OMBU. Ombu Enterprises, LLC Ombu The Operational Excellence Company Ph: Fax: ENTERPRISES, LLC

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1 OMBU ENTERPRISES, LLC Ombu Enterprises, LLC Ombu The Operational Excellence Company Ph: Fax: Docket Number FDA-2010-N-0274 Comments on Oversight of Laboratory Developed Tests Ombu Enterprises, LLC (Ombu) believes that FDA has the legal and regulatory authority to exercise oversight of Laboratory Developed Tests (LDTs). Moreover, Ombu believes that LTDs are medical devices as defined by the Food, Drugs, and Cosmetics Act (The Act), and that they are In-vitro Diagnostic Devices (IVDs) as defined by the current regulations. Currently, there are two paths by which a test gets to the laboratory floor. In the first path, a manufacturer develops a test kit and sells it to a laboratory. The laboratory then obtains samples, analyzes them using appropriate laboratory methods, and reports the results. In the second path, the laboratory develops a test and moves it to the laboratory floor. The laboratory then obtains samples, analyzes them using appropriate laboratory methods, and reports the results. In this two-path approach, the regulatory structure applied to the test development paths is remarkably different. There was a time, as explained at the public meeting, that LDTs were simple and laboratories could assure their safety and effectiveness by local means. The decision of FDA to exercise regulatory discretion was appropriate. Today, the situation has changed. LDTs are more complex and utilize new technology and more complex technology. Some specific areas include both genetic testing and companion diagnostics. Consequently, FDA s examination and review of its oversight of laboratory developed tests is ripe. Ombu recommends that FDA develop a one track policy for regulatory oversight of IVD tests. Moreover, since FDA believes the regulatory structure for test kits (as opposed to LDTs) is adequate, Ombu believes the same structure should apply to both test kits and LDTs. Roles in the Process In the current structure, there are two principal roles in the development and performance of laboratory tests. There is a role of test development and a role of test performance. To clarify the roles, consider a case where a company develops a test and sell it to a laboratory. Further, assume the test is a Class II device that requires premarket notification. Comments on Oversight of Laboratory Developed Tests Page 1 of 7

2 The company that develops the test assumes the role of manufacturer and is subject to a specific regulatory structure. The laboratory assumes the role of test performer and is subject to a specific, but different, regulatory structure. Considering the Quality Management System (QMS) aspects, the manufacturer follows QSR, while the laboratory follows CLIA. The issue is that the laboratory, in producing a laboratory developed test, has taken on the role of manufacturer while bypassing the regulatory oversight of a test kit manufacturer. Ombu recommends that the regulatory structure should follow the role the firm takes, i.e., manufacturers implement QSR, laboratories implement CLIA, and firms in both roles implement both systems. Table 1 shows the roles and corresponding QMS requirements. Laboratory Not a Laboratory Manufacturer QSR CLIA QSR Not a Manufacturer CLIA N/A Table 1 QMS by Role In the QMS roles, the regulatory structure has some differences of note. For example, FDA will classify the complexity of the test when issuing a clearance letter. The laboratory must meet the CLIA complexity requirements to run the test. If the test is Class I (and doesn t involve software) the manufacturer does not have to meet Design Controls. Risk Based Classification FDA has stated that it desires to apply a risk based approach to the oversight of LDTs. At the public meeting some presenters offered suggestions for the structure of risk. Ombu believes that FDA already has a structure in place for test kit manufacturers. This structure should apply equally to LDTs. In this structure, FDA classifies each device by panel and risk (Class I, II, or III) and issues a corresponding regulation. As appropriate, the regulations also enumerate special controls, QMS requirements, etc. Ombu recommends that FDA use the existing medical device structure, currently in place to classify test kits, to classify LDTs. Conceivably, there is an LDT that isn t classified, but this should not be an impediment. A test kit manufacturer could bring the same kit to market, and FDA has the mechanisms in place to address the issues raised. There is one issue, however, that can cause confusion. The reagents in a test kit may be in Class I. The reagent kit manufacturer will often develop controls, calibrators, and control verifiers to accompany the test kit. Depending on the kind (assayed or unassayed), the controls etc. may be Class II devices requiring pre-market notification. In practice, but probably not often, the laboratory may develop or modify an instrument to conduct the test. If a test kit manufacturer were to develop this instrument, it would be an IVD device. The same regulatory framework should apply to the laboratory that develops or modifies an instrument. Comments on Oversight of Laboratory Developed Tests Page 2 of 7

3 Ombu recommends that FDA make it clear to laboratories that the classification may involve as many as five different parts of the system, and each part may have a different classification and regulation. The five parts are: the reagents, the calibrators, the controls, the control verifiers, and the instrument used to run the test. The Role of Manufacturer in a Laboratory Ombu takes the position that a laboratory that develops and markets a test is a manufacturer and should follow all the requirements for a test kit manufacturer outside the laboratory. In particular, Ombu believes the following medical device manufacturing paradigms should apply to laboratories that produce LDTs. As explained below, however, FDA should phase in the requirements to prevent potentially unintended consequences and disruption of test availability. Ombu recommends that FDA require LDT manufacturers to comply with the following, recognizing that FDA should adjust the requirement date using regulatory discretion: registration, listing, conformity assessment, QSR, labeling, and post-market surveillance. Registration All manufacturers, including laboratories producing LDTs, should register following the requirements of 21 CFR Part 807. Listing All manufacturers, including laboratories producing LDTs, should list all devices as required by 21 CFR Part 807. Conformity Assessment by FDA All LDT manufacturers should follow the current requirements for FDA pre-market notification or pre-market approval for the tests offered. Quality System Regulation Laboratories that produce LDTs are manufacturers, as explained above, and should design and manufacture the LDTs following the Quality System Regulation in 21 CFR Part 820. Labeling IVD tests have specific labeling requirements found in 21 CFR Part 809, Subpart B. These requirements are designed to communicate information from the manufacturer to the user. Laboratories that develop LDTs need to develop the same information and transmit it from the manufacturing function to the laboratory function. In particular the requirement of 21 CFR (b) that requires specific information in one place applies. Post Market Surveillance Laboratories that produce LDTs must follow 21 CFR Part 803. In the role as laboratory, these establishments are user facilities covered by 21 CFR Part 803 Subpart C. In their role as device manufacturers, these establishments are manufacturers covered by Subpart E. Comments on Oversight of Laboratory Developed Tests Page 3 of 7

4 Implementation Timing As FDA brings LDTs into the medical device structure, the timing is very important. FDA runs the risk of disrupting the availability of certain tests. Such unintended consequences would not foster the public health mission of FDA. FDA has two models to guide its decision making. The revision of cgmp for devices resulting in the current QSR followed two phases. The first was the new regulation followed by enforcement of Design Control one year later. FDA used regulatory discretion for one year and grandfathered completed portions of designs. FDA should use a similar approach for LDTs. The second model is the recognition that hospitals that reprocess single use devices are manufacturers. This case is very similar to the recognition that laboratories are manufacturers. Hospitals had to submit pre-market notifications to FDA. FDA worked with industry to prioritize the devices and set time frames. FDA should use a similar approach for LDTs. Registration and Listing FDA should require manufacturers of LDTs to register and list their devices by the end of Because FDA does not have a list of the facilities involved or the tests that each facility produces, this information is important to help scope the magnitude of the effort. Ombu recommends that, by October 1, 2010, FDA issue guidance requiring all laboratories to register and list LDTs by December 31, Laboratories will then come under the annual registration and semi-annual listing requirements thereafter. Conformity Assessment As part of listing, each LDT manufacturer will determine important information about the device including the panel, the class, the product code, and (hopefully) the CLIA complexity. FDA can use this information to determine the program for submissions when required. In general, Class III high complexity tests should go to the top of the list while Class I low complexity tests will not be on the list. FDA can refine the list using the product code. In addition, laboratories should perform existing tests (under regulatory discretion) until FDA makes a determination on each submission. For existing Class III devices, the laboratory should make an initial submission by the end of This would allow more than one year for a laboratory to gather the data and make a submission. (Laboratories with many Class III devices could have a capacity problem, and could request a different schedule.) For existing Class II devices, the laboratory should have made an initial submission by the end of Comments on Oversight of Laboratory Developed Tests Page 4 of 7

5 For existing Class I devices, the laboratory should not have to make a submission. However, devices with reagents in Class I and controls and calibrators in Class II should follow the Class II expectation. New devices, i.e., those not in the initial listing, require the current conformity assessment procedures during and after the transition period. For example, a new LDT introduced in February 2011 would have to have been classified and approved or cleared as appropriate. Ombu recommends that by October 1, 2010 FDA issue guidance that all LDTs developed and in use by December 31, 2010 will have one year to submit premarket approval applications and two years to submit premarket notification applications. After December 31, 2010 all new LDTs are subject to the same conformity requirements as any other device. Quality System Regulation FDA issued the final rule for QSR on October 7, 1996 with an effective date of June 1, This was a nine month transition. In addition, FDA deferred the Design Control portion of the regulation with a special 1-year transition program. Design controls became effective on June 1, Ombu recommends that by October 1, 2010 FDA issue guidance that QSR applies to all LDTs manufactured after June 1, As stated below, the labeling requirements of and Part 809 should be effective on the same date. As stated below, the complaint files requirements of and the post market surveillance requirements of 21 CFR Part 803 Subpart E should be effective on the same date. QSR design control requirements apply only to design phases initiated after June 1, 2011, with regulatory discretion applied until June 1, Labeling Ombu recommends that by October 1, 2010 FDA issue guidance that the labeling requirements of 21 CFR Part 809, Subpart B applies to all LDTs manufactured after June 1, (As stated above, the labeling requirements of QSR and Part 809 should be effective on the same date.) Post Market Surveillance Laboratories should have already implemented the user facility requirements of 21 CFR Part 803. (There is, potentially, a laboratory that uses only LDTs and, therefore, may not consider itself a user facility.) Laboratories that produce LDTs must also perform the post market surveillance activities of a manufacturer. Ombu recommends that by October 1, 2010 FDA issue guidance that all laboratories that produce LDTs are also manufacturers subject to 21 CFR Part 803 Subpart E after June 1, Comments on Oversight of Laboratory Developed Tests Page 5 of 7

6 2010. (The post market surveillance requirements of 21 CFR Part 803 Subpart E and the Complaint File requirements of 21 CFR should be effective on the same date.) Additional Considerations Ombu recommends that FDA review the need to define Analytic Specific Reagents (ASR) and General Purpose Reagents (GPR). Ombu recommends that FDA apply both the labeling requirements and intent of RUOs and IUOs as found 21 CFR (c). In particular FDA should reaffirm that RUO and IUO status is not a substitute for clearance or approval, but is, instead, an instance of IDEs specific to IVDs. List of Recommendations Ombu recommends that FDA develop a one track policy for regulatory oversight of IVD tests. Moreover, since FDA believes the regulatory structure for test kits (as opposed to LDTs) is adequate, Ombu believes the same structure should apply to both test kits and LDTs. Ombu recommends that the regulatory structure should follow the role the firm takes, i.e., manufacturers implement QSR, laboratories implement CLIA, and firms in both roles implement both systems. Ombu recommends that FDA use the existing medical device structure, currently in place to classify test kits, to classify LDTs Ombu recommends that FDA make it clear to laboratories that the classification may involve as many as five different parts of the system, and each part may have a different classification and regulation. The five parts are: the reagents, the calibrators, the controls, the control verifiers, and the instrument used to run the test. Ombu recommends that FDA require LDT manufacturers to comply with the following, recognizing that FDA should adjust the requirement date using regulatory discretion: registration, listing, conformity assessment, QSR, labeling, and post-market surveillance. Ombu recommends that, by October 1, 2010, FDA issue guidance requiring all laboratories to register and list LDTs by December 31, Laboratories will then come under the annual registration and semi-annual listing requirements thereafter. Ombu recommends that by October 1, 2010 FDA issue guidance that all LDTs developed and in use by December 31, 2010 will have one year to submit premarket approval applications and two years to submit premarket notification applications. After December 31, 2010 all new LDTs are subject to the same conformity requirements as any other device. Ombu recommends that by October 1, 2010 FDA issue guidance that QSR applies to all LDTs manufactured after June 1, As stated below, the labeling requirements of and Part 809 should be effective on the same date. Comments on Oversight of Laboratory Developed Tests Page 6 of 7

7 As stated below, the complaint files requirements of and the post market surveillance requirements of 21 CFR Part 803 Subpart E should be effective on the same date. QSR design control requirements apply only to design phases initiated after June 1, 2011, with regulatory discretion applied until June 1, Ombu recommends that by October 1, 2010 FDA issue guidance that the labeling requirements of 21 CFR Part 809, Subpart B applies to all LDTs manufactured after June 1, (As stated above, the labeling requirements of QSR and Part 809 should be effective on the same date.) Ombu recommends that by October 1, 2010 FDA issue guidance that all laboratories that produce LDTs are also manufacturers subject to 21 CFR Part 803 Subpart E after June 1, (The post market surveillance requirements of 21 CFR Part 803 Subpart E and the Complaint File requirements of 21 CFR should be effective on the same date.) Ombu recommends that FDA review the need to define Analytic Specific Reagents (ASR) and General Purpose Reagents (GPR). Ombu recommends that FDA apply both the labeling requirements and intent of RUOs and IUOs as found 21 CFR (c). In particular FDA should reaffirm that RUO and IUO status is not a substitute for clearance or approval, but is, instead, an instance of IDEs specific to IVDs. Comments on Oversight of Laboratory Developed Tests Page 7 of 7