So You Want to Develop a Test? Navigating the Regulatory Waters of Laboratory Developed Testing

Transcription

1 So You Want to Develop a Test? Navigating the Regulatory Waters of Laboratory Developed Testing Professor of Pathology, Microbiology, and Immunology Associate Medical Director of Clinical Operations Medical Director, Clinical Chemistry Vanderbilt School of Medicine Nashville, Tennessee james.h.nichols@vanderbilt.edu 1 Objectives Define Laboratory Developed Tests Identify CLIA and other regulations that impact LDTs Describe proposed changes to the FDA regulations that affect LDTs 2 Case As medical director of the hospital toxicology service, your staff are performing colorimetric testing for urine acetaminophen and salicylate. This testing requires a hood and heating of chemicals. Your new automated chemistry analyzers perform serum acetaminophen and salicylate testing. Converting the urine toxicology testing to the automated system would provide several advantages: Less labor Provide quantitative rather than qualitative results Automate the reporting of manual results Reduce chemical use and eliminate need for a hood in the lab 3 1

2 Audience Poll Which of the following is true about implementing the urine acetaminophen and salicylate testing on the automated chemistry instrument? A. Since the serum assay performance is already verified, just implement the urine change B. The laboratory will need to find specific urine controls before implementing the change C. Although the test is FDA approved, the laboratory will need to verify the performance of the assays on urine samples, contact their accreditation agency and upgrade their CLIA licensure to high complexity D. All of the above 4 Definition Laboratory developed tests" or "LDTs are tests that are created by a lab because a commercial test is not currently available or are modified from an FDA approved test to fill an unmet clinical need. Examples of test modifications: Developed for one purpose, used for another (diagnosis vs screening) Change in sample type urine on a serum test Different assay parameters incubation time, temp, etc Altered reagents change in antibody, chemistries, etc FDA definition of LDT = An IVD that is intended for clinical use and designed, manufactured and used within a single laboratory. 5 FDA approval FDA reviews test methods for Truth in Labeling Technical performance meets product claims C reactive protein for diagnosis of infection (pediatrics) versus determination of cardiovascular risk Cardiovascular risk requires lower range sensitivity than for diagnosis of infection U.S. marketing of all lab tests for patient care require FDA approval The performance data required will depend on the complexity of the test FDA approval extends to specified specimen types as appear in the package insert 6 2

3 Audience Poll Which of the following could be considered an LDT? A. An i stat blood gas analyzer used to test whole blood B. A serum hcg test used for diagnosis of ovarian cancer C. Analysis of ALT from a dark green vacutainer on an FDA approved test for heparinized samples. D. Use of a urine drugs of abuse IA test to monitor for pain management compliance of opiates 7 History Labs historically have transitioned research tests into clinical applications or developed tests to solve an unmet clinical need. Colorimetric tests for metabolites Trinder s reagent/salicylates, Reinsch test/ heavy metals, or bleeding times/clotting disorders. HPLC for drug and therapeutic monitoring Molecular testing for new strain of respiratory virus (SARS or MERS) Mass spectrometry for endocrine and drug confirmations Lamellar body counts for fetal lung maturity 8 Audience Poll Some labs use a common disclaimer, RUO, to indicate that the performance of the assay is not known, what are the challenges with this approach? A. Test result cannot be interpreted for patient care B. Reimbursement for the test may be rejected C. The test may not have an appropriate reference interval D. All of the above 9 3

4 The Research to Clinical Gap FDA approved and laboratory developed tests cannot be utilized for patient care until lab is fully CLIA compliant with that test Must report results as: Research Use Only or the clinical performance of this test has not been established This transition from research to clinical test may take years!! During this time period, articles may appear describing research results on patients Physicians see the articles and want the test 10 History LDTs have become more complex over time Traditional tests combined into predictive algorithms Genome analysis marketed to public for risk prediction Single lab LDTs sold to companies for wide marketing Next generation sequencing RUO/IUO disclaimers on test results known to be used for clinical diagnosis and management The variety and complexity of LDTs now raises questions about quality of individual laboratories! 11 Increasing Concerns About Public Health Impact of LDTs Incorrect diagnoses of ovarian cancer Led to unnecessary surgeries to remove ovaries Profiled in The New York Times (Aug. 28, 2008) Incorrect prediction of tumor types (Duke Univ. Study) Exposed some patients to ineffective therapies Left other cancer patients untreated Profiled in The New York Times (July 7, 2011) Incorrect diagnoses of whooping cough False whooping cough epidemic at Dartmouth medical center Thousands given unnecessary antibiotics and/or vaccine 1,000 healthcare workers furloughed Profiled in The New York Times (Jan. 22, 2007) 12 4

5 FDA Perspective Through the 1976 medical device amendments to the Federal Food, Drug, and Cosmetic Act, FDA has the authority to regulate all laboratory tests, regardless of whether they are commercially distributed or developed by a laboratory FDA is charged with ensuring that IVDs are safe and effective (do what they say they will do) for their intended use so that patients are not unnecessarily harmed 13 Benefits of FDA Oversight Independent Premarket Review Independent assessment occurs prior to clinical use of test Ensures test limitations are described Ensures test performance claims are supported Clinical Validation Provide assurances that test provides clinically meaningful results Post Market Surveillance and Post Market Controls Mechanism to assist manufacturers and FDA in identifying problems with tests and assuring the performance of the IVD through out its life cycle Oversight of Investigational Stage Devices Ensures patients and physicians understand the scientific evidence supporting use of a diagnostic test Enforcement Discretion: Definition: When FDA does not enforce some or all applicable laws and regulations on certain categories of products (drugs, devices, biologics, etc.) Key Points: Enforcement discretion not unique to LDTs Enforcement discretion does not change the fact that the law applies Many different reasons for this practice (risk, history, timing, resources, etc.) Practices like this do occur, but may change (often because of changes in risk profile of the products) 5

6 test kit manufacturer Despite new public health risks, today s LDTs are still marketed under enforcement discretion by FDA. CLIA-certified lab FDA Enforcement Discretion Performed in CLIAcertified lab Performed within same lab that developed test Increasing Concerns About Public Health Impact of LDTs Incorrect diagnoses of ovarian cancer Led to unnecessary surgeries to remove ovaries Profiled in The New York Times (Aug. 28, 2008) Incorrect prediction of tumor types (Duke Univ. Study) Exposed some patients to ineffective therapies Left other cancer patients untreated Profiled in The New York Times (July 7, 2011) Incorrect diagnoses of whooping cough False whooping cough epidemic at Dartmouth medical center Thousands given unnecessary antibiotics and/or vaccine 1,000 healthcare workers furloughed Profiled in The New York Times (Jan. 22, 2007) 17 FDA Proposed Changes Require laboratories to notify the FDA of their LDTs Undergo Premarket Review of new LDTs, tests would need to document test limitations and clinical validity Lab must document that performance of LDT is meeting Quality System Requirements Notify FDA (Medical Device Reporting) of adverse events as post market surveillance of LDTs FDA proposes to continue enforcement discretion based on risk of individual LDT 18 6

7 FDA s Current Proposal 1. Collect basic information on all LDTs through new notification process (i.e., no fee alternative to Registration & Listing) 2. Use public process (i.e., advisory committees) to obtain input on risk and priority for regulation 3. Phase in regulatory framework over ~9 years based on risk 4. Continue some enforcement discretion for specific categories determined by FDA to be in the best interest of public health Impact on Clinical Laboratories Applaud the FDA for seeking to improve quality of lab testing and ensuring tests meet clinical expectations as well as phasing in the regulations so as no immediate impact. Quality of clinical laboratories has historically been overseen by CMS through CLIA 88 and private accreditation agencies (CAP, Joint Commission, COLA) CLIA, however: Does not regulate the safety and effectiveness of diagnostic tests; Does not require pre market review of tests; Does not require demonstration of clinical validity (whether the test is meaningful for clinical decision making); Does not require systematic adverse event reporting; Does not have a process for corrections or recalls. 20 Impact on Clinical Laboratories Two entry ways to offering and marketing a test: Traditional manufacturer development and FDA approval process Clinical LDTs where quality is monitored by high complexity CLIA regulations. Two oversight mechanisms with overlap and different perspectives will be confusing for both lab and industry. FDA notification, premarket review, QSRs, and medical device reporting is new to labs. Clinical laboratories not trained or staffed appropriately to respond to proposed changes. Manufacturers have whole departments devoted to government affairs and FDA review. Clinical labs have quality staff but they are not familiar with the FDA application and review process! 21 7

8 Impact on Clinical Laboratories Added expense: Studies to meet FDA review process Filing fees for premarket review Staff training and added staff to handle new regulations Delays and limitations in clinical care: Longer lead times for implementing new LDTs by labs Possible discontinuation of currently offered LDTs Some labs will no longer be able to offer LDTs because of added expense and overhead of meeting new regulations 22 Role of CMS? CMS and CLIA currently regulate quality in clinical labs Requires validation of accuracy, precision, reportable range, establish reference interval and interferences. Limited to analytical validation of tests, FDA proposes to enforce clinical validation in addition How will labs have to change their validation studies to prove clinical utility of a test? Specifically, if test already being offered, clinicians are utilizing results in patient care, what more will be needed for approval? Clinical validation of rare disorders may be challenged by frequency of some diseases (number of positives available) 23 Implementing the FDA Review Process How will risk be determined? Initial enforcement for high risk tests, while low risk will need to notify FDA for later review. Which tests will be considered for first review process? What will be the process for labs introducing low or moderate risk LDTs during FDA phase in of regulations? What will be the process for those LDTs currently offered versus new LDTs being considered? Will labs have to stop analyzing current LDTs while they undergo FDA review which could impact patient care? 24 8

9 Audience Poll What specifications require manufacturers to monitor the quality of their products and source chemicals? A. CMS CLIA B. FDA C. ISO D. CDC 25 Quality System Requirements Many labs utilize outside sources for components of the LDT (ASRs, solvents, calibrators, controls), these require documentation as to source and how component of assay meets lab s specification for use in the LDT Manufacturers have ISO9000 specifications for quality management of products, but no corollary for labs to meet FDA QSRs? Will labs be able to continue to use RUO/IUO disclaimers on test results once new regulations are implemented? How will labs need to additionally document the quality and consistency of their source reagents for LDTs? 26 Post Market Surveillance Lab medical directors currently have close relationships with the physicians who utilize results of LDTs. When errors happen, institutions handle the corrections through direct communication with physician clients. How will medical device reporting requirements of postmarket surveillance be accomplished? Will every test correction need to be reported to the FDA? If not, what severity of correction? 27 9

10 Unforseen Consequences Proposed changes to FDA regulations while intended to enhance quality could have the opposite outcome Costs could prevent labs from developing new tests which would stifle development and improvements in future patient care Increased regulations could lead to removal of currently offered LDTs from market impacting patient care Limited FDA resources could delay even further manufacturer entry of new tests to the market Dual systems of oversight (FDA and CMS) with overlapping but different views could confuse the market and further discourage new test development Increased oversight could interfere with lab director physician communication and relationships 28 Packaging and Shipping Regulations Department of Transportation, IATA, others at 49CFR Dangerous Goods Regulations Hazardous Materials Strict policies and enforcement (post 9/11, ValuJet crash) All staff who package or ship potentially infectious materials (blood or other samples) must be trained and hold a valid, current certificate Training certification is required every 2 years at minimum, and again whenever the regulations change (!) All mailing/shipping occurring outside of the institution (such as blood and urine specimens) Infectious cultures or organisms require special handling (and more!) FAA inspections can engender ~ $30,000 fines per instance of shipping infraction (such as a package is not labeled correctly) Fines can be assessed against companies or individuals who fail to comply with regulations (civil penalties can also include jail sentences) 29 Billing and Compliance Enforced by Office of Inspector General Illegal to bill patient s insurance for laboratory testing required as part of a research protocol i.e. use of RUO/IUO and billing for test! Also, illegal to provide free or no charge lab tests Medicare can fine a hospital $10,000 per day per event that money has been inappropriately reimbursed Hospitals and academic institutions have been fined millions of dollars from fraudulent billing related to research Often had been viewed as a gray zone by clinicians who claimed that the test would normally be required despite the protocol Staff have phrased as routine or standard of care Best policy if the test is part of the research protocol, there is less risk to bill the sponsor than to bill the patient s insurance inappropriately 30 10

11 Summary Laboratory Developed Tests (LDTs) are a necessary component of any clinical laboratory operation Historically, quality of LDTs has been overseen by CMS through CLIA high complexity regulations FDA is changing its approach to LDTs, while currently under enforcement discretion, the FDA proposes to require review and approval of LDTs High risk LDTs will be targeted first followed by moderate and low risk tests. Some enforcement discretion will continue during the implementation phase of the changes over next several years. Many questions remain unanswered. Other agencies may impact the performance and billing of LDTs I want to thank and acknowledge the content of several slides to Alberto Gutierrez and the FDA draft documents