Project Description

Potential Impact of the VALID Act on IVD Manufacturers

Background:  A Brief History

In 1976,amendments to the Food, Drug, and Cosmetic (FD&C) Act gave the Food and Drug Administration (FDA) the authority to regulate in vitro devices (IVDs, see Inset 1).

INSET 1.  in vitro devices (IVDs) are defined as “reagents, instruments, and systems intended for use in diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae”.

Following the initial passage of the 1976 Amendments, the Agency concluded that Laboratory-developed Tests (LDTs, see Inset 2) were generally used within the restricted environment of a hospital and for the benefit of institutional clinicians only.  Thus, their use and interpretation were limited, andFDA chose to exercise “enforcement discretion” over the commercialization of LDTs.

INSET 2.  Laboratory developed tests (LDTs) are defined as IVDs “intended for clinical use and designed, manufactured and used within a single laboratory”.

Beginning in 2010 the Agency signaled a need to regulate LDTs.  Pharmaceutical companies complained that FDA needed to provide clear and consistent standards for all IVDs, and Genentech submitted a Citizen Petition to that effect1.  Other professional societies and industry groups joined the discussion, with some for and some against FDA regulation of LDTs2.

In 2014, FDA published two Guidance Documents within which they proposed a framework for regulation of LDTs3 and notified Congress of their intent to regulate LDTs.  The guidance was not implemented, however, and following the election in 2016, FDA stated publicly that they would not pursue regulation of LDTs4.

Meanwhile, in 2015,a consortium on representatives from laboratories and test manufacturers provided a proposal to reshape FDA regulation of IVDs10.  These recommendations were later encompassed in new proposed legislation framed as the Diagnostic Accuracy and Innovation Act (DAIA) sponsored by Larry Bucshon (R, IN) and Diana DeGette (D, CO).

In early 2017, FDA issued a discussion paper describing their latest proposals for regulation of LDTs5 as an update to the essentially defunct 2016 documents.

FDA ratcheted up the pressure on laboratory developed test providers in 2018 when they issued a Safety Communication aimed at companion diagnostic tests where they believed that the relationship between test results and patient response to specific medications was not well established6.

FDA subsequently notified several manufacturers who removed references to specific medications in their labeling and test reports.  When Inova Genomics declined to do so, FDA issued a Warning Letter7dated April 4, 2019.  The American Clinical Laboratory Association responded with a strongly worded letter asking FDA to refrain from their recent enforcement actions because they may impact patient care, increase costs, and have a negative impact on the ongoing discussions between industry, FDA and Congress to redesign regulatory oversight of all laboratory tests8.

FDA and Industry – when the going gets tense, the tense go to Congress

As the tension between FDA and the laboratory industry has increased, new legislation has been under development in Congress.  On the one hand, FDA says “We shouldn’t subject similar tests to different approaches just because they are made by different developers;” on the other hand, the laboratory industry supports new legislation aimed at providing FDA with clear authority to regulate LDTs and streamline theprocess9.

Following the initial draft of DAIA in 2015 (see above), FDA proposed a revised draft, and the proposal later resurfaced as a Discussion Draft titled the “Verifying Accurate Leading-edge IVCT Development Act of 2018”, the VALID Act (currently a Bill), still sponsored by Bucshon and DeGette11.  This new proposal includes novel provisions that change how laboratory tests – IVDs – are regulated.

Definitions – a case of less said the better?

First, FDA redefines IVDs as In Vitro Clinical Tests (IVCTs, see Inset 3) with a multi-page definition intended to encompass all possible conditions and contingencies.  Of great importance to clinical labs, the proposed legislation would give FDA unambiguous authority to regulate all IVCTs regardless of where they are manufactured – meaning that LDTs would fall under FDA jurisdiction.

Traditional Class I, II and III (low to high risk) regulatory tiers would be replaced with two tiers:  High Risk and Low Risk (see link in Inset 3, ‘‘Subchapter J—In Vitro Clinical Tests, Definitions, Subsections 7 and 8, respectively).  The definition of high risk is somewhat gray but includes cross-referenced tests and first-of-a-kind tests.  Low Risk Tests would be exempt from premarket review.

INSET 3:  In Vitro Clinical Tests (IVCTs) include devices used to collect specimens from the human body for “identifying, diagnosing, screening, measuring, detecting, predicting, prognosing, analyzing, or monitoring a disease or condition” and for “selecting, monitoring, or informing therapy or treatment for a disease or condition.”  See in definition in full in Sec. 2 Definitions in the PRELIMINARY DISCUSSION DRAFT, presented to the 115THCONGRESS 2nd SESSION, Title “To amend the Federal Food, Drug, and Cosmetic Act to provide for the regulation of in vitro clinical tests, and for other purposes,” time stamped: December 6, 2018 (3:04pm), see, e.g., https://www.genomeweb.com/sites/default/files/valid_act_discussion_draft_12.6.18.pdf

High risk tests would require a demonstration of analytical and clinical validity which would seem to preclude demonstration of “clinical utility” which is a higher bar requiring evidence of benefit to the patient or the healthcare system.  It is not clear if premarket approval would require submission of a manufacturing section and a pre-approval manufacturing audit.

Pre-certification Program – good intentions, but …?

The current VALID Act includes a “Pre-certification Program” in which one test representing a “test group” is subject to the preapproval requirement, but the remainder of the tests in the class are exempt.  Test groups would be required to share the same analyte type, specimen type, method, purpose, disease state, patient population and context of use.  FDA claims that this provision would apply to 40-50% of all IVCTs, but it is difficultto imagine this will be the case, given that each analyte,in effect, defines its own test group.

In addition, pre-certification excludes test platforms, collection devices, software, certain blood tests, first-of-a-kind tests, home use tests, high risk tests, companion and complementary diagnostics and direct to consumer tests.  While well intentioned, this approach is so restrictive as to be of limited value to manufacturers.  Other provisions would allow a five-year window to laboratories that utilize research-use only (RUO) platforms to switch to FDA-approved platforms.

Preapproval Requirements – condition kudos …

Some tests would be exempt from preapproval requirements, e.g., “grandfathered tests,” those in use 90 days prior to passage of the Act.  Low risk tests, tests for rare diseases (< 8000 individuals tested per year), and pre-certified tests would also be exempt.

The draft ACT includes a good faith effort to minimize the number of tests subject to pre-approval requirements.In fact, Scott Gottlieb stated before he left the Agency that recent FDA proposals would subject only 10% of all IVCTs to preapproval requirements.  The current draft of the Act may not achieve that objective, but the effort is to be applauded.

What happened to Provisional Approvals?

Notably missing from the discussion draft is reference to provisional approvals.  This path has traditionally afforded protection to small biotech start-ups from the time and cost burdens of bringing novel technologies through FDA.  Omitting this path may reflect a reality of favoring the needs and interests of larger institutional firms over those of smaller, more agile businesses that respond quickly to customers’ needs.

Parting thoughts

Given the recent course of events, a few points seem morecertain:

  • FDA is intent on pushing to regulate LDTs;
  • Industry and in Congress are ready to support new (IVCT) legislation;
  • The VALID Act could create a more comprehensive and harmonized FDA regulatory framework for diagnostic tests.

Note well:  There is still time to contribute to the development of this legislation.  Industry partners of all stripes should make every effort to participate in the development of the final language.  Small business should especially take notice to strengthen the current draft to recognize and represent their needs and interests.

References

  1. Genentech Citizen Petition: https://www.genomeweb.com/archive/genentech-files-citizen-petition-urging-fda-regulate-all-lab-developed-tests
  2. Sarata AK and Johnson JA. Regulation of Clinical Tests: In Vitro Diagnostic (IVD) Devices, Laboratory Developed Tests (LDTs), and Genetic Tests.  Congressional Research Service 7-5700.
  3. https://www.fda.gov/media/89316/download
  4. https://www.statnews.com/2016/11/18/fda-lab-test-loophole/
  5. https://www.fda.gov/media/102367/download
  6. FDA Safety Communication (2018): https://www.fda.gov/medical-devices/safety-communications/fda-warns-against-use-many-genetic-tests-unapproved-claims-predict-patient-response-specific#actions
  7. Inova Genomics Warning letter (2019): https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/inova-genomics-laboratory-577422-04042019
  8. ALCA Letter to FDA (2019): https://www.fda.gov/medical-devices/safety-communications/fda-warns-against-use-many-genetic-tests-unapproved-claims-predict-patient-response-specific#actions
  9. https://www.fda.gov/news-events/fda-voices-perspectives-fda-leadership-and-experts/fda-proposes-new-steps-advance-clinical-testing-deliver-new-cures
  10. http://www.fdalawblog.net/wp-content/uploads/archives/docs/DTWG_final_proposal.pdf
  11. Discussion Draft of VALID Act (2018): https://bucshon.house.gov/uploadedfiles/valid_act_discussion_draft_12.6.18.pdf