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AIPLA Annual Meeting Joint Biotechnology Committee/ Special Committee on FDA Law Program October 21, 2010 Marriott Wardman Park Hotel – Washington, DC. FDA Regulation of Diagnostic Tests. Jeffrey N. Gibbs Hyman, Phelps & McNamara, P.C. Washington, DC jgibbs@hpm.com. Introduction.

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fda regulation of diagnostic tests

AIPLA Annual Meeting

Joint Biotechnology Committee/

Special Committee on FDA Law Program

October 21, 2010

Marriott Wardman Park Hotel – Washington, DC

FDA Regulation of Diagnostic Tests

Jeffrey N. Gibbs

Hyman, Phelps & McNamara, P.C.

Washington, DC


  • In Vitro Diagnostics (IVDs) are playing an increasingly important role in medicine.
  • Many new types of diagnostics being developed.
  • Introducing new diagnostics to the market presents potential regulatory challenges.
definition of an ivd
Definition of an IVD
  • A product intended to be used to “diagnose a disease or other condition” is regulated as a device.
  • “Diagnose” has been given a broad interpretation by the courts.
  • “Diagnose” also encompasses screening, monitoring, prognosis, etc.
  • Technology does not determine whether product is regulated as a device.
  • Not all tests are diagnostic, e.g., genealogy, ancestry, etc.
intended use a pivotal concept
Intended Use: A Pivotal Concept
  • “Intended Use” is governed by the objective intent of the company – 21 C.F.R. § 801.4.
  • Intended use can determine whether Premarket Approval (PMA), 510(k) Premarket notification, or no FDA review.
  • Intended use can determine how much data and what type, e.g., prospective large scale study for screening study vs. small retrospective study for monitoring.
  • Affects reimbursement.
  • Relationship to IP?
intended use a pivotal concept cont d
Intended Use: A Pivotal Concept (cont’d.)
  • Needs to be considered at an early stage and integrated with regulatory, clinical and marketing input.
  • Needs to match clinical data and study population.
  • Controls claims for IVD once cleared/approved.
  • Subtle differences can have a large regulatory impact, e.g., “rule out” vs. “rule in.”
intended use a pivotal concept cont d1
Intended Use: A Pivotal Concept (cont’d.)
  • Intended use can include population tested, purpose of test, etc.
  • An intended use is more specific than “A test for Cancer X.”
  • Closely related term is “indications for use.”
  • Subject to intensive negotiations with FDA.
    • What companies end up with can be very different from their starting point.

To sum up: Can determine whether PMA or 510(k), what data need to be collected (time and cost), reimbursement coverage, and marketing strategy.

in vitro diagnostics ivds routes to the market
In Vitro Diagnostics (IVDs):Routes to the Market
  • Premarket Approval Application
  • 510(k) premarket notification
  • De Novo Reclassification
  • Investigational Use Only
  • Research Use Only
  • Analyte Specific Reagents
  • Laboratory Developed Tests
fda classification scheme
FDA Classification Scheme
  • Level of regulation linked to product risk.
  • Class I – low risk.
    • 510(k) generally not needed; may be exempt from Good Manufacturing Practice (GMP) regulation.
    • Example: Equine encephalomyelitis virus serological reagents.
  • Class II – moderate risk.
    • Usually subject to 510(k) and GMP.
    • Example: Glucose.
    • May also need to meet special controls.
  • Class III – highest risk.
    • PMA required.
    • Example: Human Papilloma Virus assays and cancer screening tests.
  • Risk is independent of performance of the assay.
510 k premarket notification
510(k) Premarket Notification
  • Most common route to market with new assay.
  • Need to show “substantial equivalence” to a “predicate device.”
    • Predicate devices on the market beforeMay 28, 1976 or cleared by FDA through a 510(k).
    • PMA approved device cannot be a predicate device for a 510(k), unless reclassified.
510 k premarket notification cont d
510(k) Premarket Notification (cont’d.)
  • Substantial equivalence.
    • Same intended use, though FDA has some flexibility in applying requirement.
  • Same technology, or technological differences do not raise different issues of safety or effectiveness.
    • Typically, the use of novel technology, such as protein-based markers, does not preclude 510(k) clearance.
    • Will need to provide performance data.
  • The kinds of data requested may be affected by type of technology and its novelty.
  • Clinical data will be required for new types of assay.
  • Analytical test data, e.g., reproducibility, will be required.
510 k premarket notification cont d1
510(k) Premarket Notification (cont’d.)
  • FDA can find Substantially Equivalent, allowing IVD to be marketed.
  • Can find 510(k) Not Substantially Equivalent, i.e., reject it.
  • Ask for more information.
  • 90 days per review cycle.
  • Recently, many criticisms of 510(k) process.
  • FDA has unveiled internal reports on the 510(k) process, with many recommendations.
    • In general, will make 510(k)s more challenging.
de novo classification
De Novo Classification
  • Some low or moderate risk devices lack predicate device.
  • For these products, FDA can use de novo classification process.
    • Company submits 510(k).
    • Found Not Substantially Equivalent.
    • Then submit petition for de novo classification.
    • FDA can then clear the device.
    • FDA will issue special controls guidance document.
de novo classification cont d
De Novo Classification (cont’d.)
  • FDA has used de novo process about two times per year for IVDs, e.g., circulating tumor cells for breast cancer, and recent ovarian cancer test.
  • FDA prefers to use 510(k) if possible because less work, since no guidance document needed.
  • Subsequent applicants can use 510(k) process.
premarket approval application
Premarket Approval Application
  • Requires clinical data.
  • Voluminous submission.
  • 180 day review cycle.
  • Advisory panel for at least the first submission for that type of assay.
  • Pre-approval GMP inspection.
  • FDA typically monitors study sites.
  • More costly than 510(k)s and generally takes longer.
  • Once obtain approval, harder to make changes.
  • 510(k) route is preferred.
  • Potential exclusivity impact of IVD intended to be used diagnostically with drug?
  • Can get patent term extension.
investigational use only iuo
Investigational Use Only (IUO)
  • IUO products are intended for use in clinical investigations.
  • Vehicle for generating clinical data to support marketing application.
  • Can charge for IUO products within limits.
  • Product must be labeled as IUO.
  • Sponsor needs to receive some data back from investigators.
  • Limited promotional claims.
  • Manufacturer can sell IUO products.
  • Clinical trial agreement between sponsor and investigator.
    • Should include IP-related clauses
  • IUO products may have protection from patent infringement claims.
investigational use only iuo cont d
Investigational Use Only (IUO) (cont’d.)
  • Generally, FDA approval not needed to begin study.
    • Typically will need approval from an institutional review board for prospective studies, and possibly for retrospective.
    • May need to obtain patient informed consent.
  • Banked specimens can be used under some circumstances.
  • Exempt from GMP regulation.
research use only ruo
Research Use Only (RUO)
  • RUO products are intended for use in basic research or to identify a potential clinical application.
  • Cannot claim safe, effective, or has diagnostic utility.
  • Can charge for RUO products.
  • No need to collect data.
  • Exempt from GMPs.
  • Can create reimbursement issues for laboratories.
  • Useful for niche products, but not a successful long-term strategy for products with diagnostic value.
  • FDA has been concerned about misuse of RUO category, and plans to issue a new draft guidance document aimed at RUO manufacturers.
analyte specific reagents asrs
Analyte Specific Reagents (ASRs)
  • ASRs are building blocks for assays developed by laboratories.
  • They are generally exempt from 510(k) or PMA, but do need to comply with GMPs.
  • In a guidance document issued in September 2007, FDA substantially narrowed the scope of ASRs.
    • Can contain only a single marker, e.g., no primer/pair probes.
    • Cannot be on a bead or something similar.
laboratory developed tests ldts
Laboratory Developed Tests (LDTs)
  • LDTs are subject to the Clinical Laboratory Improvement Amendment.
  • FDA first said it could regulate LDTs in 1992.
  • According to FDA, all LDTs are medical devices and subject to full device regulation.
  • FDA did not seek to exercise power until a few years ago.
  • Exercising it more frequently, e.g., Warning Letter to LabCorp regarding OvaSure.
  • Issue: How much work does a lab need to do for a test to qualify as LDT?
laboratory developed tests ldts cont d
Laboratory Developed Tests (LDTs) (cont’d.)
  • FDA has stated it intends to no longer exercise “enforcement discretion” over LDTs, but will actively regulate them.
  • Two-day public meeting in July to discuss.
  • Commenters did not oppose concept of FDA regulation.
  • Considerable concern about manner in which regulation would occur, particularly for rare/orphan diseases and emerging diseases, and cost of regulation.
  • FDA has said prioritization scheme will be risk-based.
  • Diagnostics that guide drug therapy will be priorityfor being brought under FDA regulation.
laboratory developed tests ldts cont d1
Laboratory Developed Tests (LDTs) (cont’d.)
  • Will take some time for details of framework to be developed.
  • FDA has said does not intend to disrupt current testing.
    • Grandfather period for tests on the market.
    • Grace period, i.e., delayed effective date.
    • Impact on innovation?
    • Impact on FDA workload?
  • FDA’s regulation of LDTs may prompt litigation.
  • Begin by requiring registration of laboratories?
  • Public health impact increasing.
  • IVDs represent a large and growing industry.
  • Complex, evolving regulatory environment.