LDT’s and the role of information in the regulatory

scheme PNWSP

October 2016

Ken Gatter, MD, JD

• NO conflicts of interest

• Not intended as legal advice

$9 billion to $800 million? $4.5 billion to nothing

Stealth Research, J. A. Ioannidis, JAMA 2015;313(7):663

Theranos Halts New Zika Test After FDA Inspection

http://www.wsj.com/articles/theranos-halts-new-zika-test-after-fda-inspection-1472598332

Good =

- lower cost,

- better access,

- less pain

Bad =

- lack of accuracy/precision,

- over diagnosis

“One tiny drop changes everything”

How should we adopt new tools?

• Regulatory – FDA, CLIA

• Clinical practice

• Reimbursement

Progress Innovation

Safety Efficacy Cost/Access

Dr Eric Kolodziej: As already mentioned, the science is moving at an unprecedented pace in terms of molecular biology and technology. This rapid pace really lends itself to open platforms like LDTs rather an IVD environment. However, as we all know, the lack of controls and regulation of LDTs carries risk, and it also creates disadvantages for those manufacturers seeking IVDs.

Senior VP, Global Regulatory Affairs, Roche Diagnostics, comments at FDA public meeting June 2011 on sequencing

So let me review some of the barriers to IVDs starting with LDTs, which is near and dear to my heart. As you all know, LDTs aren't manufactured under GMPs. They have little clinical validation, but they are widely used for clinical diagnosis. This creates an uneven playing field. The double standard penalizes both patients and clinicians who really don't understand that IVDs and LDTs are not equal.

outline 1. Introduction to LDTs

A. FDA and CLIA

2. The Role of Information in device regulation A. Off label and the First Amendment?

B. VUS and negligence?

Proposed Framework for LDT Oversight

• Two draft guidance documents:

• Draft Guidance for Industry, Food and Drug Administration Staff, and Clinical Laboratories: Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs)

• Draft Guidance for Industry, Food and Drug Administration Staff, and Clinical Laboratories: FDA Notification and Medical Device Reporting for Laboratory Developed Tests (LDTs))

• Published October 3, 2014

• Public meeting January 2015

• Comment period closed March 2015

Basic Overview

• FDA proposed oversight of LDTs: • Risk-based

• Phased-in

• Premarket review, QS for most LDTs

• Requirement for “notification” for all LDTs

• Requirement for adverse event reporting for all LDTs

“Carve-outs”

• Continued enforcement discretion for: • Rare tests

• Tests for unmet need

• Traditional LDTs

• Forensic (Law Enforcement) LDTs

• LDTs Used in CLIA-Certified, High- Complexity Histocompatibility Laboratories for Transplantation

• Intent: preserve access, promote innovation

• FDA - Traditional LDTs 1. Designed, manufactured and used within single lab

2. For a patient in that facility or system

3. Comprised of components legally marketed for clinical use

4. Interpreted by qualified lab professional (CLIA) without use of software

• CAP 3 tier proposal based on risk like all devices

• AMP CLIA modernization proposal

Next Gen Sequencing

July 2016

CLIA and FDA regulate differently

FDA Product Clinical validity, efficacy and safety

CLIA/CMS Lab Analytic validity

62 FR 62249 (1997)

“While FDA has stated that "clinical laboratories that develop [in-house] tests are acting as manufacturers of medical devices and are subject to FDA jurisdiction under the Act, ….

the Agency has generally exercised enforcement discretion over standard LDTs.”

Authority?

- ACLA 1992 and 2013

- Wash Legal Foundation 2006

Draft Guidance for Industry,

Clinical Laboratories, and FDA

Staff

In Vitro Diagnostic Multivariate

Index Assays

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.

Document issued on: July 26, 2007

Comments and suggestions regarding this draft document should be submitted within 30 days

of publication in the Federal Register of the notice announcing the availability of the draft

guidance. Submit written comments to the Division of Dockets Management (HFA-305),

Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.

Alternatively, electronic comments may be submitted to

http://www.fda.gov/dockets/ecomments. All comments should be identified with the docket

number 2006D-0347.

For questions regarding this document contact Courtney Harper at 240-276-0694

(courtney.harper@fda.hhs.gov). For questions regarding this document as applied to devices

regulated by CBER contact Martin Ruta at 301-827-3518

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Devices and Radiological Health

Office of In Vitro Diagnostic Device Evaluation

and Safety

Center for Biologic Evaluation and Research

Preface

The definition of a device is set forth at section 201(h) of the Food, Drug and Cosmetic Act ("the Act"). It provides in relevant part: "The term 'device' . . . means an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is . . . (2) intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals . . . ." (21 USC 321(h)).

Where are we today?

• LDTs meet device definition

• Draft Guidance • Risk based approach

• Comment period closed 2015

• Carve out for “traditional LDTs”

• Separate approach for NGS • Comment period about to close

Part 2: Information

a. Off label use and the First Amendment

US Constitution and LDTs?

• "To promote the progress of science and useful arts, by securing for limited times to authors and inventors the exclusive right to their respective writings and discoveries.” Article I, Section 8, Clause 8

• “Congress shall make no law [ ] abridging the freedom of speech” First Amendment

Commercial speech

“the Constitution imposes no … restraint on government regulation of purely commercial advertising.” Valentine v Chrestensen (1942) - overruled by Va Bd of Pharmacy v Va Citizens Consumer Council (1976)

“The First Amendment ... does not prohibit the evidentiary use of speech to ... Prove motive or intent”

US v Caronia: FDA, off label and the 1st Amendment

• Trial court • “Caronia’s constitutional attack calls into question America’s

regulatory regime for the approval and marketing of prescription drugs.” 576 Fsupp 2d 385 (2008)

• US v Caronia, (2nd Circ. 2012) • “[it] is generally recognized (even by the FDA) that off-label

prescriptions can constitute a medically recognized standard of care and, therefore, that it is important for physicians to have access to accurate information about off-label uses.”

Caronia (cont)

• “government’s application of the FDCA permits physicians and academics [ ] to speak about off-label use without consequence, while the same speech is prohibited when delivered by pharmaceutical manufacturers. … This construction thus has the effect of preventing [pharma] from communicating with physicians in an effective and informative manner.”

• “promotion of off label uses is not inherently misleading simply because the use is off-label.”

• “FDA exaggerates its overall place in the universe [in] asserting that any and all claims about the safety, effectiveness, contradictions, side effects and the like regarding [] drugs are presumptively untruthful or misleading until the FDA has had the opportunity to evaluate them.”

After Caronia (2012)

• Ct recognized manufacturer can make “truthful and non-misleading statements about off-label uses.”

• No appeal • Truth? • Intent to sell misbranded drug • Bias • Criminal case

• Amarin Pharma v FDA

• Pacira Pharmaceuticals

• US v Vascular Solutions - device case and failure to have 510(k) modification

• BUT: Acclarent – device ( no new 510(K) for sinus spacer for saline used for steroids)

Part 2a Summary

• Increasing tolerance for promoting off label use

• As long as “truthful and not misleading”

• Still uncertainty about what role 510(k) mod may play

Part 2b - information:

VUS and negligence?

timeline • 2005 – Christian is born

• 2005 – seizures at four months • Working diagnosis mitochondrial disorder

• Prescribed sodium channel blockers

• 2007 – SCN1A DNA sequence clinical diagnostic test reported as VUS (missense mutation)

• 2 publications that mutation assoc with Dravet Syndrome (severe myoclonic epilepsy in infancy (SMEI) in 2006 and 2007

• One of the lab directors was an author*** • Mother requests report but doesn’t get access

• 2008 – Christian dies

• 2014 – Dr friend requests report

• 2015 – Revised report, Known disease associated mutation. Report does not specify if additional testing done.

• Summer 2016 – Lawsuit filed

Plaintiff’s claims

1. Negligence/wrongful death – respondeat superior

2. Negligent misrepresentation 1. Cover-up

2. Didn’t include articles in revised report in violation of CLIA

3. Civil conspiracy

4. Unfair trade practices

Distinguishing Williams v Quest/Athena Labs

• Case is pending

• Germline not cancer

• Information about variant available at time of report

Some legal and policy issues: 1. What and whose responsibility for revisiting/updating? (not yet a

part of this case, but … .)

2. Role of CLIA/CFR violations? Med mal or ordinary negligence?

3. Lab transparency?

4. 10 years ago GAO called CMS oversight inadequate, - FDA stepping into the breach. How?

Summary

• 5 draft guidance documents – waiting for final versions

• Changing approach

• Exciting times - stay tuned

Thank you

FDA timeline

• 1906 - Food and Drug act – Gov’t must prove fraud.

• 1938 - FDCA premarket safety review – Gov’t need not prove fraud

• 1962 - efficacy added

• 1976 - Medical Device Amendment

• 1990 - Safe Medical Devices Act – reporting requirements for hospitals, nursing homes, etc

• 1997 - FDA Modernization Act

• 2015 - Precision Medicine Initiative - $10 million to FDA

501(k) modification enforcement as emphasizing conduct instead of speech