FDA s Proposed Regulatory Changes to Laboratory-Developed Tests (LDTs) By Roz Sweeney, Ph.D., Nerac Analyst

Transcription

1 FDA s Proposed Regulatory Changes to Laboratory-Developed Tests (LDTs) By Roz Sweeney, Ph.D., Nerac Analyst Introduction The FDA recently issued updated draft guidance for proposed regulatory changes affecting laboratory developed tests (LDTs). Laboratory developed tests (or LDTs) are traditionally IVDs developed and used by CLIA labs for treating or testing patients within that lab s associated healthcare facility. They have historically fallen under FDA enforcement discretion, under the rationale that they fall within the practice of medicine, which is not regulated by the FDA. (While the specific tests are exempt, the labs are regulated under the Clinical Laboratory Improvements Amendment of 1988.) Over the past years, LDT s have evolved considerably as medicine has gotten more complex. The FDA believes that the claims of certain LDTs are not adequately supported with evidence and that certain LDTs may lack appropriate controls yielding erroneous results. The FDA is aware of harm caused by faulty LDTs. For example, the Agency is aware of harm caused by biomarker tests for early detection of ovarian cancer. In this case, patients received inappropriate treatments or even harmful treatments as a result of these tests. Other reasons for the need for increased oversight include LDT s being used on larger populations (e.g. outside of the local healthcare facility) and in situations where more stringently regulated devices exist (e.g. same indication and use as PMA approved devices). The proposed regulations are intended to even the playing field in safety, efficacy, and performance of LDT s with class I, II, III IVDs. What tests are covered? Depending on the risk-level of the test, FDA has proposed several different levels/ tiers of requirements. In general, the guidance is primarily intended for higher risk testing- tests that could be considered class II or III devices. Lower-risk testing or tests that fulfill a particular unique niche are subject to fewer new requirements (if any). Table 1 provides an overview of the tiers of testing and the proposed requirements. Table 1: LDT Oversight Framework Category R&L* Manufacturer Reporting Premarket review QS** Regulation Forensic testing CLIA-certified HLA transplantation LDTs for rare disease Traditional LDTs Unmet Needs X X

2 FDA s Proposed Regulatory Changes to Laboratory-Developed Tests (LDTs) 2 Class I (low risk) X X Same intended use as cleared/ approved companion Dx Same intended use as Class III medical devices Tests for determining safety/ efficacy of blood/ blood products X X Enforced for currently marketed LDTs that have not made a premarket submission within 12mo of guidance document finalization. Enforced for new LDTs first marketed after finalization of guidance document. Enforced after PMA submitted or FDA issues clearance order Class III (high risk) X X Enforced on a riskbased, phase-in basis FDA to announce priority list within 24 months of guidance finalization Class II (moderate risk) X X Enforced on a risk-based, phase-in basis Enforced after FDA has completed Class III phase-in FDA to announce this priority list within 4 years of guidance finalization Enforced on a risk-based, phase-in basis until manufacturer submits PMA Enforced on a risk-based, phase-in basis FDA issues 510(k) Tests for Infectious Agents used in blood/ blood components All requirements currently enforced Source: adapted from FDA Draft Guidance, October 3, 2014, Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs) R&L= Registration and Listing QS= Quality Systems The different categories of tests proposed by the FDA are not necessarily mutually exclusive. The FDA intends to provide more definition and clarity as it receives public feedback and conducts advisory panel meetings. The FDA will continue to maintain enforcement discretion over certain lower-risk tests. These tests include the following: Tests for Forensic use (or those tests primarily used by law enforcement) HLA testing used in Transplantation (The reason is that transplant diagnostics already have oversight of their own.) Low risk testing

3 FDA s Proposed Regulatory Changes to Laboratory-Developed Tests (LDTs) 3 Traditional LDTs. Defined in the FDA guidance as (1) an LDT (designed, manufactured and used within a single laboratory); (2) manufactured and used by a health care facility laboratory (such as one located in a hospital or clinic) for a patient that is being diagnosed and/or treated at that same health care facility or within the facility's healthcare system; (3) comprised only of components and instruments that are legally marketed for clinical use; and (4) interpreted by qualified laboratory professionals without the use of automated instruments or software. (Many LDT s today do not strictly meet this definition.) Rare diseases (In the current guidance, the FDA is defining a rare disease as one where there are 4,000 or fewer patients tested per year.) Unmet needs where there is no FDA-cleared or approved alternative. The FDA intends to begin enforcement with the highest risk tests first. These tests are defined as follows: Tests with the same intended use as cleared or approved IVDs Tests that could be considered Class III devices Certain LDTs for testing blood/ blood products. Enforcement of the remaining high or moderate risk tests, requiring a PMA or 510(k), will be phased in over 9 years after the guidance is approved. Proposed Timeline As of November, 2014, the FDA is in the 90-day public comment period, which will end around year end After that, the FDA will begin working on edits to the draft guidance. If the changes are extensive, the Agency may need to issue another version of the draft. However, we expect changes to be relatively minor and the overall structure to remain the same. If this is the case, the guidance could go into effect as soon as a year from now (e.g. around Q4:2015). Below is an overview of the timeline for implementation. At the time guidance goes into effect As soon as the guidance goes into effect, any new LDTs or IVDs in the following categories will be subject to the regulations: Same intended use as currently approved/ cleared companion IVDs Same intended use as Class III IVDs Certain IVDs for determining safety/effectiveness of blood or blood products. That means that a PMA must be approved in order for any of these new devices to be placed on the market. 6 months At 6 months, notification and Adverse Event (AE) reporting will be required for all currently marketed LDT s, except for forensic tests, and CLIA-certified transplantation testing. All new IVDs/ LDTs (even class II) must complete notification prior to marketing or use of the test. This includes notification of any significant changes to existing LDT s. Year 1 At year 1, PMA submission will be required for all currently marketed diagnostics under the following categories: Same intended use as currently approved/ cleared companion IVDs

4 FDA s Proposed Regulatory Changes to Laboratory-Developed Tests (LDTs) 4 Same intended use as Class III IVDs Certain IVDs for determining safety/effectiveness of blood or blood products. While the PMA is being reviewed, the tests can still be used, but if the PMA is rejected, they will likely have to come off the market. At the time of PMA submission, these devices will be subject to Quality System regulations. And they will be subject to registration and listing requirements upon PMA approval. Year 2 At year 2, the FDA will publish a priority list of the remaining high-risk LDT s. This list will be based on the public review process and advisory panels. FDA expects to publish this as a guidance document Based on their initial assessment, FDA is thinking this category of devices could include: Devices acting like companion diagnostics Screening devices for serious disease used in asymptomatic patients, with no other confirmation methods Certain infectious disease Devices not in the initial group will be required to submit a PMA in later years. Years 3-5 In years 3-5, FDA will implement enforcement of the remaining high-risk LDTs. They expect there to be 2 priority groups. The first group (higher risk) will be required to submit a PMA at year 3, while the remaining devices will need to submit a PMA by year 4. At the time of PMA submission, these devices will be subject to Quality System regulations. And they will be subject to registration and listing requirements upon PMA approval. Year 4 In year 4, the FDA will shift attention to the moderate risk or class II devices. A priority list of these devices will be published at year 4. As with the PMA devices, this list will be based on the public review process and advisory panels. FDA expects to publish this as a guidance document. Years 5-9 In years 5-9, the 510k process will be phased in for the moderate risk devices. They will be subject to quality system regulation at the time of 510k submission and subject to registration and listing requirements upon 510k approval. The FDA expects to use third party reviewers for this process, due to the sheer number of devices.

5 FDA s Proposed Regulatory Changes to Laboratory-Developed Tests (LDTs) 5 Conclusion The FDA wants the implementation of these new regulations to be as seamless as possible to avoid disruption to the practice of medicine in the United States. The FDA recognizes that many CLIA labs have limited experience in preparing regulatory submissions. Labs with questions about the type of data they intend to use for their submissions are encouraged to submit a presubmission to the FDA in order to get feedback that could help them potentially avoid having devices pulled from the market., The FDA has stated that labs can utilize published clinical data for their submissions. Many LDTs have been on the market for a while and have significant published data. Nerac has expertise in conducting clinical literature evaluations and data analysis to support regulatory filings and ongoing regulatory requirements. Call us to learn more at About the Analyst Roz Sweeney, Ph.D. Roz Sweeney, Ph.D., advises medical technology clients on new market opportunities, reimbursement, and regulatory issues. While at Nerac, she has assisted many clients in supporting the value proposition of their products through literature reviews and health economics modeling. Before joining Nerac, Dr. Sweeney was an associate with Mitchell Madison Group, a global management consulting firm focusing on cost reduction for clients in healthcare, high tech manufacturing, and financial services. She also worked in healthcare equities research at Royal Bank of Canada (RBC), covering small and mid-cap biotech companies. Dr. Sweeney has an academic background in cell and molecular biology (Ph.D. University of Texas) and was a postdoctoral fellow at California Institute of Technology, where she conducted research in nanoparticle-based drug delivery systems. She is an avid tennis player and competed on the varsity team at the University of Wisconsin, Madison. Credentials Postdoctoral Fellow, Chemical Engineering, California Institute of Technology Ph.D., Cellular and Molecular Biology, University of Texas at Austin B.S. Biochemistry, University of Wisconsin at Madison About Nerac is a global research and advisory firm for companies developing innovative products and technologies. Nerac provides expert insights that equip clients with the knowledge to develop or refine a technology, explore market growth opportunities, evaluate intellectual property strategies and respond to regulatory changes. Nerac serves approximately 20,000 users worldwide and answers over 5,000 research questions each year. Nerac has a long, successful consulting history in a wide-range of industries with a strong focus in the areas of pharmaceutical, food and nutraceuticals, medical device, engineering, energy and advanced materials.

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