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Regulatory Hurdles: Looking ForwardIs the Status Quo Appropriate?
Debra G.B. Leonard, MD, PhD, FCAPWeill Cornell Medical College
June 9, 2009
IOM / NCPF Workshop onPolicy Issues in the Development of Personalized Medicine in Oncology
Title of Workshop:Policy Issues in the Development of Personalized Medicine in Oncology
Talking about:FDA-Reviewed Tests
vsLaboratory-Developed Tests (LDTs)
Need to resolve this issue and talk about important stuff!
Two Pathways for Clinical Tests
• FDA-Review of Clinical Tests– Grew out of food and drug safety and efficacy– Developed and validated by industry– Regulated by FDA
• Laboratory-Developed Tests – Developed and validated under the practice of
medicine – Now largely practiced by Pathology and Laboratory
Medicine physicians– Regulated under CLIA
History of FDA• Only patchwork state laws regulating composition and
labeling of food and therapeutics
• 1883: USDA Dept of Chemistry investigation of misbranding of foods & drugs in US
• 1887-1893: 10-part series “Food and Food Adulterants”
• Lobbying for new federal law to set uniform standards for food and drugs sold in interstate commerce
• 1902: Biologics Control Act in response to diphtheria toxin collected from a horse named Jim that also had tetanus resulting in several deaths
History of FDA - 2• 1906: Food and Drug Act
– Prohibits under penalty of seizure of goods– Interstate transport of adulterated food
• containing fillers of reduced quality or strength, • coloring to conceal damage or inferiority, • formulation with additives injurious to health, or • use of filthy, decomposed or putrid substances
– Interstate transport of adulterated drugs• standard of strength, quality, or purity of the active ingredient was
not either stated clearly on the label or listed in the United States Pharmacopoeia or the National Formulary).
– Examination of foods & drugs for adulteration or misbranding responsibility of the Bureau of Chemistry of the USDA.
• 1912 Amendment added false and fraudulent claims of curative or therapeutic effect to the Act's definition of misbranded.
• 1930’s: Outcry for stronger regulation of “bad” products
History of FDA - 3• 1938: Food Drug and Cosmetic Act (basis of current FDA)
– Increased federal regulatory authority over drugs by mandating apre-market review of the safety of all new drugs
– Banned false therapeutic claims in drug labeling without requiring that the FDA prove fraudulent intent.
– Authorized factory inspections and expanded enforcement powers– Set new regulatory standards for foods– Brought cosmetics and therapeutic devices under federal regulatory
authority– Enforced by Food and Drug Administration (FDA)
• 1951: Amendment creating “prescription-only” drugs
• 1938-1962: FDA review of ~13,000 new drug applications
History of FDA - 4• 1962: Amendment requiring substantial
evidence of efficacy in addition to safety
• Resulted in very slow approval of drugs
• 1967: Amendments giving authority over diagnostic tests; implemented in 1969-70
• Test oversight focused on devices, not LDTs, mostly due to resource issues
• 1980’s: AIDS epidemic drove creation of more rapid drug application review and drug use for patients with no other treatment options
Two Pathways for Clinical Tests
• FDA-Review of Clinical Tests– Grew out of food and drug safety and efficacy– Developed and validated by industry– Regulated by FDA
• Laboratory-Developed Tests – Developed and validated under the practice of
medicine – Now largely practiced by Pathology and Laboratory
Medicine physicians– Regulated under CLIA
Historical Perspective: 400 BC
Diagnosis: Boils
Hippocrates (460-377 BC)
Kidney Disease&
Chronic Illness
50 AD: Rufus of Ephesus
Failure of Kidneys toProperlyFilter the
Blood
Hematuria
Isaac Judaeus (850-932)
• Wrote a treatise of uroscopy (De urinis)• Summarizes knowledge of the ancients on
the significance of the density, color, clarity, etc. of urine and gives fixed rules on diagnosis and prognosis (10 chapters)
• Used as a reference source in European medical schools and in the Muslim world for more than five centuries
Interstate Commerce for Uroscopy
Practice of Uroscopy
across state lines
would raise major
FDA oversight issues today
Skip a few centuries…• Microscope applied to medicine – cell theory• Pasteur and Koch develop Microbiology in 1800’s• TB, cholera and diphtheria discovered in 1880’s• Tests available for these organisms by mid-1890’s
Diagnostic Test
Methodfor Syphilisfrom 1900Medical
Textbook
Diagnostic Test
Methodfor Diphtheria
from 1900Medical
Textbook
Skip a few centuries…
• Microscope applied to medicine – cell theory• Pasteur and Koch develop Microbiology in 1800’s• TB, cholera and diphtheria discovered in 1880’s• Tests available for these organisms by mid-1890’s• Spirochete that causes syphilis discovered in 1905• Wasserman test in use by 1906
Skip a few centuries…
• Microscope applied to medicine – cell theory• Pasteur and Koch develop Microbiology in 1800’s• TB, cholera and diphtheria discovered in 1880’s• Tests available for these organisms by mid-1890’s• Spirochete that causes syphilis discovered in 1905• Wasserman test in use by 1906• Tests routinely developed & performed by MDs• Continued with microbiology, as well as clinical
chemistry, hematology, endocrinology
Skip a few decades…CLIA• In 1980’s, concern about quality of PAP
smear interpretation and physician office labs• 1988: Clinical Laboratory Improvement
Amendments of 1988 (CLIA ’88)– CMS oversight and certification of clinical
laboratory quality, including physician office labs– Inspections began in early 1990’s– Deemed status by 6 entities, including CAP,
NYSDOH, JCAHO– Must be CLIA-certified to bill Medicare/Medicaid
Clinical Testing for Patients• Practiced by physicians for centuries
• Currently practiced by specialists in Pathology & Laboratory Medicine
• Science drives new understanding of disease
• New understanding drives application to medicine
• Tests first developed by pathologist experts and offered in CLIA-certified laboratory
• Test standardization with time and use
• IVD kits cleared by FDA used by all pathologists
Two Pathways for Clinical Tests• FDA-Review of Clinical Tests
– Grew out of food and drug safety and efficacy– Developed and validated by industry– Regulated by FDA
• Laboratory-Developed Tests – Developed and validated under the practice of
medicine – Now largely practiced by Pathology and Laboratory
Medicine physicians– Regulated under CLIA
• Neither test implementation process is perfect– FDA is not the gold standard– No evidence of harm from LDTs
SACGHS found
no evidence of poor quality of genetic tests,most of which
are LDTs
0.9810.987608560110.98457485657Total0.9800.96075721.0007272HB S/C interp0.9800.96075721.0007272HB S/C0.9330.87524211.0002121DMD0.9690.9943433410.944338319HH interp0.9971.0003483480.994339337HH0.9910.9891801780.994170169PW interp0.9900.9812672621.000247247FMR interp0.9900.9852652610.996246245FMR1 status0.9800.9852602560.974229223FMR10.9450.9614914720.928457424MTHFR interp0.9890.9884824760.991458454MTHFR0.9890.9898087990.988765756PT interp0.9900.9897987890.992764758PT0.9960.9988358330.995786782FVL interp0.9940.9968348310.992784778FVL
PercentPercentTotalCorrectPercentTotalCorrect2006 A+B2006 B2006 B2006 B2006 A2006 A2006 AAnalyte
Table 2. 2006 MGL PT Performance
0.9760.99214867147540.96414678141460.9721477914372Total
0.9661.00056560.93562580.9665856Troponin T qual
0.9720.9883303260.9563203060.971314305Troponin T quant
0.8770.96658560.90876690.7717054Troponin I qual
0.9270.994305530360.889282625110.89127812479Troponin I quant
0.9180.9527987600.8347856550.968756732Myoglobin(ng/ml)
0.9930.994625762170.991596859200.99458995863CK-MB (ng/ml)
0.9790.9901931910.9752412350.973220214CK-MB (U/L)
0.9980.999412041120.998440043920.99746814669HIV-1 Screening
%%TotalCorrect%TotalCorrect%TotalCorrect
Total2007C2007C2007C2007B2007B2007B2007A2007A2007AAnalyte
Proficiency Test Results for Non-Genetic Tests
Comparison of PT Performance
83.4 – 100%97.6%Non-Genetic Test
87.5 – 100%98.1%Genetic Test
Range CorrectAverage CorrectType of Test
No evidence of unusual quality issues with genetic LDTs
compared to other laboratory tests.
Current LDT Oversight• FDA:
– Review of IVD tests; – Not currently reviewing LDTs
• CLIA: – Certification of laboratories that perform tests;– Minimal review of LDT test validation data; ask FDA
• College of American Pathologists: – Certification of laboratories that perform tests; – 12 questions in Molecular Pathology checklist on new
test validation for LDTs• New York State Department of Health:
– Requires test submission and approval for any non-FDA reviewed tests, genetic or otherwise, performed on a NYS resident anywhere in the US
NYSDOH: Test Approval Process• Notification
– Laboratory Information– Test Information and Categorization– Intended Use– Performance Evaluation
• Assay Description– Methods– Requisition and Reporting– References– Initial Validation Protocol and Data
• Pre-Analytic Phase• Analytic Phase
– Quality Assurance
• Post-Analytic Phase• Specimen Run Data Examples
NYSDOH: Genetic Test Approval• Overview• Collection/Shipping Requirements/
Specimen Rejection Criteria• Materials and Methods• Results and Interpretations• Validation Data• Consent Form• Sample Requisition/Information for
Physicians/Flyers• Sample Reports
LDT vs FDA
SlowRapid
Post-market report monitoring by FDA
Ongoing monitoring by onsite expert
Used in many laboratoriesUsed in a single laboratory
Approved by FDA (using template from pathology)
Approved by expert review (Lab, CAP, NYSDOH)
Safety & efficacyAnalytic validityDeveloped by industryDeveloped by expertFDA-Approved TestLaboratory-Developed Test
HFE Test Adoption by US LabsHFE Test Adoption by US Labs
Merz et al, Nature 2002; 415:577-579.IVD test not available in 2000 by end of survey
Conclusions about LDTs vs FDA• No special quality concerns for LDTs regulated under CLIA,
CAP or NYSDOH• Test development is part of medical practice• Two pathways for clinical tests
– LDTs for tests at fore front of medical practice– FDA for test kits for broader medical use
• Do not eliminate the rapid pathway for test availability• If want greater assurance:
– Assure “expert” oversight of LDTs (director qualifications)– Require PT for all tests under CLIA, as required by CAP & NYSDOH– Use NYSDOH model or FDA review for:
• Highly complex tests (e.g., IVDMIAs)• High risk tests (e.g., blood supply tests)• Tests not performed for patients from own institution / service area
– DO NOT single out genetic/genomic tests; apply to all LDTs
Title of Workshop:Policy Issues in the Development of Personalized Medicine in Oncology
Talked about:FDA-Reviewed Tests
vsLaboratory-Developed Tests (LDTs)
Need to resolve this issue and talk about important stuff!
Bigger Issues than Regulation of LDTs
PHC & Healthcare Reform• Personalized Healthcare = Genomics + HIT (NIH definition)• Healthcare Reform = Improved Health Outcomes + ↓ Costs
– Medical Home Model will not work for PHC– New tests and drugs good for PHC, but also need to use current
tests and drugs properly• Pathology expertise underutilized for proper test selection,
interpretation and data mining because pathologists paid for volume, not value such as:
– Checking CBC result prior to issuing blood reduces blood utilization by one fourth
– Glucose level data returned to inpatient units improves glycemiccontrol for diabetic patients
• Pathology data mining can improve health outcomes and improves cost-effectiveness
New Model for New TestsBedside
Bench
Research driven by clinically relevant
questions
CLIA-CertifiedClinical Laboratory
Standardize Test Method and
Assure Test Quality
Registry of Test &Treatment Outcomes
With PaymentNeed National EHR Database
Clinical utility eitherestablished orstop using
Details of Registry for Discussion• Need data for all patients with relevant disease
– tested or not, – treated or not, – all ages and racial/ethnic groups, – from real medical practice
• Assure submission of testing, treatment and outcomes data either from large cohorts or nationally
• Interoperability of IT systems (clinical, pathology, pharmaceutical, radiology)
• Protection of data• Access to database• Monitoring of accumulated data for endpoints• Decision-making process for continued use or not• Payment by healthcare payers if data provided to registry
Final Thoughts
• Refine oversight and definition of LDTs• Stop focusing on LDTs and genomic tests
as special risk• Focus on quality and proper use and
interpretation of all tests• Use analysis of test data by pathologists to
reduce costs and improve outcomes• Create a pathway to generate clinical
validity and utility data without RCTs
Regulatory Hurdles: Looking ForwardIs the Status Quo Appropriate?
Absolutely Not!But we have to think
outside the box.
IOM / NCPF Workshop onPolicy Issues in the Development of Personalized Medicine in Oncology
Thank You for Your Attention!
A Brief History of Healthcare Economics• 1965: Medicare/Medicaid Established
– Fee for service reimbursement system– Incentive for ↑ service & complexity– Labs as profit centers for hospitals
• 1965: Medicare/Medicaid Established• 1970’s: ↑ Healthcare Expenditures
– New technologies– ↑ Number of physicians– ↑ Elderly population– Financial incentives of open-ended reimbursement– Labs making money for hospitals and Pathology Dept
A Brief History of Healthcare Economics
Healthcare Costs in United States
110
1001,000
10,000100,000
1,000,00010,000,000
100,000,000
1960 1980 1995 2007 2016
Tot
al C
osts
(in
1000
's)
0
5
10
15
20
25
% G
DP
8.9%5.1%% US GDP$247B$26.9BTotal HC Costs
10X↑↑
• 1965: Medicare/Medicaid Established• 1970’s: ↑ Healthcare Expenditures• 1983: Congress Legislates PPS/DRG System
– Prospective Payment System (PPS) based on Diagnosis Related Groups (DRGs)
– Medicare inpatient reimbursement based on predetermined cost/case based on diagnosis
– Created powerful incentive to ↓ unnecessary services, ↓ LOS, ↓ admissions & ↑ outpatient care
– Labs became cost centers → lab budget cuts
A Brief History of Healthcare Economics
• 1965: Medicare/Medicaid Established• 1970’s: ↑ Healthcare Expenditures• 1983: Congress Legislates PPS/DRG System• 1990’s: Rapid Growth of MCOs
– Managed Care Organizations pay regular prospective capitated payments for beneficiaries
– Theory: ↓ Costs by cost-sharing across beneficiaries, ↓ admissions & LOS, ↑ outpatient care
– Reality: ↓ services to patients, ↑ care efficiency, reduced income of MDs and other providers
– Placed all financial risk on MDs & hospitals– Further lowers lab revenues & budgets
A Brief History of Healthcare Economics
• 1965: Medicare/Medicaid Established• 1970’s: ↑ Healthcare Expenditures• 1983: Congress Legislates PPS/DRG System• 1990’s: Rapid Growth of MCOs• 1992: CLIA’88 Implemented
– Reduced required minimum standard of education for technical staff from usual practice of 4 yr bachelor degree to 2 yr associates degree
– Combined effects of MCOs & CLIA result in • Lab staff layoffs, • ↑ technicians in place of technologists to ↓ costs, • Salaries held constant • ↓ Benefits
A Brief History of Healthcare Economics
• 1965: Medicare/Medicaid Established• 1970’s: ↑ Healthcare Expenditures• 1983: Congress Legislates PPS/DRG System• 1990’s: Rapid Growth of MCOs• 1992: CLIA’88 Implemented• 1993: Universal HC Coverage Legislation Fails
A Brief History of Healthcare Economics
Healthcare Costs in United States
110
1001,000
10,000100,000
1,000,00010,000,000
100,000,000
1960 1980 1995 2007 2016
Tot
al C
osts
(in
1000
's)
0
5
10
15
20
25
% G
DP
13.4%8.9%5.1%% US GDP$991B$247B$26.9BTotal HC Costs
• 1965: Medicare/Medicaid Established• 1970’s: ↑ Healthcare Expenditures• 1983: Congress Legislates PPS/DRG System• 1990’s: Rapid Growth of MCOs• 1992: CLIA’88 Implemented• 1993: Universal HC Coverage Fails• 1995: Growth of Outpatient Specialty Businesses
– MCOs seek efficient healthcare services– Surgicenters, MRI/CT facilities, urgent care centers– Decreased hospital provision of these services– Lab services as a commodity, not a medical service– Growth of commercial laboratories– Continued increase of US health care costs
A Brief History of Healthcare Economics
Healthcare Costs in United States
110
1001,000
10,000100,000
1,000,00010,000,000
100,000,000
1960 1980 1995 2007 2016
Tot
al C
osts
(in
1000
's)
0
5
10
15
20
25
% G
DP
20%16%13.4%8.9%5.1%% US GDP$4.2T$2.3T$991B$247B$26.9BTotal HC Costs
4.3X National Defense Budget
Impact of Recent Economic History on Labs• 1965–1970’s: Labs as profit centers• 1980’s: Under PPS/DRG, labs become cost
centers, hospitals cut lab budgets, ↓ staff• 1992: CLIA’88 allows lower staff qualifications• 1990’s: MCOs drive commoditization of labs
– Testing volumes continue to increase– Labs learn to do more with less
• Replacement of technologists by technicians• Automation• Staff cuts, lack of salary increases, loss of benefits
• 2000-Present: Labs Adjust to MCO Environment– Labs consolidate to ↓ costs– ↑ Outreach testing– Reacquisition of outpatient testing
Changing Lab Market Shares
37%39%20%Reference Labs
55%46%52%Hospital Labs
8%15%28%Physician Office Labs
200719961986Laboratory Type
CLIA’88 Implemented
Growth of MCOs
↑ Outreach Testing by
Hospital Labs
