Sunday, February 11, 2018

Procalcitonin in Antibiotic Stewardship Programs: 8 Links

Stover KR, Kenney RM, King ST, Gross AE.
Pharmacotherapy. 2018 Feb;38(2):271-283. doi: 10.1002/phar.2069. Epub 2018 Jan 16. Review.
2.
Broyles MR.
Open Forum Infect Dis. 2017 Oct 3;4(4):ofx213. doi: 10.1093/ofid/ofx213. eCollection 2017 Fall.
3.
Fung AWS, Beriault D, Diamandis EP, Burnham CD, Dorman T, Downing M, Hayden J, Langford BJ.
Clin Chem. 2017 Sep;63(9):1436-1441. doi: 10.1373/clinchem.2017.272294. Epub 2017 Jun 20. No abstract available.
4.
Ammar AA, Lam SW, Duggal A, Neuner EA, Bass SN, Guzman JA, Wang XF, Han X, Bauer SR.
Pharmacotherapy. 2017 Feb;37(2):177-186. doi: 10.1002/phar.1887. Epub 2017 Feb 3.
5.
Salahuddin N, Amer L, Joseph M, El Hazmi A, Hawa H, Maghrabi K.
Crit Care Res Pract. 2016;2016:6794861. doi: 10.1155/2016/6794861. Epub 2016 Jul 14.
6.
Cai Y, Ee J, Liew YX, Lee W, Chlebicki MP, Goh YC, Kwa AL.
J Infect. 2014 Oct;69(4):412-5. doi: 10.1016/j.jinf.2014.06.008. Epub 2014 Jun 23. No abstract available.
7.
Liew YX, Chlebicki MP, Lee W, Hsu LY, Kwa AL.
Eur J Clin Microbiol Infect Dis. 2011 Jul;30(7):853-5. doi: 10.1007/s10096-011-1165-6. Epub 2011 Jan 29.
8.
Harbarth S, Albrich WC, Müller B.
Crit Care. 2009;13(4):165. doi: 10.1186/cc7935. Epub 2009 Jul 13.

Wednesday, January 10, 2018

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













Tuesday, January 9, 2018

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.

Tuesday, January 2, 2018

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.

Friday, December 15, 2017

DAB Draws Fence Around Categorical vs R&N Decisions and Appeals Processes

Medicare ALJs are allowed to review LCDs for validity, and prior decisions have held this is true even if the LCD is couched in other formats such as an "article."   DAB has ruled that in some cases the articles are de facto LCDs and therefore they reach legal review channels as LCDs.

However, not every published adverse coverage decision gets to ALJ review under this concept of the broad category of LCD and de facto LCD.

In case 2782 in April 2017, the Department Appeals Board rules that a MAC published viewpoint that CGMs are considered "precautionary and non covered under the DME benefit" could not be reviewed as if it were an LCD. 

Link here.
https://www.hhs.gov/sites/default/files/board-dab-2782.pdf

The risk, of course, is that MACs could be wily and insulate non coverage decisions from review by tactially saying that XYZ, whatever XYZ is, is "precautionary or screening and therefore not a benefit," rather than stating that it is not reasonable and necessary.  For any topic.  Because DME category decisions include findings of fact about medical purpose, the category decision can have areas of conceptual overlap with an R&N decision.  And I agree with the poor over-ruled ALJ that "precautionary" is a weird concept, not found in CMS manuals or regulations.   Even regular  glucose blood tests could be seen as "precautionary" to find out if your insulin dose must be raised or lowered, and things like INR testing in warfarin patients is "precautionary" to find out if the INR level is too high or low.   For a patient with severe unilateral headaches, an MRI is "precautionary" to see if there is a brain tumor.

Brain teaser for the reader.  Since ALJ's are only allowed to review LCDs based on "reasonable and necessary" decisions, can a MAC frame its decisions in an Article and as "investigational and experimental" and thereby evade ALJ review?   In this hypothetical, MACs could stop putting out LCDs that services are "not reasonable and necessary" and instead put out articles that  services are "investigational and experimental," wording that is not reviewable by an ALJ...Perhaps double insulating its decision by stating the service is "not a benefit category" because it is "experimental and investigational."



Monday, December 11, 2017

Consultants Corner: Successful Deck Used in Changing the CMS 14 Day Rule

This deck came from a July 2017 article in AXIOS by Bob Herman, here.  For some additional follow-up, here.  For my cloud copy of the deck in case the original goes away, here.

A group of industry and association stakeholders met with CMS in May 2017 to discuss long-postponed and much-needed changes to the 14 Day Rule.  Below, I use the document's pagination (large numbers on the pages).   This PPT and meeting didn't sway CMS alone; there were many other touchpoints and stakeholders involved over a couple years.   But since this deck was associated with a success, it's probably worth study.

  1. The title is "The Impact of the Date of Service 14 Day Rule."  So the "point" is "The Impact" and the "topic" is the 14DR.
    • The stakeholders were Biodesix, Boehringer-Ingelheim, Guardant Health, LUNGevity, Myriad Genetics, Veracyte.  
  2. Slide 2 is a detailed OVERVIEW with three sections, about ten bullet points, and a concluding signal to the "recommendation" or ask.
    • So if you walk out after slide 2, you know everything the meeting was about.
  3. Slide 3 is a detailed "history of the problem" from 2001-2017.
  4. Slide 4 actually explains the whole 14DR, with a lot of text, but in a friendly "[Question]?" format.
    • Note they chose to place "the history of the problem" ahead of "what the 14DR is."  In part, they could be confident the people they were talking to knew what 14DR was.   On the other hand, and we don't know, if this was a meeting with The Administrator, rather than mid level policy staffers, you couldn't assume that content knowledge.
  5. Slide 5 is clinical: "Impact on Lung Cancer Outcomes."  ("Delay in treatment can result in worse outcomes, ^tiny journal footnote.")
    • "Impact" here echoes the title of the whole deck.
  6. Slide 6 is similar, but colorectal cancer.
  7. Slide 7 is a fancy flow chart infographic of the whole landscape presented visually and organized L to R by time.
    • Is the message "here's how the Swiss watch works" or "This damn thing you've created is more complex than a Swiss watch! It hurts my eyes!"
  8. "Consequences of These Billing Policies."  Three bold categories, visual, "Inconsistent billing," "Beneficiary Access Problems," "Reduced Efficacy of Treatment" due to 14DR delay.
    • From "Impact" to "Consequences."
  9. Slide is titled, "Real World Examples" but consists of a bullet description of the 7 stakeholders.   Possibly this slide was a "backdrop" for a planned discussed segment with a script for each stakeholder.
    • Make the problem real.  Tell a story.
  10. "Evaluating the DOS Rule Effects."  This is actually a short description of a CMS demo (requested by Congress) in 2012-2014, reported in 2016, that had no conclusions.
    • Years go by and you CMS do nothing.  At the least, do the following, next slide:
  11. ASK Recommend that CMS Solicit Comments on DOS in Proposed Regulation."   Flagged for CMS what points to request comment on.   Stakeholders, in this deck, did not tell CMS what an "edit" or "redline" should be.
  12. "Additional Outreach."   Coalition has a broad swatch of Hill meetings and has previously met with CMS at different level, and with groups like OMB.  Notably, the group had already also formally asked in 2016 that CMS take public comment on 2017, the same ask that is already on record and being repeated in this deck.
  13. "The Landscape of Precision Diagnostics."  Unclear why this occurs here, but it states that typical precision medicine tests are by a "lab that is unaffiliated with a hospital and specialized in one type of molecular testing."   It states that "some" ADLTs are performed by a "single laboratory" but I think all ADLTs must be sole source.
  14. Landing slide; Simple "Thank you" (not an ask or other message.)

Friday, December 8, 2017

How FDA Approved KEYTRUDA for All Solid Tumors based on MSI status

In 2017, FDA approved KEYTRUDA for all solid cancers based on LDT "MSI" status ("locally developed PCR tests for MSI-H").

Labeling here
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s014lbl.pdf


Clinical study table 24, table 25, page 41.  In colorectal cancer, N=90, ORR rises from 36% to 46%.  But Duration of Responses rises from 1.6 months to 22 months.

Other cancers were studied - in total 59, of which 14 endometrial, 11 biliary, 9 gastric, etc.  Many cases were studied N of 1.  There were variable but meaningful increases in ORR but big increases in DOR.

Click to enlarge.





For the Keytruda discussion in a December 2017 article on precision medicine in Nat Rev Clin Onc, by Moscow, Fojo & Schilsky (NCI, Columbia, ASCO), see here and clipping below.

click to enlarge

The December 21, 2017 NEJM has an interesting letter from Yarchoan and colleagues at Johns Hopkins plotting three things together:  ORR, TMB, and Tumor Type in one graphic.