Informally Summarizing the FMI CDX Concordance Studies

The FDA homepage for NGS PMA tests is here, product code PQP.  The FMI F1 CDX large panel test is P170019, here.

This is a very brief, freehand, and informal summary of some key S&E FDA review information. 

On page 36, the test has coverage of 702-793X in exomes.  Sequencing error rate was below the requirement of .01, specifically, about .003 (about 30% of the requirement).

Specimens passing all QC ranged from 96-100.   Four tissue types had <90% adequacy rates: pancreatic (83%), appendix (88%), pericardium (79%), prostate (84%).   

Longevity of paraffin block specimens was directly tested to 6 months with further tests underway.  However, two of the concordance studies used clinical samples with much older blocks.

Concordance studies were broken in seven groups:

1. EGFR Exon 19 DEL & L858R, cobas V2.
1. These two errors are about 85% of EGFR mutations.
2. EGFR T790M, cobas V2. 
1. This is a resistance mutation so only seen after treatment.  It is about 50% of resistance mutations.
3. ALK rearrangements  Ventana and Vysis
4. KRAS   Therascreen
5. ERBB2/HER2   Dako FISH
6. BRAF V600    Cobas V600 ThXID
7. BRCA 1-2    FMI Prior Art / FoundationFocus CDx BRCA

click to enlarge

Generally, concordance was based on Noninferiority of Li et al. (2016).   

Controls were CCD1 and CCD2 (duplicates of the control, which provides variance of the prior art PMA assay).  

Only two of the examples were based on clinical trial blocks (EGFR T790M, ALK), and these had more problems with missing samples or poor performance of CCD2 (possibly due to age).  Generally, about 200-300 blocks were used and samples were weighted to be about balanced positive and negative (based on CCD1).   Data was presented also as corrected for expected real world prevalence, which as FDA notes gives data somewhat lower than the lab data on the artificial prevalences.

In those two cases where clinical trial blocks were used, the data assessment is based on analytical validity (analytical concordance).   Also note that while FMI reports full sequence analysis, the FDA PMA evaluations can be based on much simpler point-mutation concordance.

EGFR EXON 19 DEL & L858R

Samples were convenience samples pre screened to give positives and negatives.   406 samples were tested.  84 were duplicates.  267 samples were available for final testing after discarding various process failures.

As in other "pure external concordance" cases, agreement was quite high.  There were 112 positives and 170 negatives.   Of the few mismatches a few were explainable by unusual mutations.  However, when corrected for real world prevalence, % agreement was slightly lower.  

Nearly all the % agreement were >97%.  

T790M

Blocks were based on AURA trials for osimertinib.  However, of 354 samples, 227 had full comparison data.   There were 145 positives, 167 negatives.  CCD2 had more common mismatches (e.g. 27 CCD2 negative out of 145 CCD1 positive).  This could be due to block age.

Most of the % agreement were anywhere from 72% to 95%.

HER2

317 retrospective convenience samples were available.   There were 125 positive, 192 negative.  CCD2 had some mismatches, e.g. 12 of 125 and 9 of 192.   Of 113 CCD double positives, 12 were F1 negative.

Most of the % agreement were from 80% to 96%. 

ALK

175 samples were from Roche ALEX alectinib vs crizotinib study (including screen failures to provide negatives).   Repeat Ventana IHC was not available, Retro VYSIS data was used as a surrogate.   Of 487 samples, 172 had insufficient slides.  Total positives 134, negatives 139.   Final samples were 175 after excluding missing data.  

For example, of 103 CCD double positives, 6 were F1 negative.  Of 134 CCD1 positives, 11 were CCD2 negative.  A smaller sample analysis was also presented (Table 41, 140 samples).  

% agreement ranged from 65% to 98%.   

KRAS

343 retrospective convenience samples.  As with other convenience samples, correlations were very high.   There were 177 positive and 165 negative.  

% agreement mostly >98%.

BRAF

305 retrospective convenience samples from advanced melanoma.   167 positive and 138 negative.  Concordance was nearly perfect.

% agreement was mostly > 98%.

BRCA

The two tests use the same reagents, equipment, and procedures except for lower DNA input for library construction and "enhancements in the analysis pipeline" which "have no impact" on the assay. See PMA P160018.

Summary Figures

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For a 27 page deck on the Japanese regulatory approach to NGS CDX, see here.

CMS OPPS APPENDIX D

CMS outpatient claims policy is driven by a document, revised quarterly, called "APPENDIX B" which has a column for "status indicators."  However, Status Indicators are only defined in a DIFFERENT document called APPNENDIX D1 which is issued in a zip file with final annual rulemaking. 

Cloud copy HERE.

I've also web-clipped the Appendix D for CY2018 below.

	ADDENDUM D1.─ OPPS PAYMENT STATUS INDICATORS FOR CY 2018
Status Indicator	Item/Code/Service	OPPS Payment Status
A	Services furnished to a hospital outpatient that are paid under a fee schedule or payment system other than OPPS,* for example:	Not paid under OPPS.  Paid by MACs under a fee schedule or payment system other than OPPS.
		Services are subject to deductible or coinsurance unless indicated otherwise.
	●  Ambulance Services
	●  Separately Payable Clinical Diagnostic Laboratory Services	Not subject to deductible or coinsurance.
	●  Separately Payable Non-Implantable Prosthetics and Orthotics
	●  Physical, Occupational, and Speech Therapy
	●  Diagnostic Mammography
	●  Screening Mammography	Not subject to deductible or coinsurance.
B	Codes that are not recognized by OPPS when submitted on an outpatient hospital Part B bill type (12x and 13x).	Not paid under OPPS.
		●  May be paid by MACs when submitted on a different bill type, for example, 75x (CORF), but not paid under OPPS.
		●  An alternate code that is recognized by OPPS when submitted on an outpatient hospital Part B bill type (12x and 13x) may be available.
C	Inpatient Procedures	Not paid under OPPS.  Admit patient.  Bill as inpatient.
D	Discontinued Codes	Not paid under OPPS or any other Medicare payment system.
E1	Items and Services:	Not paid by Medicare when submitted on outpatient claims (any outpatient bill type).
	●  Not covered by any Medicare outpatient benefit category
	●  Statutorily excluded by Medicare
	●  Not reasonable and necessary
E2	Items and Services:	Not paid by Medicare when submitted on outpatient claims (any outpatient bill type).
	for which pricing information and claims data are not available
F	Corneal Tissue Acquisition; Certain CRNA Services and Hepatitis B Vaccines	Not paid under OPPS.  Paid at reasonable cost.
G	Pass-Through Drugs and Biologicals	Paid under OPPS; separate APC payment.
H	Pass-Through Device Categories	Separate cost-based pass‑through payment; not subject to copayment.
J1	Hospital Part B services paid through a comprehensive APC	Paid under OPPS; all covered Part B services on the claim are packaged with the primary "J1" service for the claim, except services with OPPS SI=F,G, H, L and U; ambulance services; diagnostic and screening mammography; all preventive services; and certain Part B inpatient services.
J2	Hospital Part B Services That May Be Paid Through a Comprehensive APC	Paid under OPPS; Addendum B displays APC assignments when services are separately payable.
		(1)  Comprehensive APC payment based on OPPS comprehensive-specific payment criteria.  Payment for all covered Part B services on the claim is packaged into a single payment for specific combinations of services, except services with OPPS SI=F,G, H, L and U; ambulance services; diagnostic and screening mammography; all preventive services; and certain Part B inpatient services.
		(2)  Packaged APC payment if billed on the same claim as a HCPCS code assigned status indicator “J1.”
		(3)  In other circumstances, payment is made through a separate APC payment or packaged into payment for other services.
K	Nonpass-Through Drugs and Nonimplantable Biologicals, Including Therapeutic Radiopharmaceuticals	Paid under OPPS; separate APC payment.
L	Influenza Vaccine; Pneumococcal Pneumonia Vaccine	Not paid under OPPS.  Paid at reasonable cost; not subject to deductible or coinsurance.
M	Items and Services Not Billable to the MAC	Not paid under OPPS.
N	Items and Services Packaged into APC Rates	Paid under OPPS; payment is packaged into payment for other services.  Therefore, there is no separate APC payment.
P	Partial Hospitalization	Paid under OPPS; per diem APC payment.
Q1	STV-Packaged Codes	Paid under OPPS; Addendum B displays APC assignments when services are separately payable.
		(1)  Packaged APC payment if billed on the same claim as a HCPCS code assigned status indicator “S,” “T,” or “V.”
		(2) Composite APC payment if billed with specific combinations of services based on OPPS composite-specific payment criteria. Payment is packaged into a single payment for specific combinations of services.
		(3) In other circumstances, payment is made through a separate APC payment.
Q2	T-Packaged Codes	Paid under OPPS; Addendum B displays APC assignments when services are separately payable.
		(1)  Packaged APC payment if billed on the same claim as a HCPCS code assigned status indicator “T.”
		(2)  In other circumstances, payment is made through a separate APC payment.
Q3	Codes That May Be Paid Through a Composite APC	Paid under OPPS; Addendum B displays APC assignments when services are separately payable.
		Addendum M displays composite APC assignments when codes are paid through a composite APC.
		(1)  Composite APC payment based on OPPS composite-specific payment criteria.  Payment is packaged into a single payment for specific combinations of services.
		(2)  In other circumstances, payment is made through a separate APC payment or packaged into payment for other services.
Q4	Conditionally packaged laboratory tests	Paid under OPPS or CLFS.
		(1)  Packaged APC payment if billed on the same claim as a HCPCS code assigned published status indicator “J1,” “J2,” “S,” “T,” “V,” “Q1,” “Q2,” or “Q3.”
		(2)  In other circumstances, laboratory tests should have an SI=A and payment is made under the CLFS.
R	Blood and Blood Products	Paid under OPPS; separate APC payment.
S	Procedure or Service, Not Discounted When Multiple	Paid under OPPS; separate APC payment.
T	Procedure or Service, Multiple Procedure Reduction Applies	Paid under OPPS; separate APC payment.
U	Brachytherapy Sources	Paid under OPPS; separate APC payment.
V	Clinic or Emergency Department Visit	Paid under OPPS; separate APC payment.
Y	Non-Implantable Durable Medical Equipment	Not paid under OPPS.  All institutional providers other than home health agencies bill to a DME MAC.
	* Note -- Payments "under a fee schedule or payment system other than OPPS" may be contractor priced.

AHA vs CMS: No standing to sue CMS on 340B; case not ripe

In November 2017, CMS finalized rulemaking to lower the payments from CMS Parts A/B to hospitals where the drugs in question had been purchased under hefty 340B discounts.  AHA sued to stop the implementation.   Court rules that AHA has no standing to sue, as it has not exhausted remedies with the agency regarding specific claims.

The case is of interest as it documents the high barriers to getting a payment grievance into federal court, without exhausting other adminstrative remedies.

Case (Civil Action 17-2447) AHA vs HARGAN, online here.