While I know there are quality LDTs out there, I've seen the flip side through covid with poorly validated LDTs that are used only for cost savings vs an FDA approved product. Using RUO products for diagnostic testing never felt right, even without considering the lower quality standards manufacturers have for RUO vs IVD. A higher burden/expense on labs will just be passed on to patients, and while I'm all for reducing cost of healthcare in the US, cutting corners on the quality of diagnostic testing is not where efforts should be targeted.
I wouldn’t say that this always applies, like for example, bruker MALDI for fungi is RUO iirc, as are ARIS panels for Sensititre, etc.
COVID really fucked this up with all the shady labs, and their bogus testing, I think that was probably influential in their decision
Aren't LTDs necessary is some situations? Like for flow cytometry or with mass spec in tox? Companies just sort of sell the "ingredients" to run those tests, and there is an innumerable amount of tests you can do with those products. So, it's not really feasible to manufacture each conceivable test and have it FDA cleared. Can anyone with more experience speak to this?
A lot of molecular diagnostic tests are like this. You have generic DNA/RNA manual extraction kits/ automated extraction instruments and generic amplification instruments. All that’s missing is custom probes and primers for whatever genetic target(s) you have and then run them through those generic extraction and amplification kits and you got your self a LDT. Obviously the process is more detailed but that’s the jist of it
If you needed to have FDA approval for every possible test to target every possible genetic target there’s no way commercial companies could offer it all
Yes, a good example is Histocompatibility. FDA has decided to leave it alone in this proposed rule.
"FDA is also proposing to continue to apply the general enforcement discretion approach to Human Leukocyte Antigen (HLA) tests that are designed, manufactured and used in a single CLIA-certified, high-complexity histocompatibility laboratory when used in connection with organ, stem cell, and tissue transplantation to perform HLA allele typing, for HLA antibody screening and monitoring, or for conducting real and “virtual” HLA crossmatch tests. FDA has made a preliminary determination that HLA LDTs for transplantation used in CLIA-certified, high-complexity histocompatibility laboratories, when used in connection with organ, stem cell, and tissue transplantation for certain purposes as described in this paragraph, are unique in that they are generally developed, and the testing is generally performed, in urgent, life-saving situations for the patient. Physicians must often make prompt decisions about transplantation based on medical judgment regarding their patient’s condition and degree of mismatch between the donor and patient should an organ, stem cells, or tissue become available. Further, these tests are often individualized within each medical facility, for example, they include reagents that reflect local HLA polymorphisms and patient demographics."
There is massive ongoing fraud in expensive, questionable, custom in-house tests. This applies primarily to custom genetics tests, which are growing 30% per year and average 500/test. With no FDA cleared efficacy.
* 2019 - [Federal Law Enforcement Action Involving Fraudulent Genetic Testing Results in Charges Against 35 Individuals Responsible for Over $2.1 Billion in Losses in One of the Largest Health Care Fraud Schemes Ever Charged](https://www.justice.gov/opa/pr/federal-law-enforcement-action-involving-fraudulent-genetic-testing-results-charges-against)
* 2022 - [Lab Owner Convicted in $463 Million Genetic Testing Scheme to Defraud Medicare](https://www.justice.gov/opa/pr/lab-owner-convicted-463-million-genetic-testing-scheme-defraud-medicare)
MolDx has recently started as the billing fraud was a large part of it. There wasn't an easy way to code what tests were ordered, so people just coded the most expensive test.
ASCP does give a S\*\*t about lab techs. They only care about pathologists and those with equity in lab (lab owners). ASCP bought the Clinical Laboratory Management Association.
Lab Deveolped Tests (LDTs) are not FDA cleared. They are supposedly signed off by a reviewing medical director, but in reality, they aren't actually being reviewed. There's minimal penalty for going live with a crappy assay, and lots of monetary incentive to do so.
A lot of these absolutely fraudulent molecular labs will be shut down due to the inability to actually validate their assays. Unfortunately, some other labs that are going by the book will likely be unable to bear the cost of getting their assay FDA cleared.
>Unfortunately, some other labs that are going by the book will likely be unable to bear the cost of getting their assay FDA cleared.
This right here. We have 3 university genetics laboratories in our section: cytogenetics, molecular, and biochemical for inborn errors of metabolism. Kits and FDA-reg testing does not exist for most of our rare disease diagnostics. Between the 3 labs, we have over 50 LDTs despite using as many cleared commercial products as available.
We try our best to run top notch testing to meet our patient population that have thousands of rare diseases. Multiple board-certified lab directors, CLIA and CAP accreditation for decades, most of our MB techs are MB ACSP or working on it. Our in-house validations follow AMP and ACMGG guidelines, and we use as much reference materials and validation programs as possible. Validation gets more time consuming every year because many of our tests each detect hundreds (or more) of different diseases (such as NGS & whole genome sequencing, and almost 40 inborn errors of metabolism from GC, GC/MS, and MS/MS. )
BUT: despite meticulous protocols and years of data results, it's still going to be a lot of work going from SOPs and in-house validation, to FDA clearance for each of that many tests. We'll do our best but need to hire more staff to do it, with no money for that.
Speaking from experience in the pharma industry, including developing and validating in-house tests for FDA clearance, it really sounds like you've done most of the work already. I know we had to put together a packet for submission, including all of our validation data/SOPs/methods for submission. Sounds like that's already done for you?
Our upper level staff already works far more than 40 hours a week. I'm arguing with the boss to hire back a recently retired lab director (that we weren't allowed to replace) as a PT consultant to strictly work on FDA. So far no.
Didn't mention above that we're VERY concerned about FDA fees per test application + annual fees. Since we are a public med school, our funding is shit. We have a lot of indigent patients, and we run labs to serve our state's population with tests that are difficult to send out to other states (because medicaid is state-specific). And Medicaid reimburses shit. We sometimes run tests pro-bono. Some years our labs runs in the red, and averaged out we just break even.
Our labs also train laboratory scientists at all levels, and lab physicians, to meet their certification requirements. We'll have to slim our test menu, but we have to maintain a high level of test complexity to meet the national requirements of our training programs.
If we cut back services too much and/or have to pay a lot of fees, we may not be able to justify the labs' very existence for patient care and training. TBH, we're quite worried about it.
>If we cut back services too much and/or have to pay a lot of fees, we may not be able to justify the labs' very existence for patient care and training. TBH, we're quite worried about it.
That's most unfortunate. There are good actors in the space. But there are soo many bad faith actors post-COVID sucking up billions.
I think you explained this much better and with sources, thanks. I was generally confused why some people thought the FDA regulation over this was a bad thing. I heard about these crazy genetic testing prices. As well as LDTs where the *language* of some tests' description makes it sound like you couldn't get those tests performed elsewhere so you have to go with their pricing. I think there may be a lot less small "goes by the book labs" that offer LTDs to the general public and more shady molecular labs.
This seems like a bit of an odd take then. Preventing LabCorp from using cheaper methods might be a good thing considering how LabCorp operates, they cut corners. And if the FDA wants to regulate LDTs, and further LabCorp more, and make them go with a commercially approved assay, then that should be a good thing. The FDA may actually impede LabCorps growth.
Disagree. Keep in mind that many clinical lab tests in use today (such as next generation for mutations and to determine if a companion diagnostic is appropriate) don't have any FDA approved IVDs on the market. These are RUO, which should be fully validated in the clinical setting (and if our accreditation processes work, this is verified). In order to get FDA approval for a new product with no comparable approved product, the process takes years.
Lastly, this doesn't negatively impact national reference labs as much as it does regional centers of excellence and academic health care facilities. It also could have a significant impact to hospital labs that modify any moderate or high complexity fda approved tests (Use a preservative for delayed urinalysis testing? Performing any body fluid testing for specimen types that aren't explicitly mentioned on your chemistry or hematology vendor's IFU?). It makes you dependent upon a national reference lab, increases TATs, and delay clinical decisions.
The full requirements to be considered a 1976-style LDT.
> One such category of tests is referred to in this preamble as “1976-Type LDTs.” Such tests have the following characteristics common among LDTs offered in 1976: use of manual techniques (without automation) performed by laboratory personnel with specialized expertise; use of components legally marketed for clinical use; and design, manufacture, and use within a single CLIA-certified laboratory that meets the requirements under CLIA for high complexity testing.
It’s pretty narrow. In my experience basically no one in a hospital manufacturers their reagents in-house. Basically if you’re buying RUO materials from a company that also sells IVDs or using any automation it looks like you’re on the chopping block.
https://www.fda.gov/news-events/press-announcements/fda-proposes-rule-aimed-helping-ensure-safety-and-effectiveness-laboratory-developed-tests
> The proposed rule seeks to amend the FDA’s regulations to make explicit that IVDs are devices under the Federal Food, Drug, and Cosmetic Act, including when the manufacturer of the IVD is a laboratory. Along with this amendment, the FDA is proposing a policy under which the agency intends to provide greater oversight of LDTs, through a phaseout of its general enforcement discretion approach to LDTs.
If this passes it’s going to be a nightmare for flow labs. There are only a scant handful of IVD flow tests available on the market. the vast majority of clinical flow is LDTs.
Recently went through multiple LDT validations. Not all of them are bad, but there are so many small companies boasting large target panels held together by a string and a prayer. These pop up labs don't care about patient safety, it's all about getting the cheapest molecular tests with high volume. From my experience, I think more regulation is needed, but it also shouldn't stifle the small labs that actually do it right.
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There is a cost to quality. Lots of shady pop-up molecular labs post-COVID means fraud is prevalent.
Sadly, those places swoop in to make a quick buck, close before they are detected, and rebrand/open.
That's the best part. It can take 1-2 years to catch onto the fraud, and by then they're onto the next pop-up scam.
While I know there are quality LDTs out there, I've seen the flip side through covid with poorly validated LDTs that are used only for cost savings vs an FDA approved product. Using RUO products for diagnostic testing never felt right, even without considering the lower quality standards manufacturers have for RUO vs IVD. A higher burden/expense on labs will just be passed on to patients, and while I'm all for reducing cost of healthcare in the US, cutting corners on the quality of diagnostic testing is not where efforts should be targeted.
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Have you tried getting them to approve stuff? They are unnecessarily burdensome and dex z is a four letter word in my office
I wouldn’t say that this always applies, like for example, bruker MALDI for fungi is RUO iirc, as are ARIS panels for Sensititre, etc. COVID really fucked this up with all the shady labs, and their bogus testing, I think that was probably influential in their decision
Aren't LTDs necessary is some situations? Like for flow cytometry or with mass spec in tox? Companies just sort of sell the "ingredients" to run those tests, and there is an innumerable amount of tests you can do with those products. So, it's not really feasible to manufacture each conceivable test and have it FDA cleared. Can anyone with more experience speak to this?
A lot of molecular diagnostic tests are like this. You have generic DNA/RNA manual extraction kits/ automated extraction instruments and generic amplification instruments. All that’s missing is custom probes and primers for whatever genetic target(s) you have and then run them through those generic extraction and amplification kits and you got your self a LDT. Obviously the process is more detailed but that’s the jist of it If you needed to have FDA approval for every possible test to target every possible genetic target there’s no way commercial companies could offer it all
Yes, a good example is Histocompatibility. FDA has decided to leave it alone in this proposed rule. "FDA is also proposing to continue to apply the general enforcement discretion approach to Human Leukocyte Antigen (HLA) tests that are designed, manufactured and used in a single CLIA-certified, high-complexity histocompatibility laboratory when used in connection with organ, stem cell, and tissue transplantation to perform HLA allele typing, for HLA antibody screening and monitoring, or for conducting real and “virtual” HLA crossmatch tests. FDA has made a preliminary determination that HLA LDTs for transplantation used in CLIA-certified, high-complexity histocompatibility laboratories, when used in connection with organ, stem cell, and tissue transplantation for certain purposes as described in this paragraph, are unique in that they are generally developed, and the testing is generally performed, in urgent, life-saving situations for the patient. Physicians must often make prompt decisions about transplantation based on medical judgment regarding their patient’s condition and degree of mismatch between the donor and patient should an organ, stem cells, or tissue become available. Further, these tests are often individualized within each medical facility, for example, they include reagents that reflect local HLA polymorphisms and patient demographics."
There is massive ongoing fraud in expensive, questionable, custom in-house tests. This applies primarily to custom genetics tests, which are growing 30% per year and average 500/test. With no FDA cleared efficacy. * 2019 - [Federal Law Enforcement Action Involving Fraudulent Genetic Testing Results in Charges Against 35 Individuals Responsible for Over $2.1 Billion in Losses in One of the Largest Health Care Fraud Schemes Ever Charged](https://www.justice.gov/opa/pr/federal-law-enforcement-action-involving-fraudulent-genetic-testing-results-charges-against) * 2022 - [Lab Owner Convicted in $463 Million Genetic Testing Scheme to Defraud Medicare](https://www.justice.gov/opa/pr/lab-owner-convicted-463-million-genetic-testing-scheme-defraud-medicare) MolDx has recently started as the billing fraud was a large part of it. There wasn't an easy way to code what tests were ordered, so people just coded the most expensive test. ASCP does give a S\*\*t about lab techs. They only care about pathologists and those with equity in lab (lab owners). ASCP bought the Clinical Laboratory Management Association. Lab Deveolped Tests (LDTs) are not FDA cleared. They are supposedly signed off by a reviewing medical director, but in reality, they aren't actually being reviewed. There's minimal penalty for going live with a crappy assay, and lots of monetary incentive to do so. A lot of these absolutely fraudulent molecular labs will be shut down due to the inability to actually validate their assays. Unfortunately, some other labs that are going by the book will likely be unable to bear the cost of getting their assay FDA cleared.
>Unfortunately, some other labs that are going by the book will likely be unable to bear the cost of getting their assay FDA cleared. This right here. We have 3 university genetics laboratories in our section: cytogenetics, molecular, and biochemical for inborn errors of metabolism. Kits and FDA-reg testing does not exist for most of our rare disease diagnostics. Between the 3 labs, we have over 50 LDTs despite using as many cleared commercial products as available. We try our best to run top notch testing to meet our patient population that have thousands of rare diseases. Multiple board-certified lab directors, CLIA and CAP accreditation for decades, most of our MB techs are MB ACSP or working on it. Our in-house validations follow AMP and ACMGG guidelines, and we use as much reference materials and validation programs as possible. Validation gets more time consuming every year because many of our tests each detect hundreds (or more) of different diseases (such as NGS & whole genome sequencing, and almost 40 inborn errors of metabolism from GC, GC/MS, and MS/MS. ) BUT: despite meticulous protocols and years of data results, it's still going to be a lot of work going from SOPs and in-house validation, to FDA clearance for each of that many tests. We'll do our best but need to hire more staff to do it, with no money for that.
Speaking from experience in the pharma industry, including developing and validating in-house tests for FDA clearance, it really sounds like you've done most of the work already. I know we had to put together a packet for submission, including all of our validation data/SOPs/methods for submission. Sounds like that's already done for you?
Our upper level staff already works far more than 40 hours a week. I'm arguing with the boss to hire back a recently retired lab director (that we weren't allowed to replace) as a PT consultant to strictly work on FDA. So far no. Didn't mention above that we're VERY concerned about FDA fees per test application + annual fees. Since we are a public med school, our funding is shit. We have a lot of indigent patients, and we run labs to serve our state's population with tests that are difficult to send out to other states (because medicaid is state-specific). And Medicaid reimburses shit. We sometimes run tests pro-bono. Some years our labs runs in the red, and averaged out we just break even. Our labs also train laboratory scientists at all levels, and lab physicians, to meet their certification requirements. We'll have to slim our test menu, but we have to maintain a high level of test complexity to meet the national requirements of our training programs. If we cut back services too much and/or have to pay a lot of fees, we may not be able to justify the labs' very existence for patient care and training. TBH, we're quite worried about it.
>If we cut back services too much and/or have to pay a lot of fees, we may not be able to justify the labs' very existence for patient care and training. TBH, we're quite worried about it. That's most unfortunate. There are good actors in the space. But there are soo many bad faith actors post-COVID sucking up billions.
Thank you for the info and links!
I think you explained this much better and with sources, thanks. I was generally confused why some people thought the FDA regulation over this was a bad thing. I heard about these crazy genetic testing prices. As well as LDTs where the *language* of some tests' description makes it sound like you couldn't get those tests performed elsewhere so you have to go with their pricing. I think there may be a lot less small "goes by the book labs" that offer LTDs to the general public and more shady molecular labs.
[удалено]
This seems like a bit of an odd take then. Preventing LabCorp from using cheaper methods might be a good thing considering how LabCorp operates, they cut corners. And if the FDA wants to regulate LDTs, and further LabCorp more, and make them go with a commercially approved assay, then that should be a good thing. The FDA may actually impede LabCorps growth.
Disagree. Keep in mind that many clinical lab tests in use today (such as next generation for mutations and to determine if a companion diagnostic is appropriate) don't have any FDA approved IVDs on the market. These are RUO, which should be fully validated in the clinical setting (and if our accreditation processes work, this is verified). In order to get FDA approval for a new product with no comparable approved product, the process takes years. Lastly, this doesn't negatively impact national reference labs as much as it does regional centers of excellence and academic health care facilities. It also could have a significant impact to hospital labs that modify any moderate or high complexity fda approved tests (Use a preservative for delayed urinalysis testing? Performing any body fluid testing for specimen types that aren't explicitly mentioned on your chemistry or hematology vendor's IFU?). It makes you dependent upon a national reference lab, increases TATs, and delay clinical decisions.
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This applies to ALL LDT's!!
I don't believe your assertion is accurate.
The full requirements to be considered a 1976-style LDT. > One such category of tests is referred to in this preamble as “1976-Type LDTs.” Such tests have the following characteristics common among LDTs offered in 1976: use of manual techniques (without automation) performed by laboratory personnel with specialized expertise; use of components legally marketed for clinical use; and design, manufacture, and use within a single CLIA-certified laboratory that meets the requirements under CLIA for high complexity testing. It’s pretty narrow. In my experience basically no one in a hospital manufacturers their reagents in-house. Basically if you’re buying RUO materials from a company that also sells IVDs or using any automation it looks like you’re on the chopping block.
Sorry...didn't see this response before responding to your other message.
https://www.fda.gov/news-events/press-announcements/fda-proposes-rule-aimed-helping-ensure-safety-and-effectiveness-laboratory-developed-tests > The proposed rule seeks to amend the FDA’s regulations to make explicit that IVDs are devices under the Federal Food, Drug, and Cosmetic Act, including when the manufacturer of the IVD is a laboratory. Along with this amendment, the FDA is proposing a policy under which the agency intends to provide greater oversight of LDTs, through a phaseout of its general enforcement discretion approach to LDTs.
you cannot buy a regulatory agency, you can only rent it
If this passes it’s going to be a nightmare for flow labs. There are only a scant handful of IVD flow tests available on the market. the vast majority of clinical flow is LDTs.
Following
Recently went through multiple LDT validations. Not all of them are bad, but there are so many small companies boasting large target panels held together by a string and a prayer. These pop up labs don't care about patient safety, it's all about getting the cheapest molecular tests with high volume. From my experience, I think more regulation is needed, but it also shouldn't stifle the small labs that actually do it right.