When Mindy Brayman’s son Jack was born in 2002, he seemed perfectly healthy. But by the time he turned 6 months old, it was clear Jack wasn’t meeting his developmental milestones. He wasn’t eating enough either, and doctors diagnosed him with failure to thrive, a catchall that can be applied to any child with poor physical growth. Jack ended up in the hospital, where he saw a long line of doctors and underwent test after test, all of which came back inconclusive. They couldn’t find anything wrong with Jack.
By the time the Braymans understood just how challenging and mysterious Jack’s condition really was, Mindy was newly pregnant with her second son, Todd. She underwent extra testing during her pregnancy and, again, everything seemed fine. Todd appeared healthy just as his brother had — right up until he was about 6 months old. Still, there were no answers.
Finally, when Jack had just turned 2, one of the Braymans’ doctors had an idea. He thought Jack and Todd’s disorder might have something to do with the chemical messengers that send signals from one neuron to the next. Samples were sent off to a lab in Switzerland, the only place offering the relevant test at that time. The results suggested the boys had a deficiency in GTPCH, an enzyme that plays a role in the production of dopamine and other neurotransmitters. Jack and Todd’s disorder was still considered atypical.
“It didn’t exactly fit,” Mindy says of the diagnosis. Still, the Braymans were relieved to finally have some kind of an answer. They got connected with the Pediatric Neurotransmitter Disorder (PND) Association and immediately began working to raise awareness and money for the organization.
The family continued on that way for years until a doctor suggested they redo the test for GTPCH, just to be sure. The Braymans agreed, and this time the test yielded a different result. The boys’ samples showed activity in that critical enzyme, meaning that Jack and Todd didn’t have a clear case of the neurotransmitter deficiency after all. Bewildered, Mindy remembers asking the doctor, “If these were your children, what would you do next?” He told her he thought the best thing to do would be to have the boys’ genomes sequenced. But there was a major catch: Nobody was doing that yet — definitely not in kids.
Another two years went by and finally the Braymans got a break. A genetic counselor called to tell them that the Medical College of Wisconsin was the first place in the country offering genome sequencing on a limited, experimental basis in cases like theirs. The Braymans live in a suburb of Milwaukee, about 30 minutes away from the Medical College. When the voice on the other end of the phone asked if they’d like the opportunity to have such a test done, the answer was easy: “Yes, of course — whatever it takes.”
(Not) A Matter of Money
Mindy says her husband was ready to pay any amount of money to get another shot at an answer. At that point, however, it wasn’t a question of money. Funding was available to cover the costs for a limited number of kids, but the Braymans’ case would have to come before experts who would decide if they really were good candidates for sequencing in those early days. The process took months, and by the time they were approved, the money had run out. The Braymans reached out to their friends at the PND Association for help, arguing that the results might yield insight that could help other children with poorly understood neurotransmitter disorders. The association decided to fund the sequencing of Jack’s genome, the Medical College agreed to cover the analysis, and his samples were sent to a lab in California.
Fast-forward to today, and there are sure signs that this form of personalized medicine is about to become accessible to many more people with similarly mysterious genetic conditions and to their families. Howard Jacob, a member of Genome’s advisory board, directed the sequencing of Jack’s genome and those of many other sick kids before and since. He has recently moved from the Medical College of Wisconsin to the HudsonAlpha Institute for Biotechnology in Huntsville, Alabama, to lead its newly established Smith Family Clinic for Genomic Medicine. The clinic is billed as “the first clinic in the world to use whole genome sequencing exclusively to diagnose rare, undiagnosed and misdiagnosed disease.”
Interested patients and families will still need to be seen by a clinical geneticist to determine whether a whole genome test makes sense for them as a next step. But the bar for who can receive such testing is getting lower, driven partly by the high-profile successes of Jacob’s team in Wisconsin and of many other small programs that have popped up around the country. There’s a catch, how-ever: Despite evidence that DNA sequencing can be life-changing or, in some cases, even lifesaving, families looking to be seen at the Smith Family Clinic will have to foot the bill themselves.
On the clinic’s website, the second FAQ concerns costs. “We currently are not participating with any health plans,” the site reads. “Payment is expected in full at the time of your service. We will provide you with a copy of the bill for your submission to your insurance company. If whole genome sequencing is ultimately recommended, it’s important to note that most health plans do not currently cover whole genome sequencing.”
The clinic opened in November 2015, and Jacob says it’s too soon to say how much of a barrier the cost — which he puts at $6,500 for an interpreted whole genome sequencing — will present to families in need of answers. Like the Braymans, many people who find themselves in these difficult circumstances are willing to do whatever it takes. Often, they’ve already traveled from clinic to clinic, incurring costs along the way. People who can’t afford the tests often find ways to cobble the money together, whether with the help of family, nonprofits, traditional fundraisers, or online crowdfunding. (See “You Can’t Pay Your Bill. Now What?,” right).
One thing’s for sure: “We can all agree if insurance were paying, it would be much less of a barrier,” Jacob says. “Patients would want to do this earlier.”
A Hard Bargain
On questions about who pays for personalized medicine, there are many reasons to feel encouraged. For one thing, the cost of sequencing has dropped precipitously over time. In 2002, the year Jack Brayman was born, a complete human genome would run you about $100 million. Today, it’s possible to buy a complete genome sequence for as little as $1,000.
“The funding issues are less and less of a problem because the cost of sequencing has gone down considerably,” says Hugh Rienhoff, a biotech entrepreneur who analyzed his daughter Bea’s genome years ago, with equipment bought through eBay and the support of the genome technology company Illumina. “You can get a whole exome [now] for 500 bucks.”
In November, the national health plan Cigna became the first to establish coverage criteria for the sequencing of whole exomes. An exome represents a small fraction of a complete human genome but includes all of the 22,000 or so genes that encode functional proteins. For the test to be covered, a board-certified geneticist or other specialist must recommend it, with the idea that the results are likely to change clinical care. Cigna noted at the time of its announcement that requests for whole exome sequencing had been growing by 10 percent per quarter, with coverage granted only on a case-by-case basis.
In other arenas of personalized medicine, insurance is beginning to pick up the tab too, at least in some cases. Foundation Medicine, which offers a genomic test designed to help doctors make treatment decisions for patients with cancer by matching the genetic changes in tumors to targeted therapies, has made progress in winning coverage. In December 2015, the company announced that UnitedHealth Group, the country’s largest health insurer, would cover the cost of the test for use in patients with advanced metastatic non-small cell lung cancer (NSCLC).
Other approvals followed. In January 2016, Independence Blue Cross and NantHealth announced the nation’s first insurance coverage for a diagnostic test, called GPS Cancer, which combines whole genome sequencing and RNA sequencing to identify molecular alterations in a patient’s cancer. The next month, Cancer Genetics received approval to bill Blue Cross Blue Shield of Minnesota for its genomic testing services. It had previously signed similar coverage agreements with BCBS Illinois, BCBS North Carolina, BCBS Nebraska, and Wellmark.
While these are encouraging signs, in many cases today the company bills insurance for patients directly, as an out-of-network provider. Foundation Medicine and many other companies will help with appeals when insurance companies deny coverage, but there are no guarantees.
Foundation Medicine’s CEO, Michael Pellini, says it’s complicated, because a physician may want to order the same test for 10 different patients, but “the rules from the payer are likely going to be different for every single one of those patients, even if a couple of those patients have the same diagnosis and are covered by [essentially] the same plan. It’s just very difficult for providers, for physicians in particular or their staff, to be able to tell a patient, ‘This is what you can expect.’ ”
The challenge for personalized medicine, as for other forms of medical testing, is convincing payers that the tests are not only reasonable but also medically necessary. As bioethicists Patricia Deverka and Jennifer Dreyfuss explain in the Journal of Law, Medicine & Ethics, coverage and reimbursement for molecular diagnostics tests — which personalized medicine depends upon — have been slowed by limited evidence in many cases for their clinical utility. “The threshold of evidence needed for a molecular diagnostic test to gain regulatory clearance and enter the medical marketplace is considerably lower than that needed for payers to support coverage and determine reimbursement levels,” they write.
In some circles, personalized medicine also suffers from a pricey reputation. Deverka and Dreyfuss cite a UnitedHealthcare survey of more than 1,000 physicians showing that the majority of doctors expect that the booming market for various forms of genetic testing will ultimately raise healthcare costs. As the health system moves away from a fee-for-service model in favor of alternative payment models prioritizing value, evidence is needed to show that personalized medicine can be cost effective and lead to better outcomes for patients. (See “New Payment Models,” left.)
This dynamic is one that Bonnie Anderson, CEO of Veracyte, knows well. The San Francisco–based company offers a gene expression test, called Afirma, which aims to reduce unnecessary surgeries for patients with benign thyroid nodules. Traditional tests, in which pathologists look at cells under a microscope, are often inconclusive, leading many patients to undergo surgery to remove nodules that aren’t cancerous.
In 2012, a study in the New England Journal of Medicine showed that the Afirma test works, making it safe for patients with a negative test result to forgo surgery in favor of watchful waiting. Anderson says it was simple math to show that such a test is cost effective, as it allows 9 out of 10 patients to skip surgery. Medicare and many other major commercial payers, which collectively represent many millions of people, now cover the Afirma test. Veracyte is now working to build evidence in support of a second test, aimed to reduce unnecessary surgeries for patients with suspicious nodules in their lungs.
“There has to be evidence to show you are really making a difference,” Anderson says. “The value studies have to be conducted to show that the test works, that it’s changing care decisions, and the decisions being made are at a lower cost to health care.”
There are other examples suggesting that personalized medicine can come at a cost savings. In early 2014, researchers predicted that genetic tests could save money when applied to the many thousands of patients who are prescribed blood-thinning drugs after receiving a stent to open up their coronary arteries.
“Our results counter the general perception that personalized medicine is expensive,” says Dhruv Kazi of the University of California, San Francisco, where the study came out. “What we have shown is that individualizing care based on genotype may in fact be very cost-effective in some settings, because it allows us to target the use of newer, more expensive drugs to the patients who are most likely to benefit from them.” As the cost of drugs continues to go up and the cost of genetic and genomic testing continues to go down, he adds, the balance is likely to continue shifting in favor of a more personalized approach to medicine.
Stephen Kingsmore, who showed that it’s possible to perform emergency genome sequencing and obtain a molecular diagnosis within 26 hours, was recently hired to lead a new genomics institute at Rady Children’s Hospital in San Diego, where the goal is to make genome sequencing a standard of care.
To start, he says sequencing will often be covered under research protocols. But he predicts the first place that whole genome sequencing will become standard procedure is for newborn babies who find themselves in the neonatal intensive care unit with mysterious and life-threatening conditions that are likely traceable to genetic causes. In that setting, the likelihood of finding a diagnosis by sequencing is greater than 50 percent. There is also potential for an early diagnosis to save lives and reduce the need for more testing. Still, Kingsmore understands why insurance companies have been slow to expand coverage.
“From my perspective, they [the insurers] are being prudent,” Kingsmore says. “They can’t pay for every test someone wants to do. The onus is on us as a community to develop the evidence to figure out where and when these technologies should be used. There will be situations where it doesn’t make sense.”
Foundation Medicine’s Pellini agrees, noting that they’ve had success in gaining coverage by focusing on patients who stand to benefit most. Looking ahead, he says it’s not a question of if this kind of coverage will become available, but when. But at the moment, the science and medicine are moving at a pace that’s too fast for the reimbursement world to keep up. Ultimately, finding solutions will require groups coming at this from different perspectives to work together more closely.
Long and Winding Road
As for the Braymans, they’re still waiting for their diagnosis. Jack’s DNA results came back inconclusive years ago. And even after the rest of the Brayman family had their exomes (the 1 or 2 percent of the genome that codes for protein) sequenced, they still don’t have answers. There’s a chance a diagnosis might be forthcoming as research continues. Mindy says that the researchers try not to get the Braymans’ hopes up, but they come back to them now and again with additional questions or other requests. Most recently, the family submitted a sample of skin fibroblasts.
Sadly, any result will be too late for Jack. The family lost him to his condition last spring. His younger brother, Todd, recently underwent a difficult spinal fusion surgery, and the family is struggling to keep him on medications that were prescribed based on the earlier diagnosis of a neurotransmitter disorder. Mindy says they’ve tried many treatments, and some of them even seemed to help. The trouble is that no one can say why.
“I look back at how much money was spent in testing over all those years,” Mindy says. “Even though there’s no answer [yet], the [genome sequence] is still one test. Every year, the clinical program can go back and review it with all the new things that have been found.”
For the Braymans, it was money well spent. But their example does point to something HudsonAlpha’s Jacob sees as a lingering struggle for precision care.
“The challenge in terms of cost is when do you stop looking?” he asks. “If I figure out what’s wrong with the patient quickly, that’s an easy, straightforward calculation.” In some cases, with the data in hand, an answer can be had in a matter of minutes. In other cases it might take hours, days, or months, and sometimes there’s still no clear answer. “How long do you keep looking before you decide you’ve failed? That’s a variable we are still trying to get our heads around.”