Tag Archives: FDA

TOP TEN STORIES IN GENETICS, 2016: An Adolescent Science Meets the Big World

Clinical genetics is a young science, not yet come of age – a new discipline. It’s early days, say the small group of clinicians and researchers who have watched over its formative years, dreaming like proud parents of a future where genetics and genomics are integral to clinical medicine. And as for many parents, it may sometimes have seemed that the all-consuming, semi-hermetic little laboratory of childhood would go on forever.

But guess what, people? I believe we have entered the teenage years.  I believe baby has borrowed the car keys and taken it out for a spin.  I see a field boasting a few real accomplishments, and on the cusp of so many changes, from therapies for genetic disease and cancer to a suddenly burgeoning DTC marketplace. And like all parents, geneticists are poised to discover the limits of our ability to control what we have nurtured. That’s exciting, more than a little bit scary, and the theme of this year’s top ten.

  1. FDA CANCELS PLANS TO REGULATE LDT’s

Over the past two decades, a single technological advancement has revolutionized the way we practice medicine.

I am talking, of course, about overnight delivery of packages.

Years ago, laboratory testing services were divided into large companies that sold test kits and devices nationwide, and the small labs in hospitals and other clinical settings providing services to their local providers. With limited resources, government regulators focused on the tests that affected more people, and agreed by convention that ‘laboratory-developed tests’ would not be subject to the same scrutiny. Today these distinctions are virtually meaningless, as giant companies like LabCorp and Quest perform tests ‘in-house’ on samples gathered worldwide, tossed in a box and sent overnight. Still laboratory-developed tests (or LDT’s) – a category that includes virtually all genetic tests – remain in regulatory limbo.

In 2010, the FDA announced its intention to address this loophole. In July 2014, they issued draft guidance detailing their plan for a regulatory structure that divided the LDT universe into high, low and medium risk tests. While some professional organizations disputed the FDA’s right to have a role in regulation of LDT’s and threatened legal action, others approved the framework in principle but disagreed on specifics, including how to handle the thorny new territory of exome and genome sequencing. A dialogue ensued with representatives of labs, clinicians and patients that has lasted two years and included multiple workshops and public meetings. That process, it was widely assumed, was nearing its end, with the resulting draft guidance expected to be sent to Congress for approval in the near term.

And then came November 8th and the election of Donald J. Trump, ushering in an executive opposed to regulation on principle, to join a similarly inclined House and Senate. Ten days later, the FDA ran up the white flag, announcing that the agency would not take steps to finalize its existing plan and would instead reopen the discussion with a new administration and a new Congress. What this means precisely is a matter of some interesting speculation, but in general it suggests that an industry that has been struggling for years to avoid too much regulation will have to consider the consequences of living with none at all.

 

  1. IS THIS THE FUTURE? CRISPR EXPERIMENT ADDS RARE PROTECTIVE VARIANTS TO HUMAN EMBRYOS

The second experimental use of CRISPR technology to alter human embryos was reported in May of 2016, again by a group out of China. Again, the embryos used were not viable, and no attempt was made to transfer them for reproductive purposes. While this experiment did not produce the same ethical firestorm as the first, it was in several ways a more significant indicator of both the potential and the peril of human germline engineering using CRISPR.

In the first experiment investigators attempted to alter a gene variant responsible for causing hemoglobinopathy, with limited success – proof in principle that it could be done, but nothing to assure worried observers that it could be done safely. In version 2.0 there were fewer off target effects, but researchers were not able to consistently control the content of changes introduced in place of the edited DNA. This is not inconsistent with what we know so far about CRISPR: if we envision it as a word processing search-and-replace function, it is good at the finding and erasing part, but hit or miss when it comes to  putting in a replacement.

What stands out about the second experiment is that the goal was not to eliminate a disease-causing gene, but to insert a rare and protective one – in this case, the CCR5Δ32 allele that offers the bearer reduced susceptibility to AIDS. Gene editing is often envisioned as a way that individuals whose children are at risk can avoid or change genes that cause disease, but in the vast majority of these cases there are simpler and better established tools such as PGD if the goal is to obtain embryos that do not carry a specific variant associated with some catastrophic risk. Why use technology to substitute out a pathogenic BRCA variant or a double dose of the sickle cell genes when the parents are perfectly capable of producing a healthy embryo themselves? What CRISPR and related technologies can do that is not available through other means is to introduce a gene that neither parent carries. That is a powerful new option, and it is both exciting and scary in the manner of all things powerful and new.

 

8. GENETIC DISCRIMINATION MAKES A CAMEO

Many wise observers have noted that for all our deeply felt concerns about genetic discrimination, to date the examples are few, far between, and usually more clumsy than systemic (looking at you, Burlington Northern Santa Fe Railroad). These arguments, redux, were on display in 2016 as Canada debated and ultimately passed its own national genetic discrimination law. Yes, Globe and Mail Guy, there is little evidence of a big problem, and a look at law suits filed between 2010 and 2015 under GINA, America’s genetic discrimination law, proves the point. But one real unanswered question remains: is the absence of institutionalized discrimination a sign that it is destined to be a bit player in the big picture of genomics, or is it only too soon to tell? Big companies, whether they are offering insurance or providing employment, may not have had an incentive to weather a PR shitstorm in order to use genetic information to limit their exposure to risk when not that many people have been tested, and the reliability of the data is debatable – which it has been in these early days. Genetic discrimination, in other words, may be making an appearance in Act II.

Two stories got some attention in 2016; whether they are one off events or signs of the future – well, that’s crystal ball territory. Are they important? They are something to which we should be paying attention. Attention should be paid.

In January, Stephanie Lee at Buzzfeed published an account of a boy named Colman Chadam who was asked to leave his Palo Alto, CA school because he carried two mutations commonly associated with cystic fibrosis, although he did not have any signs or symptoms of the disease. The results of genetic testing, inappropriately revealed by a teacher at the school, were taken, also inappropriately, as diagnostic. The reason this got him thrown out of school was to avoid contact with another student who did have CF. The emphasis on keeping children with CF apart, which sounds weird if you don’t know much about the disease, was about the only appropriate thing that happened, because individuals with CF are at risk of passing one another dangerous and life-limiting infections.

Although Colman did not have to leave the school, and the Chadam’s lawsuit against the school district has settled, the case continues to raise issues about how genotype as distinct from phenotype can be used under the law. In addition, it may signal the need for measures to protect personal privacy (no such thing, I know, I know) in an age when genetic testing is commonplace.

Three weeks later, Christina Farr wrote an article for Fast Company about a woman who was turned down for life insurance because she had a risk-conferring BRCA1 variant. Unlike the Chadam case, this is not a result of genetic illiteracy, and it is not a violation of any law: GINA does not cover insurance for life or long-term care. It is, in fact, exactly the kind of genetic discrimination that ethicists and patients thinking about genetic testing have worried about over the years, and if systemic, would certainly be an important point for genetic counselors to raise in pretest counseling (if pretest counseling is still something we do, which is an issue unto itself…but related). According to the article, genetic testing for cancer susceptibility is not required by any insurance company, although nothing stops them from doing that, but companies are starting to request to see test results when they exist. Failure to answer questions honestly can invalidate policies if you are caught.

If this becomes the status quo, it may affect uptake of genetic testing. If it is curbed through regulation, genetic testing may change the way the insurance industry operates. Act II is going to be interesting! I am having a couple of stiff drinks and heading back to my seat.

 

7. TYPE II DIABETES: RESISTANT TO INSULIN AND EASY ANSWERS

Genome wide association studies (GWAS), a way of looking at common variants in the gene pool to identify genetic susceptibility to common diseases, have been unable to explain the degree to which liability to these common diseases is inherited, although it clearly is. If you are in genetics and this is news to you, you have not been paying attention.

Many reasons for this have been proposed, and many are likely a part of the answer. One thought was that individually rare variants might be collectively common enough to play a big role in generating risk, which would not be picked up by GWAS, as it traditionally looked only at variants carried by at least 5% of the population (“the population,” as though there was only one!). Looking at rare variants takes a village, but that is what a googleplex of Type II Diabetes researchers did to produce an epic July 2016 paper in Nature.

Okay 300 authors on the paper so close enough.

The report by first author Christian Fuchsberger showed that MEGA*GWAS produced the most GWAS-y result possible: intellectually interesting, informative and ultimately inadequate. Using exome and whole genome data to capture a broader range of variation, the study found significant association to a handful of previously unknown common variants, and then failed to replicate a good chunk of what we thought we knew. Uncommon variation? The researchers found 23 loci that appeared significant, which was meaningful, but nowhere near enough to validate the rare variant hypothesis as the smoking gun in the Mystery of the Missing Heritability. “A comprehensive and extremely well written paper,” said Dan Koboldt at MassGenomics, and you can almost hear him sigh.

 

6. DATABASES: IT’S NOT JUST FOR WHITE PEOPLE ANYMORE

We don’t have enough diversity in our databases. It’s not exactly news, and yet publication of an article called “Genetic Misdiagnoses and the Potential for Health Disparities” in the August issue of the New England Journal of Medicine felt like a slap in the face.

The methodology was not complex. For hypertrophic cardiomyopathy patients, doctors use genotyping to identify individuals and family members at risk for sudden and catastrophic cardiac events. Identification as ‘at risk’ is a traumatic and often life changing event, requiring ongoing medical screening and behavioral modifications. For these families, a lot rides on whether or not a variant is considered pathogenic. One bioinformatics tool is to look at databases, because there are limits on how bad a variant can be if it shows up regularly in healthy individuals. The study checked variants labeled pathogenic against an increasing wealth of exome data available in public databases and found that a number were common in the African-American population. Result: reclassification from pathogenic to benign of multiple variants affecting primarily African-American families.

“Simulations,” said the authors, “showed that the inclusion of even small numbers of black Americans in control cohorts probably would have prevented these misclassifications.

 

5. IMMUNOTHERAPY: A NEW STAR BURNS BRIGHT AND HOT

Earlier this week, my sister-in-law was telling me about a friend with a cancer deemed treatable but not curable. “But if they get it in remission,” she said, “and he has more time, maybe there will be something new.” There it was – the cancer prayer. May There Be Something New. And I thought, has there ever been a moment when those words felt more hopeful than right now?

Hopes have been raised before, by promises that money would bring answers, and we wandered down blind alleys and into mazes waving cash as though the scent of it would draw the answers to us, but this time, progress is lighting the way like street lamps, and money follows hope instead of the other way round. Immunotherapy – engineered cells meant to light the bodies own defenses into a controlled burn that destroys cancer cells and leaves the rest untouched – has burst onto the scene since 2015. Cancer researchers report on progress in Hemingway stories, terse narratives of a few more days, an extra month or two, and that’s a win, but suddenly we are getting Gabriel Garcia-Marquez fables of magic beans and people rising from their deathbed.

So which story is more 2016: Sean Parker’s 250 million dollar cancer institute, connecting Silicon Valley money with Car-T cells that he describes as “little computers,” and presenting to the NIH in comic sans? Or the unexpected lethal immune response that shut down a Car-T trial by Juno Therapeutics in November, after four people died of cerebral edema?

It’s the two in conjunction that tell the tale. Immunotherapy is truly a candle in the wilderness, but it’s a candle that burns rocket fuel. Or perhaps I should say, in the spirit of the season: catch a falling star and put it in your pocket – bet it burns a hole in your ass.

 

4. A NEW DTC GENETICS EMERGES WITH HELIX

In October, Helix announced the first fruit of its partnership with DNA-lifestyle start-up Exploragen and it’s grapes: Vinome, a company that promises to sell you wine tailored to your genetic profile for something like fifty bucks a bottle. I’m not a wine drinker and that sounds like a lot of money but, hey, you do you.

For Helix, the Illumina spinoff that debuted in 2015, this was one of a series of 2016 announcements giving us a more concrete vision of their plans for a sequence-once-access-often platform for DTC genomics. The structure of it is like Apple, if your IPhone didn’t even pretend to be a phone, and existed entirely as a vehicle for apps. With your first purchase, Helix will underwrite the cost of sequencing and storing your entire exome, and then sell it back to you bit by bit in the guise of applications created by partners.

Effectively, the Helix model lowers the barrier of entry for any product based on DNA testing, by spreading out the cost over a myriad of marketing opportunities. Some current players in the DTC universe have signaled their interest in playing in Helix’s playground; Geno 2.0, National Geographic’s version of ancestry testing, is already available on the Helix website. Others may take their toys and stay at home. Daniel MacArthur of the Broad Institute once penned an April Fool’s Day account of a company named Helix Health’s plans for a hostile takeover of 23andMe using Somali pirates, but for real the entry of an Illumina-backed company into the DTC space must have some Mountain View observers concerned that the current industry thought leader might end up the Blockbuster Video of the genomics world.

The uncorking of Vinome raises a few questions that existing partnerships with, say, the Mayo Clinic or the Icahn School of Medicine at Mt Sinai do not. One role that Helix could potentially play is to provide the vetting service much needed in the consumer genomics world, with its mishmash of pharmacogenetics and Warrior Gene testing and supplements designed just for your DNA.

As for Vinome, the eminently quotable Jim Evans called it “silly” in an article by Rebecca Robbins in STAT. “Their motto of ‘A little science and a lot of fun’ would be more accurately put as ‘No science and a lot of fun,’” said Evans — which I guess is true, if paying fifty dollars for a bottle of wine is your idea of fun. But like Apple, Helix is going to have to make some hard decisions about how much it takes responsibility for the quality of the partners it allows to come play in its sandbox.

 

3. GENOMES OF MASS DESTRUCTION

In February, for the first time but probably not the last, the U.S. Director of National Intelligence’s assessment of worldwide threats included genome editing as a weapon of mass destruction. Congratulations, genetics: we’ve made the big time.

The report pointed to the widespread use of new genetic technologies like CRISPR in countries with different regulatory and ethical standards, its low cost and the rapid pace of change as pre-conditions that might lead to intentional or unintentional misuse, though it was vague as to what form they thought the threat might take. More specific concerns were articulated later in the year by the Pentagon’s Defense Advanced Research Projects Agency (called DARPA of course, because…government) in announcing a program called Safe Genes intended to establish a military response to of dangerous uses engineered genes. DARPA, which Scientific American reports has been a major funder of synthetic biology, will support projects that look at ways to remove engineered genes from a variety of habitats and in a variety of circumstances, including those spread through gene drive.

 

2. A BREAKTHROUGH DEFIES CONVENTION AND GEOGRAPHY

On April 6, 2016, a baby was born after the transfer of his mother’s nuclear DNA into an enucleated donor egg in an effort to avoid the mitochondrial disease that killed the couple’s two previous children. The success of mitochondrial transfer therapy itself was not a shock, since earlier experiments had demonstrated good outcomes in animal models and in in vitro human embryos. The circumstances, however, were startling: the procedure was done in Mexico, for Jordanian parents, with the help of a New York-based fertility doctor with no known expertise in mitochondrial disease.

Some have argued that mitochondrial transfer therapy represents a violation of international norms forbidding any germline genetic change, which were meant to provide a clear dividing line between somatic changes associated with gene therapy and genetic engineering with the potential to impact future generations. Pretty clear in theory, but all of these divisions are less clear in reality – there are no guarantees that gene therapy doesn’t affect eggs or sperm, and mitochondrial DNA itself challenges any simple equivalence between the molecular structure of DNA and the intellectual concept of our ‘germline’.

Mitochondrial transfer is illegal in the United States but permitted in Great Britain under a 2015 law, and applications for clinical use have been approved for 2017. Its apparent success – independent sources confirm that the baby appears to have traces of maternal mt DNA associated with Leigh syndrome but no sign of disease – is a cause for celebration for the families whose children are at risk. The step forward is a milestone, but so is the way in which it occurred, which demonstrates the extent to which geography and national laws are no match for money and access in determining what is possible.

Personal note: on my wish list for 2017, can we PLEASE stop cheapening the concept of parenthood by using the term ‘3-parent babies’? If I donated a kidney, that person would have some of my DNA, but it wouldn’t make me their momma.

 

1. WHITE SUPREMACISTS LOVE GENETICS, BUT GENETICS DOES NOT LOVE THEM BACK

Nothing about the year 2016 was more disturbing than the empowerment of the alt right, an all-purpose term for the angry souls that crept out from under rocks to preach hate and division. Here at home and all around the world, narratives of race and ancestry emerged as powerful drivers in political and social movements based on appeals to base and tribal instincts – fear mongering about immigrants, Islamaphobia, white supremacy. In October, Elspeth Reeve at Vice ran a story about white supremacists posting their 23andMe results to prove their whiteness.

This embrace of a science that does not love them back is evident even without a deep dive into the world of Stormfront and 4chan.  Twitter trolls talk about ‘founder effects’ and ‘genetic drift’. A Breitbart tech editor, now barred from twitter, writes gleefully about associations between race, behavior and intelligence, mocking disbelievers as prisoners of an “all-consuming cult of equality.”  The L.A. Times describes the alt-right as “young, web-savvy racists who are trying to intellectualize and mainstream bigotry.”   These viewpoints aren’t mainstream, but their proponents can no longer be dismissed as fringe, with Breitbart’s founder about to be ensconced in the White House as chief strategist, and reports suggesting that the presumptive next National Security Advisor Michael Flynn taking meetings with the head of an Austrian political party founded by former Nazis.

The connection between white nationalism and population genetics is proof once again that genetics as a field is uniquely susceptible to misuse by agenda-driven movements intent on the subjugation of others. Donald Trump ran against political correctness, but his rise has proven the importance of language. As Michelle Obama says, “words matter.” Push back against the misuse of genetics to fuel ‘racialist’ theory. Ancestry sites should think very hard about the manner in which they present their findings, which stress differences without acknowledging the greater than 99% of DNA that we all share. Scientists need to address and refute the ways in which their work can be misconstrued to reinforce prejudice and unsubstantiated visions of racial differences. We all have to be careful not to promote explanations of genetic effects that oversell the determinative power of genes.

Genetics is a science of the future. Let’s not let it be used to drag us back into a tribal past. Peace out, Genetics, and here’s to a better year in 2017.

 

 

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NEW PROPOSED REGULATIONS ON TESTING FROM THE FDA ARE LONG ON INTENTION AND SHORT ON DETAIL

On July 31st, the FDA announced its intention to regulate both laboratory developed tests (LDT”s) and in vitro diagnostic (IVD) companion devices, and it will soon be asking for public comment on the proposed regulations. Should genetic counselors be among the people commenting? Well yes, as the new rules are likely to affect genetics practice, since many of the tests that look at genetic susceptibility are LDT’s and could be subject to a premarket review by the FDA that will delay or deny the clinical availability of new tests, and a mandatory process of adverse result reporting. The impact will be felt most immediately in cancer settings, where genetic tests that look at tumor DNA for purposes of choosing targeted therapies or predicting prognosis are likely first candidates to draw FDA scrutiny, but eventually the new rules should affect a range of clinical specialties. At stake is finding the balance between too much regulation, wherein it becomes prohibitively difficult and expensive to introduce new tests that can help diagnose patients and personalize recommendations for screening and treatment, and too little regulation, wherein we suspect that our information on the accuracy and reliability of new tests is not adequately accurate or reliable (an ongoing issue, by the way, with non-invasive prenatal testing. See Katie Stoll’s post here and a study, new this week, suggesting that the dreaded false positive result may be more common than test makers have led us to believe).

 

A little background on the two closely related entities that are the focus of new regulations. LDT’s are what used to be called “home-brews”: tests that are used by a single lab and not marketed as a kit or a device. Somewhat by historical accident, LDT’s have come to exist in a regulatory grey area, effectively exempt from FDA oversight. The assumption behind this was that what went on in an individual lab affected only that lab’s patients and that no agency could track every one-off solution engineered by a mom-and-pop lab. As with everything else in 2014, the status quo has been disrupted by new technology – but in this instance the new technology isn’t the magic of Google or whole genome sequencing but overnight shipping. Yes, the world of genetic testing has been turned on its ear by the likes of UPS and Fed Ex.

 

In brief, now that the Pony Express has picked up its game, laboratories can test samples from all over the world in centralized locations with sophisticated and expensive testing capability that isn’t available back on the farm. At the same time, lab tests, including genetic tests and biomarkers like measures of gene expression, play an increasingly important role in making diagnoses and determining treatment. For this reason, the FDA has moved in its determined yet glacial manner to regulate a subset of tests that are considered high or medium risk – those tests which have the potential to alter medical care, and therefore have significant implications if the information they provide is incorrect. This risk-based approach is a measured step – it allows the FDA to continue to use discretion when tests are low risk or experimental or involve a rare disease for which there is no other test.

 

IVD companion diagnostics are tests developed to be used in conjunction with a drug or other therapy – tests that can be used to refine dosages or identify good candidates for a given therapy. Obviously pharmacogenetics is a subset of this broader category of companion testing. Again, the proposed regulatory framework would stratify the tests as high risk, moderate risk, low risk – requiring pre-market approval for higher risk tests, and allowing the agency to exercise “discretion” in low risk situations (discretion is FDA-speak for a wink and a nod). With regard to IVD diagnostics, the FDA intends not just that the tests on offer be confirmed as reliable, but is instituting the requirement that companion testing be included in the development of new therapies as a matter of course. In effect the government is mandating that all new therapies be individualized to the greatest extent possible: When an appropriate scientific rationale supports such an approach, FDA encourages the joint development of therapeutic products and diagnostic devices that are essential for the safe and effective use of those therapeutic products.” The age of personalized medicine is upon us, and the FDA is ON IT.

 

If all this sounds familiar, it only means that you have been paying attention. Since 2010, the FDA has been asserting publically that it has both the intention and the authority to regulate LDT’s and IVD’s. Going back even further, the Genomics and Personalized Medicine Act of 2006, introduced by then Senator Barack Obama, emphasized the development of companion diagnostics, calling on the National Academy of Sciences to recommend incentives and requiring the Institute of Medicine to improve “oversight and regulation of genetic tests.” While the bill was never passed, it is not surprising to see a similar emphasis under the current administration.

 

So, genetic counselors, are we for or against the proposed regulations? Probably the answer to that question is — yes. Like the FDA, most people seem to be in favor of some middle option – regulating everything is virtually impossible and regulating nothing is an appealing libertarian fantasy, but in fact it would put counselors in the uncomfortable position of having to rely on figures supplied by the companies who manufacture the tests. Careful observers like the Genetics and Public Policy Center have been calling for increased oversight for genetic testing for years. Their 2006 summary of a genetic testing quality initiative sums it up this way:

 

assessment of public attitudes shows that the public widely believes that the government regulates genetic tests to ensure their quality and, moreover, that the government should play this role. In fact, however, genetic tests are subject to very little governmental oversight when compared to other health care products. There is no formal approval procedure a laboratory has to go through before offering a new genetic test, and government requirements to ensure that genetic testing laboratories are getting the right answers to patients are minimal. Moreover, there is no government requirement that a test must be clinically valid – i.e., actually relate to a particular disease or risk of disease – in order to be sold.”

 

However, both the American Clinical Laboratory Association and the American Medical Association have reacted negatively to the proposed FDA regulatory strategy. The ACLA pushback comes as no surprise – few entities welcome idea of FDA regulation – and the organization has submitted a petition claiming that only CLIA and not the FDA had authority over LDT’s (the FDA rejects this). The more measured response of the AMA reflects the concerns of clinical care-givers, and may align with the attitude of many genetic counselors:

 

The draft FDA Framework for Oversight of Laboratory Developed Tests (LDTs) announced today, outlines a risk-based approach that raises a number of questions and concerns. 

The FDA proposal adds an additional layer of regulatory requirements which may result in patients losing access to timely life-saving diagnostic services and hinder advancements in the practice of medicine. 

The AMA is committed to ensuring that the proposal that is ultimately adopted by the FDA preserves rapid access to care and medical advancements. 

What makes it difficult to respond to the FDA is that there is a lot of wiggle room left in the regulations as written. High and moderate risk tests will be required to report adverse results and apply for pre-market review according to separate timetables – but the FDA will not define those terms for up to 2 years after the regulations are finalized (Policy and Medicine has a useful chart if you are looking for specifics on timelines). In other words, the FDA has designed a system that gives them room to maneuver – and is asking for respondents to give feedback on the plan without knowing where the agency plans to draw the line. For example, breast cancer susceptibility panels probably aren’t low risk; they are medically actionable and complicated to interpret. Are they high risk or moderate risk? The somewhat hyperbolic letter from the FDA to 23andMe last fall* suggested that the agency believes the fallout from breast cancer risk prediction done badly might be unnecessary mastectomies. That sounds pretty high risk – but is that the perceived reality of counselors who work with these tests?

 

The rare disease exemption in the FDA plan means that whole exome or whole genome sequencing would not be affected, in those cases where the patient presents with an apparently genetic condition that has eluded diagnosis. WES for those with no apparent disease, who wish to use the information prophylactically? I have literally no idea what risk the FDA would assign to clinical versions of genome scanning. What about the genetic testing done for children with autism? These supplement rather than point to a diagnosis and would rarely change treatment but may have a big impact on the parents reproductive choices – is that consequence enough to bump a test from low risk to high risk?

 

I might sound like I am criticizing the FDA, but in fact I am sympathetic to the difficulties inherent in a modulated approach and appreciate that they are attempting to tread that knife’s edge. I do think it makes it difficult to provide feedback, and I would suggest that their policy be reopened for public comment at critical junctures, such as the point at which high, low and moderate risk categories are more carefully defined. Useful commentary now, I would suggest, will need to be far more granular than the FDA regulatory language itself. What tests do you feel work well for you and your patients? Are there tests in use or in the pipeline that concern you? Which ones? Why? Share your concerns here, and I will write up a response incorporating reader response when the draft regulations are posted for public comment.

 

*Note: don’t bother telling the FDA that you are concerned about direct-to-consumer testing, because the agency has already noted that this applies only to testing in a clinical context. No DTC testing will be exempt from review – a footnote to the FDA’s announcement that had DTC advocates screaming foul – for details see Jennifer Wagner’s irritated response at the Genomics Law Report.

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It’s A Slippery Slope. Get Over It.

This week, the FDA is holding hearings to examine the use of a new IVF technique that could allow women with mitochondrial disease to have children who are genetically their own without the risk of passing along the condition.  The proposed treatment involves yanking out the nucleus of a donor egg and popping in a nucleus from the mom-to-be.  Studies of monkeys have demonstrated that this method can be used to produce healthy monkeys; studies of humans thus far have demonstrated the potential to create what appear to be viable embryos.  Shoukhrat Mitalipov, the Oregon-based researcher who has done both human and animal studies, is interested in moving to clinical trials – or as Dina Fine Maron puts it in Scientific American, “human clinical trials.”

 

The issue of oocyte modification was debated last year in the UK, where the government has opted to allow nuclear transfer to be used on an experimental basis.  The story got major play in the press there, as it has here, with catnip headlines about ‘3-parent babies.’  There are some serious questions to be answered about the risks – the first studies using human eggs showed an increased rate of abnormal fertilization, although zygotes with an appropriate number of pronucleii seemed to develop normally.  Minimizing the risk of harm to any child born of this technique is an important focus of the regulatory agencies and if we can’t do it safely, we shouldn’t do it at all – which brings me to the other question under debate: should we do it at all?

 

Marcy Darnovsky of the Center for Genetics and Society, a non-profit organization that leans precautionary on the use of reproductive technologies, has been waging a one-woman war against nuclear genome transfer, protesting the UK decision in Nature, circulating a petition to the FDA to decry human germline modification and penning an OpEd for the N.Y. Times entitled “Genetically Modified Babies.”  Darnovsky brings up safety issues but the heart of her objection is the slippery slope argument.  We have informally agreed not to make changes in the germline that will be passed down to subsequent generations – not to tinker with eggs and sperm.  This is a step over that line.  If we do this, what else will we do?  It could, she says, “open the door to further germline manipulations.”

 

Last winter, I attended a panel on the ethics of germline manipulation where participants debated a resolution to prohibit genetically engineered babies.  Lee Silver (Princeton) and Nina Farahany (Duke Law) represented the anti position (i.e., let’s NOT prohibit genetically engineered babies) and won the debate by focusing on – wait for it — nuclear transfer for mitochondrial disease!  Forbid genetic engineering, they argued, and you rule out this potentially game-changing therapy for afflicted families hoping to give their kids a life free from the burden of life-long, incurable disease.  In other words, another slippery slope argument, only the other way round – accept the concept of regulation in any form, let the bureaucrats in, and you cut yourself off from progress and doom families forever to suffering that could have been prevented.

 

The thing is, I am not at all convinced this example – like many other models we construct — represents anything other than itself.  I don’t mean to say it’s trivial.  But mitochondrial replacement therapy isn’t a reasonable stand-in for the complex issues associated with genetic engineering, like trait selection or eugenics.  You can make the case that mitochondria are more like the bacteria we harbor in our gut than they are like nuclear DNA , in terms of how they affect our health and well being.  Gut bacteria have DNA too.  If we gave the 3-parent child a fecal transplant, would we have a 4-parent child?  (Is that a bad thing?  Cool or creepy?) 

 

The problem with slippery slope arguments is that they don’t relieve the obligation to assess each and every situation on its own merits.  They don’t provide some easy moral clarity or regulatory guidelines.  Everything exists on some sort of continuum, whereby you can draw a straight line from the ludicrous to the patently unacceptable.  When does life begin?  It’s a tightrope, with one end tied around infanticide, and the other clasped in the hand of some guy out of a Monty Python sketch singing “every sperm is sacred.”  Every decision we make is about drawing a line.  And every ethical quandary worthy of the name is unique enough that it deserves its own weighing of the pros and cons.

 

Are you concerned about doing PGD for later-onset conditions?  This is a line some people have suggested, between what is a good and a bad use of preimplantation technology.  What if that condition is Huntington’s?  Okay, what if it is a BRCA 1 mutation?  Or what if it is a subtly increased risk of Parkinson’s disease?  Each of these is a very different scenario.  Every family is going to experience those risks differently.  The fact that you can draw a line from here to there does not automatically absolve you of considering the facts at hand in each case, the good that can be done, what stands to be gained, what may be lost.  It’s very hard to take away happiness for one person based on what might (someday, somewhere, possibly, in a related case) happen to somebody else. 

 

The thing is, it would be so much easier if we could find that certainty.  Slippery slope arguments are a plea to make things stand still for a moment, so a person can get their bearings.  Anyone who works in genetics can relate to that sentiment.  But history is itself a slippery slope from a turbulent past to an uncertain future, and we don’t have the luxury of stepping off.  So what should we do about nuclear transfer for mitochondrial disease?  Well, let’s make a decision based on mitochondrial disease and the very sensitive nature of the human embryo, which may not take kindly to this manipulation.  Let’s not make it the last word on anything.  Let’s not pretend we are now for all time choosing to abandon sufferers to their fate, or opting for GATTACCA.  It’s hard enough and scary enough without conjuring up the ghosts of battles to come.

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THE FDA CALLS A PENALTY ON 23andMe

IS THIS THE GAME WE WANT TO PLAY?

On Monday, the FDA celebrated the start of the holiday season by sending a letter to 23andMe, informing the direct-to-consumer personal genomics service that they must cease and desist offering their signature test.  The proximal cause of this action, as described by the FDA and not disputed by the company, was that 23andMe had ceased to participate in a process of establishing their PGx test as “validated for its intended uses.”  They had, the FDA suggested, dropped the ball – well, not just dropped the ball, but kicked it out of bounds, an old soccer trick for delay of game, which Mya Thomae and Dylan Reinhardt suggest might have been exactly what the company had in mind, playing for time while they attempted to accumulate better data than what-all they have right now.

The FDA move prompted a vast twitterlanche of commentary, ranging from indignant outrage to smug satisfaction (Dietrich Stephan, founder of the erstwhile DTC competitor Navigenics, said, “Engaging the FDA as a partner to bring the most robust and safe new type of test to market is diagnostics 101”).  Genetic counselors might be suspected of indulging in a bit of schadenfreude, since the relationship between 23andMe and the GC community has inclined in the direction of mutually suspicious, if not downright frosty.   The company, which advocates for access to one’s DNA information with almost a religious fervor, sees GC’s as gatekeepers, as a self-anointed coterie of priestesses guarding the oracle at Delphi.  Genetic counselors, for their part, tend to perceive the very existence of 23andMe as an affront, as though the possibility that a subset of people might benefit from genetic testing without access to counseling was insult and injury — an existential threat.

To be fair, nobody reacts well to the suggestion that their chosen profession is a cabal that threatens the freedom and well-being of fellow citizens – not even investment bankers, and at least they get to soothe their wounded souls with lots of material goods.  But pettiness is unbecoming and unproductive, and we would all do well to remember that a groundbreaking organization like 23andme is a part of the energy and excitement of the field – an expression of an explorer’s mentality that draws people to the potential of genetics in 2013.  That’s not only fun and sort of cool but also incredibly powerful because it attracts the kind of intelligence and curiosity that makes big new ideas possible (David Dobbs does a thoughtful and balanced job making the case for 23andMe in this piece for the New Yorker).

So minus any animus toward 23andMe, was this a reasonable move by the FDA?  There are two main questions that have been raised: 1. can they regulate? and 2. should they regulate? (a third question, HOW DARE THEY?, has also gotten a lot of play but I am going to ignore that one because, c’mon guys get over yourselves this isn’t ONE STEP FROM TOTALITARIANISM).  The first one takes up the issue of whether or not a personal genomics test falls under the FDA jurisdiction.  I am going to say yes, but will not rehash those arguments here, since they have been more ably covered elsewhere – I particularly recommend this piece by Hank Greely at the Stanford Law School Center for Law and the Biosciences blog.

So, should they regulate?  The rationale for regulatory action in the letter to 23andMe is a risk of harm to customers, including the possibility that a customer might alter his medication without medical advice or misunderstand her risk for breast cancer and have an unnecessary prophylactic mastectomy.  While theoretically true, it seems wildly unlikely that very many people would insist on a mastectomy without getting more information than mail-order genetic results – and those cases might be more indicative of out-of-control anxiety issues and irresponsible medical practice than the power of a PGx report.  More commonly, misunderstanding the limits of the test in terms of risk reduction might empower a customer to skip out on appropriate preventative measures. Either way, this is nothing new — a rehash of concerns genetic counselors have had about DTC testing since its inception.  In practice, perhaps the best summary of the clinical impact to date comes from Anders Nordgren, who called it “Neither as harmful as feared by critics nor as empowering as promised by providers.”  Having spent hours poking through the generally well-written and thorough 23andMe reports, and spoken to some of their customers, I would suggest that misunderstanding the results that come from 23andMe could pose some risk — real risk, to be sure, but limited risk.

However, it is possible to envision a scenario where a genetic testing sold DTC did pose a significant danger to consumers, with inaccurate results, irresponsible advice, tests used to market scam treatments or preventatives.  None of this is farfetched, and some of it has already been documented.  For this reason alone, the possibility of FDA action is an important deterrent.  A company like 23andMe, which makes real efforts to be thoughtful and responsible, will ultimately benefit from the restraint on less scrupulous entities.  And of course, it is possible that 23andMe would have been less thoughtful and less responsible if they had not been motivated by the threat of FDA action.  So arguments against regulation in general based on the fact that 23andMe is well-intentioned are misguided.

But despite a bias in favor of showing some muscle, I have questions about how much time and energy the FDA should spend cracking down on the likes of 23andMe.  Is it, I wonder, the best use of resources?  For one thing, attempts to stop the free flow of information in 2013 are fingers in the dike. Razib Khan at Slate expands on this argument, suggesting that companies pushed by the FDA could simply move offshore, away from any regulation.

And more importantly from my point of view, the emphasis on negative action diverts us from the possibility of doing something positive.  Rather than keeping consumers away from tests we think are insufficiently documented, how about providing a resource to the general public that endorses tests that are ready for prime time?  After all, a few bold individuals may be excited at the prospect of downloading Promethease to query their own exome data but most people would rather not, thank you very much.  Most people would be happy to have some guidance.  They can get that guidance from the company, but even the classy companies have a vested interest in hyping the significance of their results – that’s what they’re selling, right?  There is an opportunity here for the government and the genetics community to create a trusted source of information that is neutral, unbiased and supports a best-case scenario use of genetic testing by those eager to take the plunge.  Hell, you could imagine tying in such a resource to something like ClinVar or GenVar, so that early adapters could contribute to publically accessible databases rather than giving it to 23andMe to sell.

After years of running up and down the pitch, the FDA has demonstrated that it knows how to blow the whistle – that’s good.  I’m pretty sure 23andMe will be back – and that’s good too.  But if we really want something great to come out of this discussion, let’s stop doing color commentary on the FDA action, and imagine what it could be like if we changed the game.

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FDA Letter to 23andMe: A Genetic Counselor’s Breakdown

FDA letter Nov 22

On Friday, November 22 Food and Drug Administration issued a warning letter to direct-to-consumer genetic testing company 23andMe. Many in the genetics community are experiencing a little déjà-vu this week, with the ensuing discussions in mainstream media and within online communities reminiscent of 2010 when FDA issued warning letters to 5 direct-to-consumer companies that were operating at that time. (Check out this post from Genomics Law Report for a good overview of the issue at that point in time.)

Regulation of direct-to-consumer genetic testing companies is complex and often confounded by thoughts and opinions regarding DTC advertising, DTC genetic testing, the validity and clinical utility of SNP-based panels, consumer rights and privacy, to name a few. I have personally fallen into a rabbit hole of articles, blog posts and twitter discussions in the past few days (see “Recommended Reading” section below). All of these outlets are debating the same issue, but this particular issue has an infinite number of very subtle angles.

The term “direct-to-consumer” conjures up strong emotions for genetic counselors. No doubt you will see some of this played out on The DNA Exchange in the next few days. However, in discussing the most recent FDA letter with a number of people (both colleagues and non-GCs) I’ve realized some basic review and clarification might be helpful. Hopefully this will serve as a nice starting point to frame our discussions on this issue in the days to come.

The full letter can be found on the FDA website here.

The 23andMe response has been posted here.

There are two basic aspects to the FDA  letter:

1. Marketing 

In the FDA’s words “…Your company’s website markets [your test] for providing “health reports on 254 diseases and conditions,” including categories such as “carrier status,” “health risks,” and “drug response,” and specifically as a “first step in prevention” that enables users to “take steps toward mitigating serious diseases” such as diabetes, coronary heart disease, and breast cancer….To date, 23andMe has failed to provide adequate information to support a determination that [your test] is substantially equivalent to a legally marketed predicate for any of the uses for which you are marketing it…”

My takeaway:  23andMe’s marketing materials claim their test can prevent serious diseases. The company does not have FDA clearance nor has it provided the appropriate evidence to make this blanket claim. This speaks most strongly to the clinical validity and utility of SNP-based testing—an issue that hits close to home for a lot of us. I think it is important that the FDA is highlighting the lack of evidence around prevention and predisposition testing for common disease.  However, we need to recognize that 23andMe is also testing for additional variants beyond SNPs.

Anecdotally, I’ve noticed that genetic counselors continue to use the terms “direct-to-consumer genetic testing” and “SNP-based testing” interchangeably, which is both incorrect and adds to overall confusion. Genetic testing for common complex disease (primarily based on SNP information) is still controversial in our profession. However, as noted in the letter, 23andMe is a direct-to-consumer company that is also providing carrier testing for Mendelian diseases as well as the 3 common Ashkenazi Jewish BRCA mutations. To dismiss the 23andMe service by saying “this test doesn’t tell you anything!” undermines some of the routine testing that we do within a clinical setting. One cannot argue that 23andMe’s service “doesn’t tell you anything” and “has the potential for serious harm” in the same breath.

2. Direct-to-consumer health information

In the FDA’s words: “Some of the uses for which [personal genome service] is intended are particularly concerning… For instance, if the BRCA-related risk assessment for breast or ovarian cancer reports a false positive, it could lead a patient to undergo prophylactic surgery, chemoprevention, intensive screening, or other morbidity-inducing actions, while a false negative could result in a failure to recognize an actual risk that may exist.”

 My takeaway: 23andMe is providing health information and test results directly to consumers without the involvement of a physician. This could lead to medical mismanagement, “serious injury or death.” I believe the DTC aspect of the testing (in comparison with the SNP-based aspect) is still the biggest challenge to the 23andMe model. Genetic testing for disease causing mutations without appropriate clinical context, family history review and individualized interpretation is where real potential for harm lies.

Suggested Reading (Or, some of the more interesting articles I have come across so far)

Also, if you’re interested in learning more about FDA regulation of medical devices, I found this video on their website.

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FDA Public Meeting on DTC Testing

March 8-9, 2011

As you may know, this week the FDA is hosting a 2-day public meeting about DTC testing, in an effort to develop some guidelines around regulation. It turns out that a handful of dedicated bloggers (namely Dan Vorhaus of Genomics Law Report) are in attendance and are invested in sharing every detail of the proceedings with the online community via Twitter.

Even if you don’t have a twitter account and/or if you tend to avoid this social media tool like the plague, there has never been a better time to test it out and learn how incredibly useful and informative it can be. For a complete play-by-play of what happened today and for real-time updates on tomorrow’s proceedings click on this link and voila!– it will be like you are sitting right there: #FDADTC

Are there any GCs in attendance at this meeting? If so, would love to hear your thoughts. When I have a chance to digest some of this myself I’ll try and share a summary and short post here, but for now you can find a quick  summary the first day on Daniel MacArthur’s blog, Genetic Future.

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