Clearance and Approval Pathways for Diagnostics. By Nancy Gerber

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1 Clearance and Approval Pathways for Diagnostics By Nancy Gerber 26

2 Personalized medicine is a rapidly evolving area as therapeutic decisions based upon single test results become more common. Physicians have always used personalized medicine as they try to fit a therapy to a patient; however, personalized medicine has been recently taken to a new level of application. Exploration of the biology of disease and treatment at the molecular level are enabling physicians to use patients genetic and protein information to provide the right therapy to the right patient at the right time. Diagnostic tests that provide information at the molecular level are the cornerstone of this evolving area of personalized medicine. Such tests have the potential to increase the safety and effectiveness of therapeutics by determining which subsets of patients have better risk/ benefit profiles for a given treatment. Diagnostic tests are being used to select patients for treatment with a particular therapeutic, determine how treatment will be administered or prevent inappropriate therapeutic use that could harm patients. Despite the clear advantages that diagnostics bring to personalized medicine, the regulatory hurdles for clearance or approval of diagnostics can be daunting and complex. The regulatory pathway for approval of a diagnostic that selects patients for treatment with a particular therapeutic involves extensive clinical testing and is considerably more rigorous than the regulatory pathway for clearance of a diagnostic that determines a disease diagnosis or prognosis. This article focuses on US clearance and approval pathways for scientifically validated diagnostic tests (in vitro diagnostics (IVDs)) and does not address pathways for laboratory-developed tests (LDTs). 1 Overview of Diagnostic Development Issues Regulatory professionals involved in the development of drugs and diagnostic tests must manage multiple regulatory issues: drug development issues, diagnostic development issues and issues associated with the integration of both into one comprehensive clinical development program. Because the development plans of the diagnostic test and the drug are linked, an unanticipated delay in one plan can significantly impact the other. Consequently, careful planning and coordination of development activities, frequent communication with FDA and continuous assessment of regulatory risks are necessary to achieve concurrent approval of a therapeutic and its diagnostic test. Regulatory professionals working on the co-development of a drug and diagnostic must have a good understanding of several regulatory areas: regulatory requirements for drug development regulatory requirements for IVD development unique regulatory issues pertaining to the specific drug and diagnostic test risks and mitigation strategies for the integrated clinical development program, including regulatory submission, review and approval Diagnostic Clearance and Approval Pathways Several regulatory pathways are available to device manufacturers seeking FDA clearance or approval of a diagnostic test. Assigning a device classification (Class I, Class II or Class III) is the first step in identifying the regulatory pathway (510(k) Exempt, 510(k) or Premarket Approval (PMA)). Device classifications are risk based and dependent upon intended use. Once a device classification and pathway are selected, the submission data requirements for the chosen regulatory pathway are established. A summary of regulatory pathways and requirements for each device classification is provided in Table 1. Device risks are linked to intended use and defined by three factors: the disease or condition the diagnostic will diagnose, the patient population and the specimen to be sampled. Specimens collected via an invasive procedure (e.g., biopsy of a major organ) carry greater risk than specimens collected by less- or non-invasive methods (e.g., blood sampling by venipuncture). Diagnostic tests involve a unique link between safety and effectiveness since the safety of the diagnostic is not generally related to contact with the patient. Therefore, the safety of the diagnostic relates to the impact of its performance, in particular, the impact of false negative and false positive results on patient health. False positives can lead to unnecessary confirmatory testing, unnecessary treatment that can be invasive or have harmful side effects and/or unnecessary psychological trauma when serious or life-threatening diseases are involved. False negative results can lead to a delay in establishing the correct diagnosis, failure to start or continue needed treatment and a false sense of security that may prevent timely follow-up and retesting and contribute to the potential spread of disease to others. 2 Consequently, the risk of the diagnostic can equal the risk of the therapeutic, particularly if the diagnostic plays a critical role in therapeutic decision making. Exemption Process Class I devices present a low risk of harm to the user and are subject to general controls that are sufficient to protect the user. General controls are the baseline requirements of the Food, Drug and Cosmetic Act that apply to medical devices in all classes. 3 General controls include the provisions of the act pertaining to adulteration, misbranding, device registration and listing, premarket notification, banned and restricted devices, Regulatory Focus 27

3 Table 1. Diagnostic Approval Pathways and Requirements Device Classification Class III Class II Class I Device Description and Risk Profile Devices that require a scientific review to ensure product safety and efficacy Devices that require additional oversight (in addition to general controls) to ensure safety and efficacy Devices that present minimal potential for harm to the user High risk or unknown risk Moderate risk or risk that can be mitigated Low risk Device Examples Most diagnostics for therapy Most diagnostics tests for screening, diagnosis or prognosis, including safety/dosing tests Heart valves X-ray machines Contact lens care products Bandages, tongue depressors, exam gloves Evidence Requirements PMA submission IDE filing prior to clinical trials 510(k) or de novo 510(k) submission Clinical studies typically unnecessary Most devices are exempt from 510(k) requirements and can launch without FDA clearance Drug Label Impact Prospective clinical studies necessary in treated and untreated patients Diagnostic required, recommended or information only (depends upon strength of evidence) Require statement of intended use and summary of scientific data to support a de novo classification or to claim equivalency to a legally marketed (predicate) device Diagnostic required, recommended or information only (depends upon strength of evidence) Notification/Review Period 180-day FDA review period Notify FDA 90 days before intent to market Postapproval Requirements Postapproval safety (AE) reporting and Annual Report required Safety (AE) reporting No impact Exempt from premarket notification [510(k)] or notify FDA 90 days before intent to market Safety (AE) reporting Requirement for postapproval clinical or nonclinical studies are possible Review Fees (Fiscal 2011) $236K plus $8K annually $4K $0K records and reports and GMP. Most Class I devices are exempt from the regulatory premarket review process. De Novo 510(k) and 510(k) Market Processes Premarket notification, also referred to as the 510(k) process, is primarily used for Class II diagnostics for which general controls alone are insufficient to provide reasonable assurance of safety and effectiveness. Special controls may provide such assurance; they include special labeling, mandatory performance standards, risk mitigation measures and postmarket surveillance. The de novo 510(k) is a mechanism for down-classifying new diagnostics that have been placed in Class III due to the lack of a legally 28

4 marketed (predicate) device. Considerations potentially enabling a de novo reclassification include the patient population, sample collection and the benefit/risk profile of the drug and the diagnostic. PMA Market Process The PMA process is primarily for Class III diagnostics. It involves a rigorous premarket review to establish safety and effectiveness, unlike the 510(k) clearance process in which FDA determines substantial equivalence to a legally marketed predicate device. PMA approval is based upon a determination by FDA that the application contains sufficient valid scientific evidence to ensure that the device is safe and effective for its intended use. Due to the risk associated with diagnostics used for therapy, most current companion diagnostics are Class III devices that require a PMA application. Limitations to FDA review of a PMA can be caused by problems in the design or conduct of the study that introduce bias in the collection of data to establish safety and effectiveness. FDA encourages the use of the pre-ide submission and/or meeting process whenever the sponsor desires early feedback for clinical studies, particularly those for novel or high-risk (Class III) diagnostics. Humanitarian Device Exemption Process The Humanitarian Device Exemption (HDE) market process encourages the discovery and use of diagnostics intended to benefit patients with rare diseases that affect fewer than 4,000 individuals in the US per year. HDEs are exempt from requirements to demonstrate effectiveness; however, the probable benefits of the diagnostic should outweigh the risks. For such products, a request for Humanitarian Use Device (HUD) designation is submitted and market approval is obtained through submission and review of an HDE. HUDs approved for marketing under an HDE have specific labeling requirements and may require postapproval studies. The HDE process requires the manufacturer to submit periodic reports. Examples of HDEs include an iris Table 2: Examples of Cleared and Approved Diagnostics Linked to Treatment Decisions Clearance or Approval Pathway Diagnostic Test Therapeutic Description 510(k) UGT1A1 mutations Irinotecan (Camptosar) Safety test: risk for genetic variants associated with toxicity CYP450 2C9 Coumadin (Warfarin) Safety test: risk for increased treatment sensitivity De novo 510(k) MammaPrint (Prognostic marker only) Safety test: risk for cancer metastasis CYP450 2D6 Therapeutics metabolized by 2D6 PMA EGFR IHC Cetuximab (Erbitux), Panitumumab (Vectibix) Safety test: treatment and dose Efficacy test: treatment Her2/neu IHC, FISH, CISH Trastuzumab (Herceptin) Efficacy test: treatment c-kit IHC Imatinib (Gleevec) Efficacy test: treatment Regulatory Focus 31

5 replacement, radioactive microspheres for cancer treatment and semi-constructed finger joints. Given the evolving regulatory landscape in the diagnostic area, including recent FDA reports on assessment of the 510(k) premarket review process and the use of science in regulatory decision making, 4,5 it is important for the regulatory professional to be aware of new guidances issued by FDA. Examples of Cleared and Approved Diagnostics Several examples of cleared and approved diagnostics are provided in Table 2. A brief overview of information related to FDA s approval to market each diagnostic (Summary of Safety and Effectiveness Data (SSED) and product labeling) is available online 6 and provides an important resource for regulatory professionals when planning and coordinating development activities for diagnostic programs. References 1. Genentech, Inc. Citizen Petition. Regulation of In Vitro Diagnostic Tests. Submitted 5 December Guidance for Industry and FDA Staff: In Vitro Diagnostic (IVD) Device Studies -Frequently Asked Questions. Issued 25 June Title 21 Code of Federal Regulations Part CDRH Preliminary Internal Evaluations Volume I: 510(k) Working Group Preliminary Report and Recommendations, August CDRH Preliminary Internal Evaluations Volume II: Task Force Utilization of Science in Regulatory Decision Making Preliminary Report and Recommendations. August Recently-approved Devices. FDA website. ProductsandMedicalProcedures/ DeviceApprovalsandClearances/Recently- ApprovedDevices/default.htm, accessed 1 January Author Nancy Gerber is a regulatory advisor at Genentech with a focus on diagnostics, globalization and policy. She has experience in protein purification and characterization at Merck, BioGrowth and Glyko. She joined Genentech in 1995 and regulatory affairs in Acknowledgements The author would like to acknowledge the helpful comments of Sam Rua and Tracy Bush of Roche Diagnostics. 32