiveness of their test, the traditional standard to which FDA holds medical devices. Anyone who reads the FDA’s warning letter to 23andme carefully cannot be in any doubt as to the FDA’s concerns.

To recap, way back in 2012 23andme submitted for FDA approval for portions of the clinical service they provide. The FDA’s 2013 letter revealed that the company has subsequently been in discussion with the Agency about
1) which regulatory pathway they have to take (whether they could get approval via the less onerous 510(k) route or instead have to undertake the more stringent process for Pre Market Approval (PMA), and
2) the types of clinical evidence which the FDA requires in order to approve 23andme’s test.

Let me reproduce the relevant parts of the letter in full:
“we provided ample detailed feedback to 23andMe regarding the types of data it needs to submit for the intended uses of the PGS. As part of our interactions with you, including more than 14 face-to-face and teleconference meetings, hundreds of email exchanges, and dozens of written communications, we provided you with specific feedback on study protocols and clinical and analytical validation requirements, discussed potential classifications and regulatory pathways (including reasonable submission timelines), provided statistical advice, and discussed potential risk mitigation strategies. As discussed above, FDA is concerned about the public health consequences of inaccurate results from the PGS device; the main purpose of compliance with FDA’s regulatory requirements is to ensure that the tests work.

However, even after these many interactions with 23andMe, we still do not have any assurance that the firm has analytically or clinically validated the PGS for its intended uses, which have expanded from the uses that the firm identified in its submissions. In your letter dated January 9, 2013, you stated that the firm is “completing the additional analytical and clinical validations for the tests that have been submitted” and is “planning extensive labeling studies that will take several months to complete.” Thus, months after you submitted your 510(k)s and more than 5 years after you began marketing, you still had not completed some of the studies and had not even started other studies necessary to support a marketing submission for the PGS. It is now eleven months later, and you have yet to provide FDA with any new information about these tests. You have not worked with us toward de novo classification, did not provide the additional information we requested necessary to complete review of your 510(k)s, and FDA has not received any communication from 23andMe since May. Instead, we have become aware that you have initiated new marketing campaigns, including television commercials that, together with an increasing list of indications, show that you plan to expand the PGS’s uses and consumer base without obtaining marketing authorization from FDA.”

So, to be clear: the FDA took action not because it wants to stop companies like 23andme selling tests direct-to-consumer, but because 23andme had failed to comply with the FDA’s requirement to provide data on the analytic and clinical validity of their test. So if you are going to run a poll on the FDA’s actions, then the question you should ask is this: do you believe that DTC genetics companies should have to comply with the FDCA and provide evidence to the FDA that gives reasonable assurance of the safety and effectiveness of their tests?

6 Comments on “Stop the poll, I want to get off”

  1. Gary Marchant says:

    If that is the case, then why isn’t the FDA demanding similar evidence for the EXACT SAME genetic tests being offered today by doctors which in the vast majority of cases have had zero FDA review. Your argument doesn’t hold water.

    • Hi Gary, thanks for your comment. I respectfully disagree with your point. The argument that I was advancing in my post is simply this: the reason that FDA forced 23andme to withdraw the clinical portion of their service from the market was that the firm had failed to provide FDA with the evidence it had asked for regarding the analytic and clinical validity of their test, not because of an intention to ban all DTC genetic tests. Had the Agency wanted to do that then they would have told 23andme that it would be a condition of approval for their service that tests be ordered by physicians. That they did not do so indicates that the FDA is willing to approve DTC genetic testing services provided that they meet FDA’s evidentiary requirements.
      You are quite correct that FDA continues to exercise what it has termed “enforcement discretion” over most of the genetic tests which are delivered as Laboratory Developed Tests, and that policy extends to LDTs more broadly, not just genetic tests. It is an open secret that the FDA has written a guidance document outlining its intentions with regards to LDTs but that guidance is stuck in the White House, held up by the Office of Management and Budget, see this report for a sense of the Agency’s frustration. However, absent that guidance FDA continues to tackle LDTs on a case-by-case basis when it feels that action is required. This piecemeal approach has tended to focus on what the Agency termed In Vitro Diagnostic Multivariate Index Assays (IVDMIAs)(uninformed readers can look to this great paper by Gail Javitt for the history of this) and has in no way been restricted to DTC genetic testing, witness the attention they paid to InterGenetics, a company which explicitly rejected DTC provision and their much more recent action against Atossa Genetics.
      So: FDA’s activity in the LDT space is not restricted to DTC genetic testing, and its approach to DTC genetic testing is not to ban it but to require the same kind of evidence which it demands for other tests going through the Agency’s regulatory process.

      • Gary Marchant says:

        Stuart – thanks for your helpful response to my comment. I agree with most of your clear explanation of FDA’s regulatory approach to genetic tests, but here is where we still disagree. While you are correct that FDA has taken some regulatory action against a relatively small number of genetic tests, there are close to 3000 genetic tests commercially available (see, most of which are LDTs as you describe and which have never been reviewed by FDA. So many (most?) of the genetic tests offered by 23andme are also offered through your doctor by a commercial testing lab. In neither case has there been any demonstration of clinical validity or utility to FDA, but FDA shut down 23andme from offering such tests, but not your doctor. To give a specific example, one of the most important tests previously offered by 23andme was the APOE4 test, showing an increased risk for Alzheimer’s. While 23andme has now been blocked from offering such a test, you can go to your doctor and get the exact same test, even though I believe FDA has never approved any LDT APOE4 tests. So FDA has acted selectively (I would argue discriminated) against 23andme by only blocking them from offering this test without FDA approval. I suspect you and I agree that there should be some FDA review for all LDT genetic and molecular tests – I believe the problem FDA faces is that they are constrained to a relatively small number of regulatory pathways (510k, PMA, de novo), none of which are really appropriate for such tests. So FDA faces an outdated regulatory structure for a rapidly moving scientific field.

      • Hi Gary, yes, we agree that FDA is being very selective in its enforcement activities. The limited nature of its current activity is not a situation of the Agency’s choosing – the draft guidance on LDTs currently locked up in OMB is, I am told on good authority, not restricted to DTC, and indeed the FDA’s last stab at this issue (the aforementioned IVDMIA guidance) was not focused on DTC tests. As to why it is focusing on DTC right now, well I think two Congressional hearings and two GAO reports have provided it with very clear political direction.
        With regard to how big a chunk of LDTs the FDA will be able to take on (assuming that guidance ever sees the light of day), the Agency has repeatedly cautioned that it has limited resources, so I suspect it is going to have to continue to be selective.
        With regard to whether the existing regulatory pathways are outdated in light of rapid scientific advance, I would suggest that perhaps the scientific advance is not so rapid as all that. If we measure that advance in terms of validated new biomarkers whose clinical validity is well-established through adequately powered and well-designed studies, and which have at least some evidence of plausible utility sufficient that they might merit clinical adoption then I would say that sadly progress is pretty slow. Also, I think there is some flexibility in the regulatory toolkit that could be applied if progress does accelerate.

  2. Scott McLean says:

    I thought that the FDA was framing the debate rather narrowly – but did so intentionally (and, in my opinion, rather cravenly) in order to sidestep the larger regulatory issue of whether they approve of DTC testing. On that point, they certainly have a dog in the fight. It really is a question about paternalism vs autonomy, and it would certainly be refreshing if we could just speak plainly about it and not skirmish in arcane bureaucratic syntax. This is a cultural issue and is too important to get lost in painful acronyms like IVDMIA.

    • Dear Scott, thanks for your comment. I agree that IVDMIA is a painful acronym, and we can certainly debate the merits of DTC testing without recourse to acronyms, but sadly if we want to think about how DTC testing fits in the regulatory landscape then people need to wade through a bunch of them to understand the lie of the land. If I never had to talk about Analyte Specific Reagents (ASRs) again, I would be a happy man.
      On the question of whether FDA has side-stepped the DTC issue, I think FDA is doing what it does best, which is rigorous evaluation of the analytic and clinical validity of tests. For it to go beyond that, I think at very least it would have to issue a draft guidance document. Perhaps the mysterious LDT draft guidance which is locked up in OMB (see my reply to Gary Marchant above) addresses this issue, but the Agency’s inability to get the White House to allow release of this document is testament to the limits of its powers.

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