FDA and LDT Laurel Estabrooks, PhD, FACMG VP Genetics Business Development SCC Soft Computers

Timeline July 2014 – FDA notified Congress of intent September 30th, 2014 – released documents Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs) FDA Notification and Medical Device Reporting for Laboratory Developed Tests (LDTs)

Timeline February 2, 2015 – 120 day Comment Period Closed Had 2 day public meeting with 6 panels (80 registered to speak) Numerous groups submitted questions and concerns Some groups hired lawyers to address this (ACLA) Unknown date – Final Guidance will be released After review of all submitted comments and concerns Responses to above questions and concerns will be provided at the time of the Final Guidance release

Cost FDA Regulation + Delay of Test Release = Reaction to FDA Draft What is the device to be regulated? Isn’t this duplicating CLIA role? Is this equation really valid? Cost FDA Regulation + Delay of Test Release = Better Health Care

Definition of LDT FDA Definition of an LDT "a type of in vitro diagnostic test that is intended for clinical use and designed, manufactured and used within a single laboratory“ Prompted New Definition of an LDP a professional service that encompasses and integrates the design, development, validation, verification, and quality systems used in laboratory testing and interpretative reporting in the context of clinical care

CLIA vs. FDA Intent CLIA Performance specifications for FDA Accuracy Precision Analytical sensitivity Analytical specificity Reportable range of test results Reference intervals Other performance characteristics deemed required for proper test performance FDA Clinical validity Ability of a diagnostic device to measure or detect the clinical condition for which the device is intended Test (analytical) validation before marketing/release QSR (Quality System Regulations) Adverse event reporting Ability to remove unsafe devices/tests

Demonstration of Clinical Validity Study with patients (clinical trials, double blind studies) Use of clinical literature Reduce investment in clinical studies to demonstrate validity

QSR (Quality System Regulations) Focus on Design Control Design controls are procedures that test developers use to guide the development and design of their devices.

MDR (Medical Device Reporting) Requires submission of reports whenever you become aware of information that reasonably suggests your LDT may have caused or contributed to a death or serious injury, or the LDT has malfunctioned and the malfunction would be likely to cause or contribute to a reportable death or serious injury should it recur

How many labs will be affected? ACLA estimates 10,000 labs in US providing more than 100,000 LDT services

Classes of Risk - Highest Class III Companion Diagnostics Tests that predict patient response to drug(s) Asymptomatic testing/screening Any test that already has an FDA approved equivalent test PMA Could take up to a year to complete process

What is a PMA? PMA (Pre-Market Approval): Provides FDA Approval Includes an FDA review May require a clinical trial Estimated Cost ~$250K

Classes of Risk - Moderate Class II FISH Arrays 510(k) Could take a few months to complete process

What is a 510(k) ? Provides FDA Clearance Likely to be performed by a Third Party Review Estimated Cost ~$4K 510(k) requires demonstration of substantial equivalence (SE). SE means that the new device is as safe and effective as the predicate device(s).

What is a 510(k) ? A device is SE if, in comparison to a predicate device it: has the same intended use as the predicate device; and has the same technological characteristics as the predicate device; or has different technological characteristics, that do not raise new questions of safety and effectiveness, and the sponsor demonstrates that the device is as safe and effective as the legally marketed device.

Classes of Risk - Lowest Class I Rare diseases (<4,000 tests/year) “Traditional LDT” (chromosome analysis) Unmet need Enforcement discretion Notification and MDR still required

Continued Enforcement Discretion with Respect to Premarket Review LDTs used for Rare Diseases # of persons tested <4,000 (FDA now recognizes testing frequency does not equal disease frequency so may alter this) HUD qualification (Humanitarian Use Device)/HDE (Humanitarian Device Exemption)

Continued Enforcement Discretion with Respect to Premarket Review Traditional LDTs If available when FDA began enforcement discretion in 1976 Interpretation by lab professionals, no automated instruments or software for interpretation LDTs for unmet needs when no FDA-cleared or approved alternative exists

Enforcement Discretion in Full Enforcement Discretion – FDA will choose not to regulate at this time LDTs used for forensic purposes LDTs used in CLIA-certified, high complexity laboratories for transplantation

What about “tweaking”? When a clinical lab alters a test in a way that can change its Intended use Performance For example: altering specimen type or target population Then the lab is subject to Premarket Requirements

Other considerations Intended Use Clinical Validity Dr. orders a test that is not intended for patient’s condition Test identifies something “unintended” Clinical Validity Some definitions of disease are still being defined Disease spectrum Reduced penetrance Pleiotrophy

What will this Cost? application type standard fee small business fee† 510(k)‡ $5,018 $2,509 513(g) $3,387 $1,694 PMA, PDP, PMR, BLA $250,895 $62,724 panel-track supplement $188,171 $47,043 180-day supplement $37,634 $9,409 real-time supplement $17,563 $4,391 BLA efficacy supplement PMA annual report $8,781 $2,195 30-day notice $4,014 $2,007

What will this Cost per “product”? 2010 Stanford study of Device Manufacturers: 24M on average average cost to take a 510(k) product from concept to market is $31 million, and that roughly 77% of that amount is spent on tasks related to FDA regulation 75M for High Risk PMA High-risk PMA costs averaged $94 million, the report states, with $75 million of that spent on "stages linked to the FDA." FDA Impact on U.S. Medical Technology Innovation: A Survey of Over 200 Medical Technology Companies • November 2010

Genetics Lab Cost Estimation Dr Genetics Lab Cost Estimation Dr. Tanner Hagelstrom, UNMC Presentation at ACMG Meeting March 2015 Assumptions: Chromosome Analysis falls under Traditional LDT NGS would require a PMA FISH + Microarray tests would require a 510(k) Fixed cost = Total of 3M PMA = 1.4M 510(k) = 1.6M

Genetics Lab Estimation Variable costs = ~400k per year Includes 0.5 FTE dedicated to FDA documentation and management Anticipated increase in cost of testing: FISH 185% Microarray 15% NGS 25%

Again Begs the Question Is this equation really valid? Cost FDA Regulation + Delay of Test Release = Better Health Care

Against FDA Regulation Which Side Are You On? For FDA Regulation AdvaMedDx Against FDA Regulation ACLA AMP CAP ASCP ACMG

Timeline Final Guidance (no date yet) What comes next: Have 6 months to complete FDA Notification ( no registration fees) 6 months post Final Guidance MDR regarding LDTs is required 24 months post Final Guidance FDA will release a draft guidance describing what tests they consider to be in the 3 Classes FDA will address Class III at year 1-5 FDA will address Class II years 4-9

How can Soft help? Clinical Validity Auto-send clinical follow-up and reminder notifications to physicians Link tests in a group to evaluate results and clinical information Provide reports of grouped individual results without patient identifiers (in progress) Query of patients based on test results and indications

In Memory of Dr. Warren Sanger

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