Category Archives: Katie Stoll

Last week, the U.S. Food and Drug Administration announced approval of Voxzogo (vosoritide), a drug developed by BioMarin for the purpose of increasing growth in children with achondroplasia. The drug is approved for children five years of age and older who have achondroplasia and open epiphyses, and is administered by daily injection. Voxzogo was approved by the European Commission (EC) in August of this year and marketing authorization reviews are currently in process in Japan, Brazil, and Australia.

This drug was developed specifically to target the effects of the FGFR3 mutation that causes the fibroblast growth factor receptor 3 to be overly active in people with achondroplasia, which prevents normal bone growth. The FDA cited this trial as the reason for the approval: a year-long, double-blind randomized trial (RTC) that showed an increase in growth (a mean of 1.57cm per year) in participants who received the drug. While some suggest that other health complications may be ameliorated by the use of vosoritide, that is purely speculation at this point. The FDA approval was based on the trial’s primary endpoint, “change from baseline of annualized growth velocity.”

The study reports:

“This study is limited in that direct evaluation of the effect of vosoritide treatment on final adult height and how this relates to functionality, quality of life, and activities of daily living in people with achondroplasia cannot be evaluated at this time. In addition, whether treatment with vosoritide will ameliorate the medical complications associated with achondroplasia and decrease the need for surgical interventions is unknown.”

Vosoritide was given the Priority Review designation by the FDA meaning that the review will be completed within 6 months. According to the FDA website, the priority review designation exists to “direct overall attention and resources to the evaluation of applications for drugs that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications.”

While a spokesperson from the FDA proclaims that this approval “fulfills an unmet medical need for more than 10,000 children in the United States”, this drug is controversial among people living with achondroplasia and other types of dwarfism. Many believe that the approval of this drug based on the ability to only increase growth is centered on corporate interests to bring a high-cost commercial drug to market without evidence that health outcomes are improved and that this approval represents deep prejudice against people of short stature. 

Vosoritide was approved under the Accelerated Approval Program, which arose from the 21st Century Cures Act, signed into law in 2016. This accelerated approval program lowers the bar for what evidence is required for FDA to approve drugs that treat serious conditions, and that fill an unmet medical need based on a surrogate endpoint. Proponents of this accelerated program say that it will help bring important treatments to patients faster. Many have expressed concern though, that these speedy approvals are putting patients at greater risk of harm given that the long term safety of these drugs is not known. With the accelerated approval process, the FDA can require additional post-approval studies. In the case of vosoritide, the approval is conditional on post-marketing study that will assess final adult height. This means that the primary justification for the drugs approval has always been increased height (not reduction in health concerns associated with achondroplasia) and that BioMarin will be able to profit off the sale of vosoritide for many years before we are certain that the drug actually increases final adult height.  

An important question up for debate here is whether a drug’s ability to increase the height of people with achondroplasia by 6-8 inches is meeting an unmet medical need. Considering the potential health effects secondary to the bone growth changes in achondroplasia such as sleep apnea and spinal compression, we won’t likely have the answer to that for some time.

Is short stature in and of itself a “serious condition” or “unmet medical need”? Maybe the answer to that question depends on whether you are viewing it through a medical model of disability lens or a social model. The medical model would hold that the condition of the person causes disability and that medicine should aim to “fix” the condition of the person. The social model would hold that it is systemic barriers in society and discriminatory views that cause disability – it is the condition of our society that needs fixing.

There is reasonable concern that the FDA’s enthusiastic support to celebrate the approval of this expensive drug to increase height can only further support discriminatory views that medical providers have had towards people with disabilities by validating that short stature in and of itself is a medical problem that needs a cure. 

The CEO of BioMarin, Jean-Jacques Bienaimé, seems to have a medical model perspective on achondroplasia judging by this quote: “It’s the difference between being able to drive a car or not, reaching stuff in closets, being able to take care of your hygiene. It would make a huge difference for those patients. There’s no question about it.”  

Daily injection of this drug is not necessary to allow people with achondroplasia to drive a car, reach the items they need, or take care of their own hygiene. Of course people with achondroplasia perform these activities all the time with assistive devices and inclusive design. This statement from BioMarin’s CEO may represent ignorance about the capabilities of someone with achondroplasia or, perhaps more likely, may be a misrepresentation to hype the importance of vosoritide.  

The stakes are high for BioMarin here. The drug is priced at $320,000 per year for the treatment, and the stock value surged with news of the FDA approval of what is being called the company’s new blockbuster product. FDA approval is linked to insurance coverage for drugs. Medicaid and Medicaid have very limited ability to decline drug coverage for FDA-approved drugs. Private insurers also must cover FDA approved drugs, although there may be more financial burden put on patients with cost-sharing arrangements. 

I have been thinking a lot about this FDA approval and the bigger system we are now in with so much interest (and money) in drug development for rare disease. There is a lot to be hopeful about for people living with rare conditions, but pervasive discriminatory views against disability in combination with massive corporate interest to rush therapeutics to market is of great concern. 

The use of vosoritide and similar drugs is likely to expand in the years to come. Studies are currently underway looking at vosoritide use in infants, and also the use of vosoritide for children with other genetic conditions that cause short stature. I would imagine fetal therapy trials may not be long in the future. The increase in therapeutics for genetic conditions will of course also fuel the diagnostic industry. I predict that as the approval of vosoritide therapies expands to younger ages, genetic testing companies will use this as a selling point for testing. Companies such as Natera and Baylor Genetics have been promoting a prenatal cfDNA test that screens for achondroplasia and other single gene conditions, and the companies have been trying to make the case that this test could result in better outcomes for families by learning about a diagnosis earlier. Having a treatment that could be started in infancy or even earlier could help make this case. 

When news of this FDA approval broke, I first learned about it on this twitter thread by Dr. Joseph Stromondo, professor of Bioethics and Disability Studies at San Diego State University. In it he says, “Did anyone ever doubt this outcome, though? There is never a moment any of us leaves our house that we aren’t greeted with ridicule and hostility. Our bodies are regarded as public spectacle just for existing in the world. How could this outcome be any different? Of course someone would find a way to profit off of these stigmas and the fears they produce in average height parents. This was inevitable. I think the more critical questions surround our response to the drug, as a community of dwarf adults and allies. What do we do now?” He concludes, “we need to find new ways to live with dwarf pride and help families see what is possible for their LP [Little People] kids. We need to come together and focus on creating a space that celebrates our lives and bodies in an otherwise hostile world.”

The development of the drug, and now the FDA approval of vosoritide has been controversial among people with achondroplasia. While some see the development of these drugs as an attack on their very existence, others are celebrating the approval with hope of the possibility of health benefits that result from use of the drug. 

Little People of America (LPA), a nonprofit support organization for people with dwarfism and their families, seems to be trying to navigate the differing viewpoints on drug development. From this FAQ on LPA and Pharmaceutical Company Engagement they state, “We have long celebrated dwarfism as a valuable contribution to human diversity. LPA also values diversity within our own community and respects the choices of its members regarding medical intervention. While LPA has never actively promoted medical research aimed at treating or curing dwarfism, LPA is not opposed to medical research if it holds the potential to improve quality of life by treating symptoms that can range from uncomfortable to lethal.” More recently in a position statement on the FDA approval of vosoritide, the LPA states that “they strongly believe that a focus on growth velocity is a search for a pharmaceutical solution for a societal problem. We want to reframe priorities in research to the most meaningful ones for our members, such as reducing spinal stenosis, sleep apnea, and the need for corrective surgeries, as well as supporting other improvements in quality of life.”

The availability of vosoritide will present parents with a decision that will be difficult for many. How do you make a choice about treatment when the potential for health benefit and the possibility of risk are impossible to quantify? While people who themselves have achondroplasia have differing views on vosoritide, it is fair to say that people with lived experience will likely have more background information from which to draw on to make a decision about whether to consent to treatment for their children with achondroplasia. While I can imagine there will be enormous pressure towards use of the treatment by healthcare providers, with most babies with achondroplasia being born to parents of typical stature, they may not even be presented with the consideration that declining the treatment as a reasonable option.

Pharmaceutical companies that profit from drug sales (and also those companies that make the tests that diagnose the conditions) have an interest in selling their products. That is the role of a company, and their primary duty is to their shareholders: to profit on products they produce. These priorities are not unexpected, and the current regulatory framework encourages it. It is expected that the information coming from BioMarin and their partners (who will also profit from this endeavor) will highlight the positive, hopeful aspects of the drug and downplay the uncertainty and potential risks. We can expect to see mass marketing of this drug that promises hope of more healthy futures for people with achondroplasia, even though we don’t yet have proof that this is the case. BioMarin projects $1 billion per year at its commercial peak in sales from vosoritide. Their chief commercial officer, Jeff Ajer recently stated that the company has teams “in place and well-prepared for what could be BioMarin’s largest brand yet.” It is likely that the perspectives and voices of those with concerns about vosoritide will be drowned out by the mountains of money that will be used to promote these drugs. 

As genetic counselors we are often the ones who will be sharing information about what life with a genetic condition could look like for a family who is hearing of a diagnosis for the first time. As new medications targeting genetic conditions are developed, we will be at the forefront of supporting our patients in navigating information about new treatments. With this privilege, we also have a tremendous responsibility. It is crucial that we are clear and honest about the limitations and unknowns. I hope all of us will take great care in evaluating the complexities of new and emerging treatments. I hope we will critically evaluate the sources of the information we are sharing with our patients. I hope we will listen to the critiques and concerns from people with lived experiences with the conditions that we are counseling our patients about. We will better serve all of our patients when we are prepared for discussions about the ethical debates surrounding treatment and people with disabilities as a historically marginalized population. 

As we consider the growing options families will have to face when considering whether or not to treat their children with new pharmaceuticals, for which the long term outcomes are still unknown, I hope that we will check our own biases and do our best to provide a nuanced assessment of the options and the concerns. And in balancing the messaging that may be coming from the big money that drives so much of this, I hope we will also seek out and share perspectives from people whose voices may be harder to hear amongst the hype.

While the world grapples with a global pandemic with enormous cost of lives and livelihoods, some companies are finding an opportunity to make a quick buck from this crisis. One such company is the direct-to-consumer genetic testing company, Orig3n, Inc. DNA Exchange readers may recall that I wrote about Orig3n a couple of years ago when I sent a swab from my dog and tap water from the kitchen sink to Orig3n for their Child Development DNA test. In both cases, Orig3n issued test reports, failing to recognize that they were not human specimens. Given this experience as well as issues raised by numerous others, I was deeply troubled when I learned that the FDA had granted Orig3n accelerated authorization for a nasal swab based RT-PCR Covid-19 test. And unfortunately, I wasn’t surprised when news broke that Orig3n is failing in their Covid-19 testing. 

Last Friday it was reported that Orig3n miscalled several hundred Covid-19 tests for residents and staff at multiple long term care facilities throughout Massachusetts. Upon retesting by Orig3n and by the Broad Institute, 383 tests have been determined to be false positive. Previously, the Massachusetts Department of Public Health (DPH) specifically recommended Orig3n to long term care facilities and has required rigorous and widespread testing for staff and residents in order to qualify for a Covid relief funding. As of August 8th, the Massachusetts DPH has halted Orig3n from performing Covid testing citing the laboratory director’s failure in providing management and the lack of quality control measures in testing. According to Robin Smith, CEO of Orig3n, “We’re currently working with the state of MA to finalize steps that will enable us to resume testing in our Boston lab,” in a statement to the Boston Globe.

Orig3n did not only perform testing for long term care facilities in MA. They have also been lauded by public health officials for providing tests to unhoused people in the greater Boston area and have been contracted by State public health systems, schools, and long-term care facilities throughout the country. Orig3n’s Chief Executive Officer reports that the lab has processed tens of thousands of Covid-19 tests over the past 90 days. This news out of Massachusetts  may be just the beginning of the test failure story. Keep an eye on North Carolina where the state department of Health and Human Services contracted with Orig3n to provide Covid testing, setting up more than 300 test sites to increase testing access for African American, LatinX/Hispanic and American Indian communities. In early August there were reports of a Covid surge in NC. A few days after the uptick in Covid cases was reported there, there was a news report that test results sent to Orig3n would be delayed due to “unforeseen circumstances” and that the State lab would now be performing these tests.

The fact that Orig3n has become a major provider of Covid-19 tests despite numerous prior concerns is a massive public health failure. While we desperately need access to testing, it is imperative that this testing is reliable and from a trusted source. There were significant limitations and gaps in regulation of laboratory testing prior to Covid, and the hopes that oversight of laboratory tests would improve have been dampened by a recent decision from the current administration and the United States department of Health and Human Services that premarket review by the Food and Drug Administration (FDA) for laboratory developed tests will no longer be required. 

In 2018, after Orig3n released a test report for my dog and water from my kitchen sink for the Child Development genetic test, I filed official complaints about Orig3n with both the FDA and with the Centers for Medicare & Medicaid Services (CMS) – Clinical Laboratory Improvement Amendments (CLIA) Region 1. In these letters I outlined concerns related to the laboratory’s technical proficiency and professional oversight, the lack of clarity of how Orig3n would store and use collected biological samples, and the bioethical issues related to direct-to-consumer genetic testing marketed for children. I received responses from both agencies. From the FDA ,“We take such reports seriously, and we will evaluate this matter to determine what follow-up action is appropriate. The type and extent of any follow-up is dependent upon the nature of the problem, the possible impact on the public health, and the availability of our resources.”  And I was assured through multiple correspondence that the Massachusetts Department of Health and CLIA-Region 1 were investigating my concerns. It should be noted that I have not been alone in reporting concerns about this lab – for an excellent summary of the pre-Covid concerns, see this Businessweek article.

How is it possible that despite the many public concerns raised, Orig3n could be fast-tracked by the FDA and recommended by the MA DPH as a vendor for testing so important as Covid-19 – the same agencies that have been investigating these issues? Certainly, questions of false results should have risen to the surface as possibly “impacting public health” when the FDA was considering authorization for Covid-19 testing, right? I can only assume that in the end, FDA and CMS just did not have adequate available resources or the authority to fully investigate and consider this and other concerns raised over the years.

Orig3n has had a troubled history, but I fear that this lab’s story is just the tip of the iceberg, especially as there are really no barriers to entering the Covid-19 testing market short of being a CLIA certified laboratory (and sadly, that seems to be a pretty low bar). Today there is a long and growing list of commercial labs throwing their hats in the Covid testing arena. Many of these once focused solely on direct to consumer testing are now pivoting their focus to on the more lucrative Covid-19 testing. I am sure genetic counselors out there recognize some of the names on this list of tests who have received Emergency use Authorization by the FDA Covid-19 testing. Although all of these labs have been granted authorization, I am certain the quality of the testing among these labs is not equal. From my discussions with friends and family who have gone through Covid-19 testing, it seems that the lab that is performing a Covid-19 test is not usually made transparent to the patient. When you put your trust in your healthcare provider, school system, long-term care facility, employer, or public health officials – you may never know what lab is performing the test.

False positive and false negative tests are a possibility with any screening test. While the issue that came to light with Orig3n was false positive tests, false negative tests are also a problem with testing for Covid-19 and issues with false negative tests are probably more difficult to recognize by laboratories and public health officials given that most tests are negative. (Side note: this story highlighted a horrible situation of two women’s real health concerns being dismissed by the medical system because of false negative tests). The algorithm published by many labs is that if your test is positive, it should be treated as positive regardless of whether or not you have symptoms. But if your test is negative and you have symptoms, you should seek a second test. But is there any way you can make sure your test goes to a trustworthy lab? As a patient, is there anyway to even know for certain, what lab is performing your test?

While we are in desperate need of testing for Covid-19, we need to ensure that the available testing is reliable. Public trust in our health system and in science itself is already incredibly fragile and fast-tracking any lab that wants to get into the Covid-19 testing business will do more harm than good in the fight against this virus. We need more resources for, and empowerment of, our regulatory bodies, at both the state and federal level, to allow for review, oversight and consumer protection of laboratory testing. With time, this Covid-19 crisis will end, but the need for this type of oversight across all types of laboratory testing, including genetic testing, will not. Orig3n’s Covid-19 testing errors are a good example of the type of harm that will constantly occur without it.

23andMe has received a lot of attention as well as significant criticism from the medical community for their ever-expanding direct to consumer (DTC) genetic test offerings. While I share many concerns about 23andMe, it is worth noting that of the hundreds of tests that are directly available to consumers these days, 23andMe is the only lab that has received marketing authorization by the FDA for DTC testing. The only one.

These days anyone can easily order testing online directly from a number of companies, for themselves or their children – from pharmacogenomic testing to whole genome sequencing. How is it possible that so many labs are offering testing when only 23andMe has been given the green light by the FDA to offer DTC health risks tests?

One answer is so called ‘Consumer-Initiated, Physician-Mediated’ testing. With this flavor of DTC testing, laboratories can offer testing directly to consumers and bypass the need for FDA approval. So long as a qualified healthcare provider is involved in ordering the test, the FDA will continue to exercise their enforcement discretion and not get involved.

“As a matter of policy, the FDA generally does not review some types of tests, called laboratory developed tests (LDTs), that are created and performed in a single laboratory, if they are offered to patients only when prescribed by a health care provider. These tests typically do not have the FDA’s independent assurance of the analytical validity, clinical validity, or clear communication of test results.” FDA Website Updated 12-20-2019

I gotta’ say that I am baffled that consumer-initiated, physician-mediated testing is expanding so rapidly without any regulatory checks or balances. It seems like every other day there is a press release about a new partnership that enables labs to offer complex genetic tests, direct to consumer, with a physician’s order.

The biggest DTC genetic testing lab in the world by the number of samples, Ancestry.com (more than 15 million samples tested according to their website), recently announced that they are entering the health testing space and will be providing customers with some results related to hereditary risk for cancer, cardiovascular disease and more. And with their partner, Quest Diagnostics, Ancestry.com plans to release full exome data to customers later this year. However, unlike their main competitor, 23andMe, they are not offering this testing DTC with blessing from the FDA. Instead they have partnered with PWNHealth, LLC, so that their tests will be “physician-ordered” and thus escape the regulatory authority of the FDA. With this model, a test is selected and paid for online by the consumer, and then the lab requests a  physician at PWNHealth to authorize the test order.  

Ancestry.com isn’t alone in the decision to market complex medical tests directly to the public; PWNHealth also counts Invitae, Flugent, Sema4, Lineagen, Pathway Genomics, OneOme, Color Genomics, Ambry Genetics, and others as their partners. Just this past year, mega labs Quest Diagnostics and LabCorp launched new patient-initiated, physician-mediated lab testing, both partnering with PWNHealth. While PWNHealth seems to be a major player in this area of physician-mediated testing, the physicians working for PWNHealth aren’t the only ones signing test orders for consumer-initiated tests.

I know this from my personal experience of initiating one of these genetic health risk tests for myself. It was remarkably easy to order an extensive genetic test for hereditary cancer susceptibility. Ordering the test did not require me to provide health or family history information that would allow a physician to determine if this test was medically appropriate for me. In fact, all that was required for the test order was my credit card number and mailing address so that the lab could ship me a test kit. I returned my DNA-containing spittle never having talked about it with my own doctor, or any other doctor for that matter. Several weeks later, I received my results with a physician’s name and address on the report listed as the “Ordering Physician,” which Google Maps shows me is a UPS Store in a strip mall in Colorado (1,400 miles from my home state of Washington). This doctor was not a name I recognized from ordering the test, and I had no communication with him prior to, or in the time since my testing. Interestingly, I was able to find him LinkedIn where under Experience he lists: “PHYSICIAN OF RECORD (POR) services provided for DIRECT-TO-CLIENT laboratory testing.”

Consistent with this, while recently tuned into a webinar hosted by a lab offering a new consumer-initiated genetic testing product, a representative of one of the companies that provides physician “oversight”  stated that the physicians signing off on these genetic test orders do not have any expertise in genetics and at the company, “genetic counselors are considered the experts and the physicians approve or reject orders based on the genetic counselor recommendations.”

My sense is that the companies promoting and selling these consumer-initiated tests are getting a free pass for now because they provide genetic counseling along with the test results. Advocates of these consumer-initiated tests say that any pathway that allows people access to their own health information is a positive, and physicians that sign off these orders as well as the genetic counselors involved may feel that they are doing more good than harm by improving access to this information.

But the idea that a physician will, in exchange for payment, sign off on test orders for people who are not under their care is quite troubling to me. If these labs were billing CMS, such arrangements, which essentially pay physicians a fee in exchange for referral to the laboratory, may be seen as illegal kick-backs. In fact, the regulatory gaps that allow for consumer-initiated, physician-mediated genetic testing are the same ones that allowed one of the biggest Medicare fraud schemes of all time to take place.

What does the movement towards a growing number of these types of DTC testing options mean for the field of medical genetics?

Perhaps people will have greater access to genetic testing. But will the information received through these tests improve people’s health? Or will they lead to people receiving inaccurate, incomplete or misunderstood information? What are the downstream costs to our healthcare system to follow-up these results for tests that were never indicated in the first place?

What does it mean when the very same doctors are signing off on genetic tests that provide information such as results of pathogenic variants in genes for which we have proven interventions to improve health outcomes (e.g. BRCA and Lynch syndrome) are also signing orders for tests that make such evidence-less claims such as to design a DNA-based weight loss plan or to personalize your cannabis experience? Could this blending of evidence-based applications of genetics with snake oil damage trust in all of the work that we genetic counselors do? 

We are at an important crossroads where regulation and policy are needed to ensure responsible implementation of genetics in medicine. With this quickly evolving field there is an urgent need to address regulatory shortcomings with regards to genetic testing to reduce fraud and to ensure that people have access to high quality genetic tests and information. If medical tests are to be available directly to consumers, we need mechanisms to ensure that such tests have a high analytical and clinical validity and results must be comprehensible by those receiving them. Given the FDA’s current enforcement discretion of LDTs, we have no regulatory body accountable to see that this is the case. 

If the FDA continues to turn a blind eye to physician-mediated DTC lab testing, individual states may need to exercise their regulatory authority over the physicians who inappropriately order medical tests for people not under their care. In 2017, healthcare attorney and physician, Kimberly Lovett Rockwell, MD, JD  suggested in a JAMA Viewpoint article that state medical boards should consider sanctions against practitioners who work for DTC testing companies and order testing for any consumer without a medical history or examination, regardless of testing utility. Imagine all of the Medicare fraud that could have been prevented had such actions been taken a couple of years ago!

Lastly, one of the most important actions that will improve access to quality genetic healthcare and reduce inappropriate genetic testing would be CMS recognizing genetic counselors as healthcare providers (#supportH.R.3235 – Access to Genetic Counselor Services Act of 2019). Such recognition would allow reimbursement for genetic counseling services that are not tied to selling genetic testing products. Lack of fair reimbursement for independent genetic counseling has contributed tremendously to the shift of genetic services out of the traditional healthcare setting and into the consumer marketplace. CMS recognition would ensure the public that genetic counselors are subject to the same fraud, waste, and abuse laws and regulations as other healthcare providers and thus less likely to be unwitting parties to supporting DTC test schemes.

It is sadly ironic  that genetic counselors are faced with opposition to CMS recognition given the opinion by some that ordering and interpreting genetic tests is engaging in the “practice of medicine”, and should only be performed by licensed physicians. Yet at the same time, so many genetic tests are being ordered by licensed physicians outside of what is considered the standard and accepted “practice of medicine”.

As is the case with many topics in genetics, I learn the most in my time away from the office, researching questions for friends and family. And the genetics questions du jour are almost all related to pharmacogenomics (PGx) testing. More specifically, PGx testing for psychiatric medications. Maybe you are getting these questions too? For me, they usually go something like this:

Are these genetic tests that promise to tell you what

antidepressant medication will work best for you a real thing?

And if they are, why isn’t everybody taking them?

I have witnessed friends and family members struggle with medication management for depression, anxiety and mood disorders. People in these situations are often desperate for help and quite vulnerable. I can fully appreciate the hope that a simple genetic test could provide the answers to ease the journey. But as we find with many things in genetics, the reality is much more complicated than the hopeful answer we wish we could give. Ultimately, I know my position on this will disappoint many who are looking for that silver bullet. While there are a handful of applications for pharmacogenomics in specific situations related to psychiatric medications that have evidence to support their use, there is little evidence that multigene panels in this area lead to better outcomes. There is concern that harm may come because of the use of this unproven information to guide important decisions with prescribing and dosing of psychiatric meds. 

My conclusions regarding these tests are in part based on critiques from reputable sources on the current state of commercially available PGx psychiatric panels, including the American Psychiatry Association Workgroup for Novel Biomarkers and Treatments. This workgroup performed a detailed review of several commercially available tests and concluded that there is a lack of sufficient evidence to support the widespread clinical use of the proprietary combinatorial pharmacogenomic models used by these labs. There are many publications that highlight issues with existing studies about these tests including concerns related to conflict of interest and problematic study design. The financial sector is also following this topic closely given much has been invested based on the promise of these testing products being adopted broadly. Recognizing the strong commercial drivers at play here also causes me to view laboratory claims with a dose of skepticism. 

But when it comes to the general public, I think the commercial push to see these tests more broadly adopted is drowning out the voices of the experts who are urging caution. It seems that since many in the field of psychiatry aren’t convinced that these tests are ready for prime time, the labs have decided to bypass the most relevant specialty, and go straight for patients and primary care providers. Additionally healthcare payers are banking on the promise that these PGx tests will more than pay for themselves by allowing for better precision in prescribing of expensive medications. Payer support is helping to move psychiatric PGx testing to the mainstream.

New pharmacy-laboratory partnerships are emerging to promote these tests. Last year, PGx lab Genomind®  announced a partnership with Albertsons Sav-On, Jewel-Osco and Acme Sav-On pharmacies: pharmacists can discuss PGx testing with patients and, if the patient consents, the pharmacists will directly contact the prescribing provider to “suggest the Genecept® Assay. ” The  sample can be collected right in the pharmacy. Last month, Myriad Genetics, Inc. announced a similar program with Kroger Prescription Plans to promote GeneSight®  genetic tests in Kroger pharmacies. From the GeneSite® press release: “pharmacists at more than 2,300 Kroger stores will provide counselling about GeneSight® to eligible employer group members and facilitate testing with their prescribing healthcare professionals.”

Pharmacists are now direct marketing genetic testing to patients. And while members of the pathology and clinical laboratory space are taking some issue with this, there hasn’t been much public concern raised by the broader medical genetics community about this proposal to have pharmacists providing “genetic counseling” and facilitation of genetic testing.   

It will be interesting to see how these programs evolve with greater attention from regulators. With several years of push and pull between labs marketing these tests and clinicians raising concerns about their clinical utility and safety, the FDA has recently started to flex their regulatory muscles in this space. In Oct 2018, the agency published a Safety Communication, warning patients not to change management based on PGx results without first discussing with their healthcare provider and to be aware that claims made by genetic testing laboratories about PGx tests are not supported by sufficient clinical evidence. The FDA cautions healthcare providers in the use of these tests and directs providers to FDA-approved drug and genetic test labels. Lastly, the communication advised test manufacturers not to include specific drug information that is inconsistent with FDA-approved drug labeling. In April, the FDA sent a letter to Inova Health System with concern that the clinical validity of their PGx tests had not been established for the reported intended uses. Shortly after this letter was issued, Inova elected to cease offering their MediMap® tests. The FDA has been in communication with several other laboratories and stated that “most firms addressed the FDA’s concerns by removing specific medication names from their labeling, including promotional material and patient test reports.”

Some of the critiques I have heard about the FDA’s engagement in regulating these tests is centered around whether or not the FDA should be the authority on the evidence required to support the relationship between certain variants and drug metabolism. A frequently referenced pain point is the difference between the PGx genes/variants that make the cut per FDA drug labeling and the evidence grade rating per the Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network (CPIC). In looking at most of the commercially available PGx tests on the market today though, it is clear that many of the variant-drug connections included on lab reports are not consistent either with the FDA-approved list or with CPIC guidelines. 

For example, the sample GeneSight® report available online as of the day of this posting, under the category of “Mood Stabilizers” shows three drugs in the red bucket, “Significant Gene-Drug Interaction” and no drugs in the green, “Use As Directed” bucket. Top of the red list is lamotrigine (Lamictal®), which has a footnote that reads “Use of this drug may increase the risk of side effects.” The justification given in the Gene-Drug Interactions table is a variant in the UGT1A4 gene. Search of the CPIC database gives the UGT1A4 – lamotrigine pair a “D” level rating. According to the website, the CPIC D Level is defined as follows: “There are few published studies, clinical actions are unclear, little mechanistic basis, mostly weak evidence, or substantial conflicting data. No prescribing actions are recommended.” How might this report affect a person with bipolar who is struggling to find the right medication? One can imagine that it may be difficult for both the patient and the prescribing provider to feel comfortable with a treatment plan when not supported by this genetic test report.

For the same GeneSite® sample report, under the “Antidepressants” heading, there are a total of 22 antidepressents for which analysis is available, with only three in the “Use as Directed” green bucket. Top of that long list of 22 drugs in the red, “Significant Gene-Drug Interaction” bucket is bupropion (Wellbutrin®). Bupropion is a medication commonly used to treat depression and has been approved by the FDA for use since 1985 with a generic version of this drug readily available. There is no data in the CPIC database to support the assertion made my GeneSight® of a “Significant Gene-Drug Interaction” with bupropion. And interestingly, the only three antidepressant medications that made it to the green “Use as Directed” category are expensive drugs for which no generic version is available: levomilnacipran (Fetzima®), desvenlafaxine (Pristiq®), and vilazodone (Viibryd®). If I received this report and didn’t know better, I might assume that these drugs would be worth the high price tag if they are genetically the most likely to treat depression without the potential for side effects. There is no gene-drug information in CPIC about any of these three preferred medications, and I didn’t have to look very far beyond the GeneSight® report to see the long list of side effects and contraindications associated with each of these medications. But imagine the difficulty a prescribing provider might have in convincing a patient to consider forgoing the expensive new drugs in the green bucket to consider a more affordable medication with a longer history of success in treatment from the red bucket. Lab reports are not often looked at as one piece of the puzzle, but rather as the *truth* by patients. And as I have previously written on a different topic, it is incredibly difficult to convince a patient that an expert assessment may be more trustworthy than what is printed on a test report. 

Regulation of genetic testing is a big and thorny issue, and I don’t claim to have easy solutions for improving these challenges. But what I do hope to do is to begin a conversation with my fellow genetic counselors on what role we should have in the dissemination of information regarding PGx testing. I feel it is our professional obligation to understand, to the best of our abilities, the evidence or lack thereof when counseling our patients, consulting with other healthcare providers and discussing these tests with friends and family. When people first started asking me about these tests, my initial feeling was one of hope and optimism. Of course it would be wonderful if a simple genetic test could provide a clear path towards the best medication for those who are suffering. Now, after having spent hours down the rabbit hole to try to better understand the current state of this field, I remain hopeful that these tools may someday provide real benefit for the masses. Unfortunately, it seems to me that at the present time, this wild west of the competitive genetic testing marketplace has resulted in bigger but not necessarily better panels, including information that is often not evidenced-based. I worry that these reports could lead people down a wrong, and potentially dangerous path.

So for now when my loved ones ask me, “are these genetic tests that promise to tell you what antidepressant medication will work best for you a real thing?” I will give the more cautious and complicated answer. While this technology holds promise for the future, the evidence we have at this point does not support that these tests will help guide better care and lead to better outcomes for most people. And I will continue to do my best to support them on the journey forward, wherever the bumpy and winding road may lead.

On summer road trips, my kids loves to play a game Would you rather?  For instance, would you rather eat a bowl of spaghetti noodles without sauce or a bowl of spaghetti sauce without noodles?  Would you rather have a unicorn horn or a squirrel tail?

In the spirit of summer road trips and the holiday weekend, I’d like to play a game of Would you rather? that only genetic counselors can appreciate.

This is a trade off we have to make with carrier screening.

Carrier screening programs intended for the general population as supported by the practice guidelines put forth by our professional societies tend to favor Option B. The reason being that more harm than good may result when providing information that is uncertain or ambiguous, especially in the context of reproductive decision making.

These days however, Option A is becoming increasingly common. Although at odds with society recommendations, which generally recommend a more targeted approach, the use of expanded carrier screening (ECS) panels that utilize sequencing are being more commonly accepted into practice with labs often claiming that more prenatal testing is better.

But is more really better?  

In theory, it makes sense to offer screening that provides as much information as possible. However, we know that what makes sense in theory does not necessarily lead to good medical practice. And there are warning tales of screening programs that were initiated with good intention but led to unfortunate, unintended consequences.

Consider the early days of carrier screening for cystic fibrosis (CF) as an example. After years of careful study and deliberation, in 2002 experts from the American College of Medical Genetics together with American College of Obstetricians and Gynecologists published recommendations for use a panel of 25 mutations in the CFTR gene. However this initial panel was revised in 2004  when it became evident that one of the originally defined mutations,  p.I148T (c.443TC) was in fact a benign polymorphism.

On a panel of just 25 mutations, in a well known gene, for a well defined condition, after years of critical expert evaluation, a mutation that  was initially included on a panel as causative of disease was eventually determined not not be, only after being put into practice. It is likely that Option A was a reality for some families in the early days of CF carrier screening.

Now consider that with expanded carrier screening panels that increasingly perform whole exon sequencing, often of >100 genes, one can imagine that many of the mutations being called with carrier screening are not disease causing. I believe that Option A will become much more frequent with greater utilization of carrier screening panels that use sequencing.  

And in addition to the possibility of incorrect variant classification, there is also a concern for increased false positive results as carrier screening expands. A reality with any screening test is that the rarer the condition, the more likely a positive result is a false positive result.

When questions arise regarding interpretation of variants on ECS panels, the labs often respond that they follow the ACMG Standards and Guidelines for Interpretation of Sequence Variants.

But here’s the thing, these guidelines were not developed for carrier screening in a healthy population. To quote the ACMG document: “The following approach to evaluating evidence for a variant is intended for interpretation of variants observed in patients with suspected inherited (primarily Mendelian) disorders in a clinical diagnostic laboratory setting.”

The authors of the ACMG Standards also warn: “Caution must be exercised when using these guidelines to evaluate variants in healthy or asymptomatic individuals or to interpret incidental findings unrelated to the primary indication for testing. In these cases the likelihood of any identified variant being pathogenic may be far less than when performing disease-targeted testing. As such, the required evidence to call a variant pathogenic should be higher, and extra caution should be exercised. In addition, the predicted penetrance of pathogenic variants found in the absence of a phenotype or family history may be far less than predicted based on historical data from patients ascertained as having disease.”

As genetic counselors we are trusted to advise patients of this information, and knowing that such information is used to make life changing reproductive decisions (i.e utilizing prenatal diagnosis, pregnancy termination, undergoing assisted reproductive technologies and preimplantation genetic diagnosis, or deciding not to have biological children) we know how important it is that the information we provide patients is unambiguous, accurate, and evidenced based.

However, we seem to be accepting the move to expanded carrier screening panels using sequencing rather than more targeted genotyping panels with little question about whether this is the right thing to do.

While many have accepted that expanded carrier screening with sequence analysis is the new normal, we should note that despite the marketing spin by the companies that this method of testing is superior, there are still no prospective studies that demonstrate clinical validity and utility of expanded carrier screening panels with sequencing. And guidance from our professional societies recommends a more limited approach to carrier screening.

While labs promote certain conditions included on their carrier screens as “recommended” by the ACMG and ACOG, they fail to acknowledge that those professional societies specifically advise against whole exon sequencing, and instead recommend a more targeted approach that evaluates, and reports on only well characterized mutations.

From the ACMG Position Statement on Prenatal/Preconception Carrier Screening (2013):  “There must be validated clinical association between the mutation(s) detected and the severity of the disorder.”  And more recently, from the ACOG Committee Opinion 691 on Carrier Screening for Genetic Conditions (2017):  “Complete analysis of the CFTR gene by DNA sequencing is not appropriate for routine carrier screening.”

Who should decide which test is best?  The testing laboratories? The professional medical organizations?  Patients?

It seems that for now, that the laboratories are steering this ship. Despite the lack of evidence proving benefit and many cautions against it, several labs have sunsetted genotyping panels and have moved exclusively to sequencing, for what seems to be an ever growing number of rare conditions. It is becoming increasingly difficult for clinicians to follow the guideline recommendations when ordering tests for patients and we seem to be quickly entering a time where Option B is not an option at all.

It should not come as a surprise that the labs are pushing this new expanded testing as there is an incentive for labs to use sequencing over genotyping from a business perspective.

Sequencing genes rather than using a defined mutation panel allows for labs to boast of a higher detection of carriers, thus provides bragging rights for their marketing materials. One lab highlights on their website that their test identifies “30% more pregnancies affected with cystic fibrosis or spinal muscular atrophy” when compared to the ACMG and ACOG  recommended panel. What is omitted on their website is that for some of the mutations identified, we do not yet have definitive information about disease causation or phenotype. And thus we are asking patients to make reproductive decisions based on uncertain information.

Another compelling reason for the labs to expand to sequencing is that detecting more mutations in the patient begets more testing of their partners. And more testing is the name of the game with laboratories that aim to increase test sales. Understandably that is their goal as it should be, we need labs to sell test in order to stay in business and provide a needed service for patients and providers. That said, lab sales and profits should not be driving best practices for patient care.

While more may seem better in some situations, this notion should be especially scrutinized in the area of reproductive carrier screening. As the professionals that are trusted to interpret these tests results and help patients understand this information in the context of their own lives, we need evidence beyond modeled hypothetical disease risk to demonstrate that these expanded tests will truly benefit pregnancy outcomes. As has been discussed on the DNA Exchange in a prior post by Bob Resta, positive change to do best for our patients in this area will require work from multiple parties. Labs should put the brakes on with regards to marketing new tests and step back while independently funded research assesses the relative harms and benefits of testing. Governments need to fund such research. And clinicians need to critically evaluate the testing that is offered to patients, especially when unproven testing strategies are being introduced and promoted that may create more harm than good.