commercializing diagnostics


Is Population Medicine Failing Us? Michel Accad

Is health the same thing for an individual as it is for a population? This question goes to the foundation of how we practice medicine today and that of most of genomic research.

Michel Accad is a cardiologist in San Francisco and the author of a new book, Moving Mountains: A Socratic Challenge to the Theory and Practice of Population Medicine, in which he uses Socrates to spar with Geoffrey Rose, a British physician and one of the architects of modern medicine.

As early as the 1950’s, Rose advocated for the idea that individuals should be treated based on bell curves of an entire population, essentially risk based medicine. This philosophy would lie at the heart of not only the British National Health Service but many public health programs. It informed the famous Framingham studies here in the U.S. In fact, the term “population medicine” is a very positive term for those working in healthcare today. Genomic medicine has been an outgrowth of population medicine.

Michel says this philosophy is failing us at the level of individual health. Third party payers, be they governments or insurance companies, are in their offices working a system based on large datasets. They develop algorithms using all kinds of risk studies. But these payers have little to no contact with the actual patients. Ironically, he says, we call it personalized medicine. Michel points to hypertension, a disease area where sixty years after Rose pushed for risk studies, cardiologists are still divided into camps over whether to treat a patient if their blood pressure lies above the average. Michel argues that population medicine is utilitarian and ultimately utopian. What are framed as scientific studies are really social engineering.

What about clinical trials, we ask Michel. Don't population studies bring doctors and patients many good drugs?

In the second half of the interview, Michel points out that a mechanistic view of biology dominates clinicians and scientists today. It’s true. Our guest last week, a well known geneticist from Stanford, compared people to cars, arguing for the need to wear health data gathering sensors.

"Right now among philosophers of science, there’s a recognition that “mechanism” is inadequate to explain cellular organisms."  The study of biology also has often been developed with tautologies, he says.  "For example, say you’re studying the beaver and you ask what is a beaver. The standard answer is to go to the genetic sequence. From the genetics, you say you have a beaver. But you have to know what beavers are in the first place in order to study a beaver. It’s a circular argument."

So what other models might we use in biology? And what can we do in healthcare if we’re not using large population studies--go back to blood letting?

(Amazon link)

How to Improve Lab Tests in the Absence of FDA Regulation?

Rubbing shoulders at molecular medicine conferences these days one senses a sigh of relief when you talk about laboratory developed tests (LDTs). With the FDA’s decision to put regulation on hold coupled with the expected confirmation of Scott Gottlieb as FDA commissioner, those in the lab testing business seem to be confidently settling back to the status quo. And those who were arguing that all we need is a “beefed up” CLIA to hold labs to better testing standards don’t appear to be motivated to do so anymore.

Several questions arise when it comes to LDTs. First of all, if regulation was truly important for enabling this revolution we call precision medicine, then why couldn’t the Obama administration get it issued? In other words, is the status quo so bad? Secondly, without the FDA even threatening to regulate, will we see the “beefed up” CLIA that many labs argued is the best way forward? Without the stick of the FDA, is the carrot gone too?

Russell Garlick is the CSO of SeraCare, a private company that has worked to improve clinical laboratory standards for over thirty years. The company recently added a new business unit for precision medicine diagnostics, and Russell was brave enough to come on today and address these questions.

As for the status quo being good enough, Russell isn't happy.

“Many of the organizations undertaking clinical trials to recruit oncology patients have lost confidence because LDTs in one geography of the United States don’t perform the same as in other parts of the United States,” he says.

Russell has worked many years with labs on IVDs--the already regulated group of diagnostic tests. He sounds disappointed that the FDA has dropped their focus on LDTs, but is hopeful that existing organizations, such as the College of American Pathologists, or even private companies such as SeraCare might step in and seize an opportunity to improve things.

“There’s a lot of status quo. And frankly it’s a little bit disappointing,” he says, “because the laboratories can benefit from [improved standards]. It’s that inertia to do something new and different."

The Story of Geisinger and Doing Genomic Medicine at the Right Pace

Mike Murray and the crew over at Geisinger are making the implementation of genomic medicine look down right easy.

In today’s interview, Mike explains GenomeFIRST Medicine, a program at the Geisinger Health System in Pennsylvania to offer care “that is based on an individual’s DNA sequence.” The healthcare provider boasts its own biobank and has partnered up with Regeneron’s Genome Center to offer exome screening to self selected patients. As of DNA Day last year, April 25th 2016, 100,000 recruits had signed up.

What has made Geisinger, who was selected to join the nation Precision Medicine Initiative, so successful with genomics? Mike points to the leadership.

“We have incredible support from the highest levels of the organization. As we’ve rolled out genomics, they are supportive and interested. As long as we’re there to explain what we’re doing and why we’re doing it, we have them on our side,” he says.

Has there been any pushback from doctors or patients?

Mike says one of the challenges they hadn’t really considered has been a “naming issue.” Sometimes one of the variants a patient tests positive for “puts their clinical story together.” But other patients may test positive for something like lynch syndrome, for example, who haven’t really had any problems.

“They really don’t have lynch syndrome, “ he says, "they have a genetic variant that goes with it. Until they have problems associated with it, they just have risk for lynch syndrome. So the problem is how do you keep something like that high enough on the radar that people and their providers know what to look for, but not so high that insurers or other entities might say, we’re going to treat them like our standard approach to lynch syndrome?”

In fact, Mike and his team have thought quite far through this challenge of how to report genomic findings back to patients. He explains what they’ve come up with in this beautifully clear interview about one of America’s most genomically experienced and progressive health systems.

New Pocket Size Nanopore Device Could Revolutionize Diagnostic and Other Testing

First of all, watch the video below.

A Santa Cruz company is now previewing a nanopore device that could be a major disruptor in molecular testing. The device is the size of a glucometer and could take all kinds of testing—perhaps someday even cancer-tracking liquid biopsies—into the home with its ease of use and ability to work with thousands of different assays.

Two Pore Guys, named for the pores not the guys, is a spinout from UC Santa Cruz and one of a growing biotech community on the west side of Santa Cruz, CA. The company has yet to do beta testing and is focused now on scaling up manufacturing of the small, relatively simple devices. CEO, Dan Heller, says Two Pore Guys has no plans to develop their own tests but will stay focused on the platform.

“We could make ten or fifteen assays and go to market with them, but why not let others make thousands and thousands of assays?” Dan asks. "They’ve already spent billions of dollars and decades developing primers or capture molecules for antibodies. Why not just give it a new life and let them sell it into the market? It's a revenue share."

So what tools might this replace? Dan lists the standard lab machines for PCR, HPLC, and mass spec. “There’s many uses of existing lab equipment that could be done on our device more quickly, cheaply, easily,” says Dan.

Based on recently developed nanopore technology, the small device looks remarkably straight forward. A molecule—just about any molecule-- is pulled through a nanopore by an electric current. The impedance of the current is the measure of the molecule. Though the device does not currently sequence DNA, its possibilities to replace other large life science tools does seem all the more real in a time when Oxford Nanopore’s small sequencing devices--also partly developed at UCSC—are proving themselves powerful tools.

Listening to Dan, the broad range of molecules and applications becomes dizzying: diagnostic testing such as liquid biopsy tests for cancer (the company is currently doing a study with UC San Francisco for a KRAS liquid biopsy test), infectious disease, border security, agriculture, animal health, and environmental testing.

It leaves us with this question in the end: why was this not done before?

Want to Stop Smoking? Start with Epigenetic Biomarker that Tells Doc the Truth

Why are there no viable psychiatric genetic tests, we ask today’s guest.

Rob Philibert is a geneticist and psychiatrist working at the University of Iowa. He admits at the outset of today’s interview that the field of psychiatric genetics is in a “quandary.”

“The results are not matching the hype,” he says.

The place Rob has found some success is in studying epigenetics. His lab perhaps leads the world in understanding the effects of tobacco, alcohol and cannabis use on DNA methylation. An epigenetic biomarker test can tell doctors, for example, whether a person smokes and how much. Rob has founded a company, Behavior Diagnostics, to commercialize the test.

So how does this help a person quit smoking?

Rob says that there can’t be therapy until there is accurate testing.

“We like to fudge when we talk about smoking. When you look at studies, half of individuals who are smokers will misrepresent their smoking to their physicians, even when directly asked.”

Think of glucose testing for diabetes, argues Rob--reliable data about the patient is at the heart of any effective treatment.

The test wouldn’t be possible without digital PCR, Rob says, giving a shout out to technology made by Bio-Rad and funding provided from the NIH.

When an Exome Test Is Part of the Therapy and Not a Diagnostic: John West on Personalis and Personalized Cancer Vaccines

About six years ago there was a wave of genome interpretation startups getting their first rounds of funding. One of them was Personalis, a company founded by a well known group of Stanford geneticists and bioinformaticians.

John West is the CEO of Personalis, and he joins us today to talk about how the company is participating in the dramatic shift in drug development toward immuno oncology drugs. Our listeners might remember John from his days at Solexa where he served as CEO and presided over the sale of the company to Illumina.

At the same time Personalis came on the scene, the first drug that would harness the immune system to fight cancer was being approved by the FDA, Yervoy by Bristol-Myers Squibb. This was the first of four drugs known as checkpoint inhibitor drugs. These four drugs have had spectacular success and together generate revenue of over 6 billion per year, a level which has doubled in the past year.

John and Personalis are working with biotech companies on a new generation of immuno therapies known as personalized cancer vaccines. These new drugs are actually custom synthesized for each patient after an “immunogram” or genetic workup of the tumor has been done. We know today that tumor growth is driven mostly by neoantigens, or new antigens which arise from mutations that happen after the cancer first appears, says John. So an immunogram done by Personalis must look at all the genes (over 20,000) and not just the original driver mutations. An immunogram could only be done in the last few years with the latest developments in next gen sequencing and algorithm creation.

How far along are these new personalized cancer vaccines? And what is the commercialization challenge for Personalis?

“We are essentially an integral part of the therapy,” says John. "So we don’t think of it as a diagnostic test. We think about it as the initial part of the manufacturing of the therapy."

Biomarker Panel to Predict Type 1 Diabetes

When we talk precision medicine on Mendelspod, we’re usually talking about oncology. But today we shift our focus to diabetes.

Raghu Mirmira is an MD PhD at Indiana University who is working on a panel of biomarkers that would predict Type 1 diabetes. That’s right. Predict.

Having already found a DNA biomarker candidate which detects dying beta cells using the new technology of digital PCR, Raghu is now working to improve the panel with other metabolites.

Will we some day have a Myriad Genetics for diabetes? Raghu says, yes. But he warns that we must also develop new treatment options to go along with a predictive blood test.

“Before we get to the point where this is a commercially available test, we need to be doing further studies to figure out what’s the outcome of individuals who test in a particular way. And what kind of interventions could improve those outcomes in some way.”

October 2016 with Nathan and Laura

Today’s show was recorded on Halloween, which now feels so yesterday. Forgive us for some spookiness.

What doesn’t feel so yesterday is the launch this past month of Helix, a company spun out of Illumina that aims to add exomes to the lineup of direct-to-consumer testing. Nathan points out their model for delivering data incrementally through various apps. Laura questions how Helix will vet the apps.

This month the genomics community gathered in Vancouver for the annual American Society for Human Genetics conference. The commentators give their highlights. Then we double back on a genetic counseling conference from last month and a big topic that we missed in our last show: population screening for BRCA.

It’s a bird, it’s a plane, it’s a turducken gone crazy. . . . . No, actually, says Nathan, “it’s a virus inside a spider costume for Halloween inside a bacterium inside a fly!"

With FDA Guidance on LDTs Still Not Out, What Are Labs Doing?

As we get closer to the election and the end of 2016, the debate over LDT regulation has gone quiet. At this time last year, there was one hearing after another, first in the Senate, then in the House. The FDA’s Jeffrey Shuren was called before congress and drilled over the nuances of the guidance as well as asked when it would be released. He said, in the first half of 2016.

Though there has been no guidance released, the FDA has continued sending letters out to individual labs, requesting certain LDTs be approved before the labs market them. In March of this year, the FDA put a couple labs and two Texas hospitals on notice that were marketing “high risk” unregulated diagnostics. This surprised many in the laboratory community. These tests were diagnostics to detect the Zika virus, and any delay could negatively impact public health. The FDA told the labs they expected them to submit a request for emergency authorization (EUA).

So what are labs across the country doing? What are they supposed to be doing? Are they shying away from developing new LDTs? Are they proactively working to develop 'clinical validity’ for their tests, something they haven’t had to do under CLIA (the current regulatory statue for labs), but would be required to pursue by the FDA?

Some lab directors, such as today’s guest, say they haven’t changed a thing and are in “wait and see” mode. John Longshore is the Director of Molecular Pathology for the Carolinas Pathology Group and Carolinas HeathCare System, an integrated health network with more than 40 hospitals. He’s optimistic that laboratories are being heard on Capitol Hill and that it won't come down to FDA guidance. Referring to a recent Senate HELP meeting in September 2016 on the topic of LDTs, he says he's confident "that we will have regulation through congressional legislation rather than FDA guidance.”

The debate continues . .

Digital PCR Opens Up New Liquid Biopsy Opportunity in Melanoma Treatment: David Polsky, NYU

The history of science is also a history of toolmaking. And nowhere is this more true than in modern biology. New instruments in the lab allow biologists additional modes of discovery, new levels of quantification, and the opportunity to pursue new and old questions with more data.

David Polsky is a dermatologist and researcher at NYU’s Langone Medical Center. Last week he received a grant from the NCI for readying a new liquid biopsy test that tracks the progression of melanoma for the clinic. Until now, there has been no blood based marker that was able to track melanoma as there is with other cancers such as prostate cancer and the PSA (prostate specific antigen) score. This new test, which could be a major breakthrough for the treatment of melanoma, targets seven mutations which occur in 70% of melanoma patients. These mutations are found in cell free, circulating tumor DNA.

In today’s interview, David points out that the test is possible only with the advent of digital PCR and its ability to measure DNA more with absolute quantification and sensitivity. We knew these mutations before, but just couldn't measure them.

“Droplet digital PCR has been a major breakthrough in our ability to detect rare events and also to quantitate them with accuracy and precision. Those two features are absolutely critical,” says David.

David and his group have been collaborating on the test with Bio-Rad, who makes the ddPCR instruments and designed these tests, and with Molecular MD. Clinical trials with Bristol-Meyers Squibb are expected. Now, with the preliminary science published, the NCI grant will go towards developing analytical and clinical validation so that the test might be commercially available for patients soon.



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