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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment 3 Guidelines, Standards, Oversight, and Incentives Needed for Biomarker Development REVIEW OF CURRENT FDA OVERSIGHT FOR BIOMARKER TESTS Since the passage of the Food, Drug and Cosmetic Act in 1938, the safety and effectiveness of medical diagnostics has been overseen by the Food and Drug Administration (FDA, 2006c). More specifically, the FDA has regulatory jurisdiction over any device or in vitro reagent that is “intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment or prevention of disease, in man or other animals” based on the Medical Device Amendments of 1976 (Hackett and Gutman, 2005). To determine the “intended use” that is so key to its regulation, the FDA considers a device maker’s advertising, product distribution, labeling claims, product websites, and any form of promotional material on the product (Heller, 2006). When the FDA asserts jurisdiction, this typically results in premarket submissions to the FDA under its premarket approval (PMA) or premarket notification (510[k]) requirements (Box 3-1). To help determine which route is most appropriate, the FDA evaluates how much risk the diagnostic poses, how it differs from other currently available diagnostics, and its intended use. Tests that pose the most risk, are the most innovative, or are intended “for a use which is of substantial importance in preventing
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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment BOX 3-1 Premarket Approval and Premarket Notification at the FDA A PMA application usually requires manufacturers to submit clinical data showing that their device is safe and effective for its intended uses. For some tests, these clinical data can be published clinical studies and/or practice standards that can help determine the clinical performance of the test or retrospective comparisons of the diagnostic’s performance with that of another device that has already been clinically tested. But often the FDA requires prospective clinical studies to assess a new device’s safety and effectiveness. The Safe Medical Devices Act of 1990 authorizes the FDA to request data on clinical sensitivity, specificity, and predictive value for diagnostic tests that undergo a PMA review. These data are costly and time-consuming to procure, and they require clinical research expertise that many small companies lack. Most manufacturers try to avoid the necessity of a PMA review of their diagnostic tests and may even forgo bringing their test to market if a PMA application is required. Manufacturers can bypass the need for a PMA application if they can show that their device is substantially equivalent to one already on the market. This qualifies their device to enter the market via a 510(k) review process. This review requires manufacturers to submit data showing the accuracy, reproducibility, and precision of their diagnostic. Manufacturers also have to provide documentation supporting their claim that the diagnostic is “substantially equivalent” to a device already on the market. As is true for PMAs, there are no well-defined performance standards for 510(k) reviews, nor does the FDA clearly define the requirements for substantial equivalence. However, the agency has issued guidance documents that indicate the standards by which it will review a variety of types of diagnostics. It has also accepted the laboratory test standards set by other organizations, such as the Clinical Laboratory Standards Institute. None of these standards, nor the 510(k) or PMA review process itself, considers the clinical safety and effectiveness of the diagnostic. SOURCES: Gutman, 2000; Hackett and Gutman, 2005; IOM, 2005; FDA, 2006a.
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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment impairment of human health” are subject to the most regulatory scrutiny (Gutman, 2000; IOM, 2005). Since the Medical Devices Act was enacted in 1976, a number of novel diagnostic tests based on genetics and other innovative molecular biology technologies have emerged. This created a large category of tests that would have had to undergo PMA review because there were no similar devices on the market on which to base a less onerous 510(k) review. The FDA Modernization Act in 1997 created a “de novo classification” for a device that is not equivalent to a legally marketed device. This classification allows manufacturers to bypass a PMA review for novel, low-risk devices. Such devices are reviewed for safety and efficacy by the FDA in a streamlined manner that usually does not require prospective clinical studies, relying instead on existing clinical literature to determine the device’s safety and effectiveness (Hackett and Gutman, 2005). A PMA or 510(k) review may not be required if a cancer biomarker test is developed by a laboratory for in-house use (a “homebrew” test). The FDA historically has not regulated homebrew tests, and laboratories offering them must label their test results with a qualifier that indicates the tests have not been cleared or approved by the FDA (FDA, 2003b). The homebrew exemption can enable manufacturers to quickly bring their tests to market. For example, there are hundreds of genetic tests currently on the market, but only four have been granted FDA approval (Hudson and Javitt, 2006). In 1992, the FDA attempted to exert more regulatory control over homebrew tests via its compliance policy guideline, which proposed applying general medical device regulation to homebrew tests. But due to strong objections from the laboratory community, which claimed that the proposed guideline would be an onerous duplication of regulations promulgated under the Clinical Laboratory Improvement Amendments (CLIA, see next section), the FDA stated that “the use of in-house developed tests contributed to enhanced standards of medical care in many circumstances, and that significant regulatory changes in this area could have negative effects on the public health” (DHHS, 2003). However, the FDA asserted that it had the authority to regulate homebrew tests should it wish to do so (Shapiro and Prebula, 2003), and it has been suggested that the agency’s choice not to regulate in-house tests was due to resource constraints (Heller, 2006). Instead, the agency tried to ensure the safety and effectiveness of homebrew tests by regulating the building blocks, known as analyte-specific
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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment BOX 3-2 FDA Regulation of Analyte-Specific Reagents In a ruling made effective in November 1998, the FDA subjected both the manufacturers of ASRs, as well as the laboratories using them, to regulation to ensure that ASRs would be made consistently over time according to the agency’s quality control requirements. It is the responsibility of the laboratory using the ASRs to develop a recipe for the homebrew test that incorporates the reagents, and it cannot share that recipe with other labs. All the testing using a homebrew diagnostic is done within the laboratory of the company or organization that developed it. Laboratories that produce ASRs must register with the FDA and satisfy the agency’s Quality System Regulations (good manufacturing practices), as well as report postmarket device failures. They are also required to indicate on the label for the ASR that its analytical and performance characteristics are not established. Makers of homebrew tests are not permitted to market their tests to other laboratories, nor can they sell packages of ASRs, or an ASR linked to a solid surface, with instructions on how to use the reagents in a testing procedure. Such packaging is considered to be a test kit subject to FDA review. SOURCES: FDA, 2003b; Shapiro and Prebula, 2003; IOM, 2005. reagents (ASRs),1 for these tests (Hackett and Gutman, 2005) (Box 3-2). In response to requests from manufacturers to clarify ASR regulations, the FDA recently issued draft guidance to better explain how FDA defines ASRs and to more clearly delineate the regulatory rules of these products for ASR manufacturers (FDA, 2006c). The document also provides examples of entities that FDA does and does not consider to be ASRs. In addition to guidance documents, the FDA has also used warning letters to assert authority and establish precedent for oversight of new tests that manufacturers thought would be outside FDA’s jurisdiction. For example, 1 These reagents are defined as “antibodies, both polyclonal and monoclonal, specific receptor proteins, ligands, nucleic acid sequences, and similar reagents, which through specific binding or chemical reaction with substances in a specimen, are intended for use in a diagnostic application for identification and quantification of an individual chemical substance or ligand in biological specimens” (FDA, 2003b).
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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment the FDA recently prevented Roche Molecular Diagnostics from registering their new microarray genetic test for drug metabolism (AmpliChip CYP450) as an ASR. The denial was based, in part, on an assessment that the intended use of the AmpliChip to identify genetic indicators of drug metabolism capabilities “is of substantial importance in preventing impairment of human health” (FDA, 2003a). Furthermore, the FDA does not regard a microarray, which uses multiple reagents to detect a genetic profile, as falling under its definition of an ASR (Hackett and Gutman, 2005). The FDA suggested seeking de novo classification for their AmpliChip, and Roche’s submission of previously published clinical literature on the genetic variants the AmpliChip detects and their clinically significant effects on drug metabolism led to FDA’s approval of the AmpliChip (Hackett and Gutman, 2005). The FDA has also required manufacturers of preanalytical systems, which collect, stabilize, and purify RNA, to submit a 510(k) premarket notification for the devices (FDA, 2005c), and it recently asked the makers of a new serum protein test using mass spectroscopy for ovarian cancer screening (OvaCheck) to consult with the agency about the appropriate regulatory status of the test. The developers of the OvaCheck test expected it would fall under the homebrew exemption from FDA review. But the FDA indicated that the test may be subject to a 510(k) review because the software used to analyze the results could be considered a device intended for use in the diagnosis of disease and therefore subject to regulation (FDA, 2004b). In September 2006, the FDA issued draft guidance for such tests that use complex mathematical formulas to interpret large sets of gene or protein data, referred to by the FDA as In Vitro Diagnostic Multivariate Index Assays (IVDMIAs) (FDA News, 2006a). The document notes that “the manufacture of an IVDMIA involves steps that are not synonymous with the use of ASRs and that are not within the ordinary ‘expertise and ability’ of laboratories that FDA referred to when it issued the ASR rule. Therefore, IVDMIAs do not fall within the scope of laboratory developed tests over which FDA has generally exercised enforcement discretion.” The FDA also recently warned Access Genetics that several of the genetic test packages it manufactures and sells contain all that is needed to perform the tests, including lab assay protocols, and therefore are not homebrew tests, which are conducted only at the site at which they were developed (FDA, 2005e). The agency also notified the Nanogen Corporation that its NanoChip Molecular Biology Workstation, NanoChip Electronic
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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment Microarray, and several ASRs were neither approved as a single system nor as separate components (FDA, 2005d; Heller, 2006). Furthermore, the FDA pointed out that some of the manufacturer’s publicity about its NanoChip system indicated that it could be used for clinical diagnostic applications and therefore could not be considered a research-only diagnostic exempt from FDA review, as the company expected (FDA, 2005d). If a test is used for research only, the FDA does not exert jurisdiction, but if the assay is used for a clinical purpose, such as for diagnosis, it is subject to regulation by the FDA. Neither the FDA nor CLIA offers any clear guidelines, however, for distinguishing the difference between a research-only diagnostic and a clinical diagnostic (Hackett and Gutman, 2005; Heller, 2006). The FDA also appears to be more assertive now in requesting clinical data for its reviews of biomarkers linked to therapeutics. Biomarkers used in clinical trials to identify likely responders to drugs (pharmacogenomic tests) will be regulated as devices in parallel with their corresponding drug candidates, and those for higher risk conditions will require PMAs. The FDA guidance (2005a) recommends submitting pharmacogenomic data when the data will be used to make approval-related decisions and when the data are relied on to define, for example, trial inclusion or exclusion criteria, the assessment for prognosis, dosing, or labeling or used to support the safety and efficacy of a drug. If a test shows promise for enhancing dosing, safety, or effectiveness or will be specifically referenced on the label, the FDA recommends codevelopment of the device and drug and coordinated applications for FDA approval (FDA, 2005a). The experience with attempts to add pharmocogenetic tests for the drug metabolizing enzyme cytochrome p450 to the labels for drugs such as warfarin indicate just how great the challenge of validation can be (IOM, 2006). In addition, in its February 2006 draft guidance on pharmacogenetic tests and genetic tests for heritable markers, the FDA stated that “For predictive screening in healthy or asymptomatic individuals, long-term follow-up (i.e., a longitudinal study) may be the only way to prove that the test was indeed predictive and to evaluate issues such as penetrance” (FDA, 2005a, p. 4). But this guidance also noted that for some genetic tests, there may be a sufficient clinical literature base to establish clinical validity of the new test without extensive new clinical studies.
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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment CMS OVERSIGHT OF CLINICAL LABORATORY PERFORMANCE Laboratory performance is overseen by the Centers for Medicare & Medicaid Services (CMS)2 under the Clinical Laboratory Improvement Amendments of 1988 (Hackett and Gutman, 2005). To be operational, a laboratory that conducts testing on human specimens for the purpose of providing information relevant to the diagnosis, prevention, or treatment of disease or physical impairments or for health assessments must be CLIA-certified (FDA, 2006b; Javitt, 2006). CLIA certification, which is renewed contingent upon inspection every two years, is intended to ensure the accuracy, reliability, and timeliness of patient test results from laboratories throughout the United States (FDA, 2006b; Box 3-3). But CLIA does not replace FDA regulatory authority over medical diagnostic tests; it does not address the clinical accuracy or usefulness of tests. There are some state requirements that are more stringent than CLIA, as well as organizational guidelines and standards that can be voluntarily adopted by laboratories to further the accuracy of their testing (DHHS, 1999; Swanson, 2002). But most laboratories follow the minimum generic standards set by CMS under CLIA. The requirements for CLIA certification vary depending on whether laboratories conduct tests of moderate or high complexity. (Low-complexity tests, such as a urine dipstick, are simple enough to be performed by unskilled laboratory personnel or even by patients. These tests are waived from requiring CLIA certification.) The FDA determines the degree of complexity of in vitro diagnostics based on the amount of expertise, oversight, interpretation, and judgment required to perform the test, as well as the potential risk to public health if the test is inaccurately performed (FDA, 2006b). 2 The Centers for Disease Control and Prevention (CDC) provides scientific and technical support to CMS and convenes the Clinical Laboratory Improvement Advisory Committee. The Committee provides scientific and technical advice and guidance regarding the need for, and the nature of, revisions to the standards under which clinical laboratories are regulated; the impact on medical and laboratory practice of proposed revisions to the standards; and the modification of the standards to accommodate technological advances. The Committee consists of 20 members knowledgeable in the fields of microbiology, immunology, chemistry, hematology, pathology, and representatives of medical technology, public health, clinical practice, and consumers. In addition, the Committee includes three ex officio members: the Director, Centers for Disease Control and Prevention; the FDA Commissioner; and the CMS Administrator.
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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment BOX 3-3 Overview of CLIA Regulation of High- and Moderate-Complexity Tests Demonstration of performance specifications Assess day-to-day, run-to-run, and within-run variation Verify test-reporting ranges from published reference ranges, kit manufacturer’s ranges, or in-house testing Provide evidence of reproducibility Quality control Create a procedure manual for each test Perform calibration procedures at least once every 6 months for each test system Perform quality control each day a test system is used, with at least two levels of control (high and low limits) Proficiency testing (PT) A lab must enroll at least one person in a PT training program for each specialty for which it seeks certification; ideally, lab members will rotate for each PT specialty or subspecialty testing program PT samples must be tested in the same manner by the same personnel as patient samples Both moderate- and high-complexity tests require laboratories to document the accuracy and reproducibility of their testing, the use of quality control procedures, and the proficiency training and testing of key personnel (Swanson, 2002; DHHS, 2003; CMS, 2006). The main difference between high- and moderate-complexity laboratories is that there are more stringent qualifications required for the personnel of high-complexity laboratories (DHHS, 2003). The FDA’s ASR ruling restricts sale of a reagent used for clinical purposes to laboratories designated as high complexity under CLIA, because these labs were thought to have the personnel and systems in place to allow for the reliable development of in-house tests. Most moderate- to high-complexity tests fall under CLIA-specified specialty areas that require more specific proficiency testing programs. These include tests within the domains of microbiology and immunology.
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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment The PT should provide a minimum of 5 samples per testing event with at least 3 testing events per year Level of accuracy for satisfactory performance for PT testing varies depending on the analyte(s) involved Personnel Labs must identify qualified individuals for the following positions: Moderate complexity: director, technical consultant, clinical consultant, and testing personnel High complexity: director, technical supervisor, clinical consultant, general supervisor, testing personnel Personnel qualifications differ depending on the position and level of test complexity; an MD, DO, DPM, or PhD with the appropriate laboratory training and experience can fill all the required positions for both complexity levels Labs must keep credentials of every lab member on file for inspection Sanctions Sanctions include suspension, limitation, or revocation of CLIA certificate, Medicare payment approval cancellation, civil money penalties, onsite monitoring, and correction plan SOURCE: CMS, 2005. But there are no specialty areas requiring proficiency testing indicated for molecular or biochemical genetic testing, despite the recognition by Congress that proficiency testing “should be the central element in determining a laboratory’s competence, since it purports to measure actual test outcomes rather than merely gauging the potential for accurate outcomes” (DHHS, 1988; CMS and DHHS, 2004; Javitt, 2006). In 2000, the Secretary’s Advisory Committee on Genetic Testing generated a report that concluded that the oversight of genetics tests was insufficient to ensure their safety, accuracy, and clinical validity and recommended that CMS develop a specialty area for genetic testing under CLIA. Draft guidelines for genetic testing quality from the international Organisation for Economic Co-operation and Development also identified proficiency testing and lab quality as critical to ensuring health (OECD,
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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment 2006). In March 2006, the Genetics and Public Policy Center of Johns Hopkins University conducted a survey of laboratory directors of genetic testing laboratories and found widespread support for creation of a genetic testing specialty under CLIA (Hudson et al., 2006). Furthermore, the survey data found that proficiency testing was linked to greater accuracy of genetic testing, although at least a third of genetic testing laboratories fail to perform proficiency assessments for some or all of their tests. In April 2006, CMS proposed rule making that would create such a specialty area, but three months later CMS stated that existing CLIA regulations are adequate to protect public health, asserting that there is insufficient “criticality” to warrant rule making for genetic testing (Genetics & Public Policy Center, 2006; Hudson, 2006). The committee agrees with the need for oversight and recommends developing a specialty area for molecular diagnostics. THE NEED FOR CONSISTENCY AND TRANSPARENCY Clearly there is significant variability in the scrutiny of biomarker tests before and after entry into the market. This lack of consistency and transparency in the biomarker development process is problematic for two important reasons. First, the variability and uncertainty associated with oversight and assessment of biomarker tests are disincentives to innovation by developers. As noted above, the FDA previously has claimed legal authority to assert jurisdiction over diagnostic tests, but it has usually withheld its authority. Recently, the FDA has taken action to create clarification and precedent on a case-by-case basis regarding molecular diagnostics through letters or guidance documents. But when oversight is variable, evolving, and thus hard to predict, it can have a major impact on the risk of development. Unanticipated action by the FDA can result in delays and greatly increase the cost of development. As noted in Chapter 4, the variability and unpredictability of health care coverage adds an additional layer of risk and uncertainty for developers. Once a test enters the market, coverage decisions often depend on convincing evidence of clinical usefulness, but those decisions are made on an ad hoc basis and vary by payor, as there are no widely accepted guidelines for evidence standards. Second, a lack of regulation and consistent assessment prior to market entry can lead to inappropriate adoption and use of biomarkers, unnecessarily increasing health care costs and potentially harming patients. Many diagnostic tests in use have not been validated or formally evaluated. Companies develop their own assessment criteria and standards for developing
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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment and marketing diagnostic tests on a case-by-case basis and generally choose the path to market of least resistance. Competition tends to erode standards of evaluation, since the more rigorous the standard, the longer and more costly the development process and the less likely it is to be first to market. Most diagnostic tests enter the clinic as homebrew tests, which are exempt from FDA approval or clearance. Furthermore, even if a company seeks and obtains FDA approval, laboratories can develop their own in-house homebrew test and use that in place of the FDA-approved test. No federal agency currently enforces the accuracy of marketing claims made for homebrew tests. Thus, there is a great need for a coherent strategy to make the biomarker development and adoption process more transparent, to remove inconsistency and uncertainty, and to elevate the standards and oversight applied to biomarker tests. No federal agency currently takes responsibility for ensuring the clinical validity of biomarkers, but oversight and ownership of the process are key to developing strategies and making effective and efficient progress in the field. The committee strongly urges the designation of an appropriate federal agency to provide leadership in the process and to coordinate and oversee interagency activities. The National Institute of Standards and Technology (NIST) is an appealing candidate. Although it has had a limited role in biomarker development to date due in part to financial restraints, it has the appropriate experience to play a broader role in the establishment of standards for biomarkers if given appropriate funding for that purpose. NIST standards work in health care and clinical chemistry is well established, and, more recently, NIST has begun some work related to cancer molecular genetics technology and standards, as well as work with the Early Detection Research Network of the National Cancer Institute (NCI) on cancer biomarker validation (Barker, 2003). An important first step would be to convene all relevant government agencies (e.g., the National Institutes of Health [NIH], the FDA, CMS, the Agency for Healthcare Research and Quality, NIST) and non-government stakeholders (e.g., academia, the pharmaceutical and the diagnostics industry, and health care payors) to work together in developing a transparent process to create well-defined consensus standards and guidelines for biomarker development, validation, qualification, and use to reduce the variability and uncertainty in the process of development and adoption. For example, FDA, CMS, and industry should work together to develop guidelines for clinical study design that will enable sponsors to run a single study (or a minimal number of studies) to generate adequate clinical data
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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment Cetuximab Cetuximab, a monoclonal antibody made by ImClone,was approved by the FDA in 2004. Approval was based on a clinical trial that used an immunohistochemisty test for EGFR expression (EGFR pharmDx made by Dako and approved simultaneously by the FDA in 2004) to select colorectal cancer patients likely to respond to cetuximab. Patients were not entered into the clinical trials of cetuximab unless they had a positive result in the EGFR test (i.e., 1 percent or greater tumor cells showing positivity). The tumor response rate was 22.9 percent in patients who received cetuximab in combination with irinotecan, and 10.8 percent in patients who received cetuximab alone. However, no trials were performed with EGFR-negative patients, and further evaluation has shown that therapeutic response does not correlate with EGFR positivity, either by the number of positive cells or by staining intensity, perhaps because the staining pattern for EGFR is often quite heterogeneous. In March 2005, Chung et al. reported that EGFR-negative colorectal cancer patients treated with cetuximab in a nonstudy setting had a 25 percent response rate, suggesting that exclusion of patients from cetuximab treatment based on EGFR status is unwarranted. Thus, the EGFR test may have increased the probability that cetuximab would be approved, but it is not a valid test for making treatment decisions in the clinic. However, the FDA-approved drug label still specifies that it be used for the treatment of EGFR-expressing colorectal cancer. Panitumumab Panitumumab, a fully humanized monoclonal antibody against EGFR made by Amgen Inc., received accelerated FDA approval in September 2006 for treatment of EGFR-expressing metastatic colorectal cancer in patients with progression following chemotherapy. A randomized controlled trial of 463 patients demonstrated a significant improvement in progression-free survival in patients receiving panitumumab (mean of 96 days versus 60 days for patients receiving best supportive care). There was no difference in overall survival however, and the approval stipulates that the manufacturer must conduct a postmarketing trial to determine whether the drug improves survival in patients with fewer prior chemotherapies. Enrollment in the phase III trial was limited to patients whose tumors were positive for EGFR expression, defined as at least 1+ membrane staining in > 1 percent of tumor cells by the Dako EGFR pharmDx test kit (approved by FDA in September 2006 to assess patient eligibility for panitumumab as well as cetuximab). The majority of patients’ tumors exhibited EGFR expression in 10 percent or
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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment more of tumor cells, with no evidence of a correlation between either the proportion of cells expressing EGFR or the intensity of EGFR expression. SOURCES: FDA News, 2003; FDA, 2004a,c; FDA News, 2004a,b; Miller, 2004; Chung et al., 2005; Hirsch and Witta, 2005; Takano et al., 2005; Amgen, 2006; FDA News, 2006b; Hsieh et al., 2006. a panel of genomic and proteomic pharmacodynamic markers to predict response to EGFR inhibitors in patients with nonsmall cell lung cancer. The trial will be supported by funds from the NCI director’s discretionary budget reserve, and it will be conducted in conjunction with the FDA and CMS (Goldberg and Golderg, 2006; Niederhuber, 2006). Progress in this field could be accelerated by better coordinating the development of biomarker diagnostics and new drugs. Such coordinated development could help companies choose the most promising drug leads, optimize clinical trial designs, and facilitate rapid and effective adoption into clinical practice (FDA, 2004b). However, there are many challenges to be addressed before this ideal approach becomes reality (IOM, 2006). For example, the cost and risks of diagnostic development are significant when clinical validity and utility must be established, and they add substantially to the existing high cost of drug development (estimated at $400–800 million, on average (Frank, 2003)). Companies may be unwilling to take the risk of investing in diagnostic development in the earlier phases of drug development, when approval of the drug is so uncertain. (On average, only 1 out of 5 Investigational New Drugs achieves FDA approval; Dimasi, 2001). But timing is key for the coapproval and marketing of drug-diagnostic combinations. Companies need to find better ways to integrate basic and clinical research efforts and emphasize the search for subpopulations based on theoretical and empirical evidence prior to phase III to avoid the rush near end of drug development (i.e., immediately prior to drug approval) to develop and validate the accompanying diagnostic. Strategies to minimize the costs of diagnostics development and to facilitate risk sharing between pharmaceutical and diagnostics companies would also encourage development efforts. One possibility would be to
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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment link FDA approvals of therapeutics and the associated response-predicting diagnostics, such that one is contingent on the other. For example, one possible approach might be to provide contingent FDA approval of a drug by requiring postapproval reporting on diagnostic performance and subsequent submission of a PMA or 510(k) application for the diagnostic (IOM, 2006; Lipshutz, 2006). However, it is not clear that the FDA could compel a diagnostics company to sponsor a submission when the drug is sponsored by an unrelated pharmaceutical company. Furthermore, it seems unlikely that the FDA would rescind approval for a drug if the biomarker is subsequently shown to be invalid, as in the case of cetuximab. The FDA should more clearly delineate the expectations and requirements for approval of diagnostic-therapeutic combinations. The FDA’s “Critical Path” white paper placed high importance on personalized medicine and the codevelopment of diagnostics and therapeutics, noting that new trial designs and methods are needed, but it did not lay out specific plans for how to how to facilitate codevelopment (FDA, 2004b). In its April 2005 concept paper on codevelopment, the FDA noted that codevelopment applies when the use of an in vitro diagnostic is mandatory for drug selection for patients, or when optional use during drug development may assist in understanding disease mechanisms and in selecting clinical trial populations. Furthermore, codevelopment applies to a device-drug combination product, as well as to in vitro devices and drugs sold separately. The concept paper explicitly stated that drug selection biomarkers, particularly for high-risk conditions, were expected to be subject to PMA reviews (FDA, 2005b). In response, industry representatives expressed concern that the paper proposed higher hurdles for diagnostic approval than current requirements and that clinical utility is not explicitly defined in the act (Hinman et al., 2006). A new guidance document specifically focused on diagnostic-therapeutic combinations is being drafted by the FDA, taking into account feedback on the concept paper (Woodcock, 2006), but the content, impact, and enforceability are unknown at this time. Because more than one FDA center will often be involved in the approval or clearance decisions in the case of diagnostic-therapeutic combinations, the agency should also clarify the roles of each center and focus on ensuring coordination between the centers to facilitate clearance or approval of molecular diagnostics. In addition, the FDA needs more dynamic ways of changing a drug’s label when new data for selecting appropriate target populations emerge. When a biomarker test linked to a drug is found to be invalid (as in the case of cetuximab), the FDA should move quickly to make
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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment the necessary label changes. Conversely, when new biomarkers are found to aid therapeutic decisions for existing drugs, a formal mechanism is needed to evaluate the evidence and consider appropriate label changes. SUMMARY AND CONCLUSIONS The standards used to demonstrate the validity of biomarkers vary considerably, in part because there is no overarching leadership in the field to set uniform consensus standards for biomarker development. The FDA and CMS have some authority over diagnostic tests, but oversight has been variable and unpredictable and, in many cases, inadequate to ensure the safety, effectiveness, and value of tests on the market. Oversight by federal agencies has been evolving recently, and FDA in particular has taken some positive initial steps, but there is still a need for clarification, uniformity, and leadership in this area. The process of biomarker development and evaluation could be improved by making it more transparent, consistent, and effective. First, government agencies, including NIH, the FDA, CMS, and NIST, and non-government stakeholders, including academia, the pharmaceutical and diagnostics industry, and health care payors, should work together to develop a transparent process for creating well-defined consensus standards and guidelines for biomarker development, validation, qualification, and use to reduce the uncertainty in the process of development and adoption. NIST or another appropriate federal agency should provide a leadership role in the process, coordinating and overseeing interagency activities. Second, the FDA should clarify its authority over biomarker tests linked to clinical decision making and then establish and consistently apply clear guidelines for the oversight of those tests. In addition, the appropriate federal agency (e.g., the FDA or the FTC) should monitor and enforce marketing claims made about molecular diagnostics. Variability and unpredictability in oversight can reduce interest and investment in developing innovative diagnostics, while inadequate evaluation and oversight could lead to harm for patients and unnecessary costs for society. Third, the FDA and industry should work together to facilitate the codevelopment of diagnostic-therapeutic combinations. The FDA should more clearly delineate the expectations and requirements for diagnostic-therapeutic combination approval, and companies need to better integrate basic and clinical research rather than waiting to contract biomarker development in the late stages of phase III testing. Coordinated development of
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