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Archive for November, 2013

23andMe, the FDA, and evolving science ethics

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27 November 2013

I’ve got a thesis to write, manuscript to edit, and a pesky microscope problem to work around, but I just cannot help but follow the current discussions surrounding the battle between 23andMe and the FDA. There’s a LOT of hype and charged discussions going on in social media at the moment, and I’ve had the pleasure of watching it all unfold. All in all, I have seen some very healthy ethical discussion on many fronts. I thought I’d share a few enlightened points I’ve come across.

First, came the announcement:

The actual letter from the FDA is a fantastic read: http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2013/ucm376296.htm

Your company submitted 510(k)s for PGS on July 2, 2012 and September 4, 2012, for several of these indications for use. However, to date, your company has failed to address the issues described during previous interactions with the Agency or provide the additional information identified in our September 13, 2012 letter for (b)(4) and in our November 20, 2012 letter for (b)(4), as required under 21 CFR 807.87(1). Consequently, the 510(k)s are considered withdrawn, see 21 C.F.R. 807.87(1), as we explained in our letters to you on March 12, 2013 and May 21, 2013.  To date, 23andMe has failed to provide adequate information to support a determination that the PGS is substantially equivalent to a legally marketed predicate for any of the uses for which you are marketing it; no other submission for the PGS device that you are marketing has been provided under section 510(k) of the Act, 21 U.S.C. § 360(k).  {emphasis added}

Matthew Herper in Forbes gives a great introduction to what is a highly nuanced ethical debate quickly becoming a macrocosm of a battle between 23andMe and the FDA:

I’d like to be able to start here by railing against our medical system, which prevents patients from getting data about our own bodies because of a paternalistic idea that people can’t look at blood test results, no less genetic information, without a doctor being involved or the government approving the exact language of the test. I’d like to be able to argue that the Food and Drug Administration is wantonly standing in the way of entrepreneurism and innovation by cracking down on 23andMe, a company that is just trying to give patients the ability to know about their own DNA, to understand their own health risks, and to participate in science.

I wish that was the story I’m about to write, but it’s not, and it all really comes down to one fact in the FDA’s brutally scathing warning letter to 23andMe, the Google GOOG +0.36%-backed personal genetics startup. It’s this quote from the letter by Ileana Elder, in the agency’s diagnostics division: ‘FDA has not received any communication from 23andMe since May.’

more here: http://www.forbes.com/sites/matthewherper/2013/11/25/23andstupid-is-23andme-self-destructing/

The blog Genotopia makes some very important distinctions about what the FDA is trying to regulate:

We must be clear that the FDA letter does not prohibit 23andMe from selling their test. It demands they stop marketing it. The difference may not amount to much in practice—how much can you sell if you don’t market your product?—but the distinction does help clarify what is actually at stake here. FDA is not attempting to instigate a referendum on the public’s access to their own DNA information. They are challenging the promises 23andMe seems to make. This is, in short, not a dispute about access, but about hype.

The company seems to promise self-knowledge. The ad copy for 23andMe promises to tell you what your genome ‘says about you.’ ‘The more you know about your DNA,’ they trumpet, ‘the more you know about yourself.’ On one level, that’s perfectly, trivially true: your genome does have a lot to do with your metabolism, body structure, how you respond to disease agents, and so forth. The problem is, we as yet know very little about how it all works. The 23andMe marketing exploits a crucial slippage in the concept of ‘knowledge,’ which FDA correctly finds misleading. In short, the marketing implies a colloquial notion of knowledge as a fixed and true fact, while the science behind the test is anything but.

Genotopia continues:

…The 23andMe product, like every genome test, provides probabilities of risk, not mechanisms. Probabilities are messy and hard to understand. They carry an almost irresistible tendency to be converted into hard facts. If you flip a coin 9 times and it comes up heads every time, you expect the next flip to come up tails. And if you get heads 49 times in a row, the next one has got to be tails, right? Even if you know intellectually that the odds are still 50:50, just like on every previous flip. You can know you have a particular gene variant, but in most cases, neither you nor anyone else knows exactly what that means. Despite the language of probability that dots the 23andMe literature, their overall message—and the one clearly picked up by many of their clientele—is one of knowledge in the colloquial sense. And that is oversell.

…the 23andMe test is being sold directly to individuals who may not have any knowledge of genetics. The tendency to convert risks into certainty is higher than ever. The knowledge they sell is a set of probabilities, and further, those probabilities are not stable. The consumer may not—indeed probably doesn’t—appreciate how much we know, how much we don’t know, and how much we don’t even know we don’t know. The company claims to be selling knowledge but in fact they are selling uncertainty.

More here: http://genotopia.scienceblog.com/379/23andme-fda-and-the-history-of-hype/

David Dobbs’s NEURON CULTURE has created a fantastic list of diverse, intelligent commentary on the ethics, regulations, and science surrounding the current story: http://daviddobbs.net/smoothpebbles/feds-muzzle-23andme-decide-public-best-be-ignorant-about-genetics/

He also offers some of his own commentary, perhaps advocating that a little messiness in the system must be weighed against the potential for positive impacts:

But do those apparently rare errors inflict more harm than the sorts of errors our medical system makes every day? Do they inflict more harm than a lack of information about important risk genes inflict? Does any harm done outweigh the great good that people gain from having inexpensive access to lots of information about medical risk?

A person learning the status of hundreds of genes of medical interest (along with information about their ancestry) with a simple spit-test may learn much actionable information — not to mention an education about genetics — that would otherwise depend on … what? Expensive access to doubtless heavily marked-up genetic tests prescribed by physicians and executed by companies happy to charges hundreds of dollars per gene? We need more such information; not less. I pray this will soon be reversed.

Lastly, there is the discussion about whether the FDA is hindering what could be a fantastic new dawn of public interest in science, not just for of un-health aversion, but just for the sake of inquiry, curiosity and education in itself. I have to admit, that this arena plucks a special chord in my heart. At the very least, I’m so glad to see these types of discussions continue, and move forward general public interest in science and genetics.

Ryon

Written by Ryon

November 27th, 2013 at 1:44 pm

Posted in Science Blog

N of 1 Study Insightful to Prostate Cancer Evolution, Therapy?

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18 November 2013

(back to science blog)

It’s tantalizing (and extremely important) to factor the fourth dimension in cancer: time. Cancer is a microcosm of evolution, the most lethal versions of which are bestowed with an immense reservoir of genetic heterogeneity, providing the raw resources to adapt to changing environments. The physical manifestations of this are the same that thwart treatment: chemotherapy resistance and metastasis (1).

Tumor heterogeneity over time is difficult to study, owing to a rarity in genomics-grade longitudinal samples in cancer patients. Last week I had the pleasure of presenting a curious N=1 study to our weekly journal club here at the Moores Cancer Center. Haffner and colleagues performed genomic and histological analyses on unusually well-preserved specimens collected over a man’s 17 year disease course with prostate cancer (2). (article available for free here)

The ensuing analyses revealed a few interesting pieces of information:

The region of the prostate surveyed that likely gave rise to a wave of lethal metastases 17 years after diagnosis (and radical prostatectomy) was of low histological grade compared to the rest of the prostate tumor region.

The lymph node metastasis removed the same time as the radical prostatectomy differed in molecular signature to the lethal metastases 17 years later, indicating a diverging evolution and suggesting, at least in this patient, that the palpable lymph node tumor did not act as a way station for the lethal, visceral metastases 17 years later in the lung, liver, and thoracic lymph nodes. This gives weight to the “embolization” theory of metastasis in prostate cancer, which posits that lymphatic and hematogenous dissemination are two separate paths, the lethal one being hematogenous. In breast cancer, this distinction was the subject of much debate until clinical trials very clearly demonstrated that aggressive removal of regional lymphatics does not reduce the risk of distant organ dissemination in breast cancer (3, 4). Perhaps the same could be true for prostate cancer? While not “essential” organs, aggressive surgical removal of regional lymphatics is far from innocuous. Even small hints at tumor evolution can glean valuable information for the most effective, least invasive means to treat prostate cancer.

Lastly, the metastatic clones that aggressively arose 17 years after diagnosis were all highly similar in both driver and passenger mutations, indicating a temporally recent progenitor. The questions that I would like to ask are:

Where were these metastatic clones hiding out for 17 years? The patient had multiple gaps without detectable disease. Also, what caused re-immergence from metastatic latency? Why then and not 10 years prior or 10 years in the future? Was there an undetected watershed moment mutation after decades of genomic Russian roulette and genomic instability that enabled the emergence of a lethal clone? Or, were there coordinated changes in many tissues at once that could have given rise to a more favorable environment for metastasis (i.e. perhaps some threshold related to aging)?

These questions cannot be answered with the current study, and I agree with Brannon and Sawyers (5) that N=1 studies could be immensely more powerful if we are able to better transpose genomics to the spatial and temporal disease course of many patients. At this point we have the technology; the real challenges in implementation are clinical and logistical, which can be overcome.

Ryon

References:
1. Klein CA. Selection and adaptation during metastatic cancer progression. Nature. 2013 09/19/print;501(7467):365-72.
2. Haffner MC, Mosbruger T, Esopi DM, Fedor H, Heaphy CM, Walker DA, et al. Tracking the clonal origin of lethal prostate cancer. The Journal of clinical investigation. 2013 Nov 1;123(11):4918-22. PubMed PMID: 24135135. Pubmed Central PMCID: PMC3809798. Epub 2013/10/19. eng.
3. Donker M, Straver ME, van Tienhoven G, van de Velde CJ, Mansel RE, Litiere S, et al. Comparison of the sentinel node procedure between patients with multifocal and unifocal breast cancer in the EORTC 10981-22023 AMAROS Trial: Identification rate and nodal outcome. Eur J Cancer. 2013 Mar 19. PubMed PMID: 23522754. Epub 2013/03/26. Eng.
4. Fisher B, Redmond C, Fisher ER, Bauer M, Wolmark N, Wickerham DL, et al. Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation. The New England journal of medicine. 1985 Mar 14;312(11):674-81. PubMed PMID: 3883168. Epub 1985/03/14. eng.
5. Brannon AR, Sawyers CL. “N of 1″ case reports in the era of whole-genome sequencing. The Journal of clinical investigation. 2013 Nov 1;123(11):4568-70. PubMed PMID: 24135144. Pubmed Central PMCID: PMC3809802. Epub 2013/10/19. eng.

Written by Ryon

November 18th, 2013 at 10:11 am

Posted in Science Blog