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Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease 5 Strengthening Evidence-Based Regulation CHAPTER RECOMMENDATIONS The previous chapters introduced the committee’s proposed biomarker evaluation framework and tested it using diverse case studies. While the committee’s evaluation framework will provide a more complete review of the evidence supporting different contexts of biomarker use, the effective implementation of the framework may require additional actions by the Food and Drug Administration (FDA) and other stakeholders. First, the committee concluded that the FDA’s current regulatory authority is not sufficient. Inadequate fulfillment of postmarketing studies and incomplete understanding of how consumers interpret food and dietary supplement claims prevent robust protection of public health. Therefore, the committee recommended that: Recommendation 5: 5a. Congress should strengthen the FDA’s authority to request and enforce postmarket surveillance across drugs, devices, and biologics when approvals are initially based on putative surrogate endpoint data. 5b. Congress should grant the FDA authority to request studies and sufficient authority to act on the results of studies on consumer understanding of claims on foods and supplements. To support this recommendation, the first section of this chapter summarizes the FDA’s role and outlines the FDA’s regulatory authority and
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Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease describes some of the limitations related to the FDA’s current regulatory capacities. Recommendation 5 has two parts due to the differing regulatory frameworks surrounding drugs, devices, and biologics as compared to foods and supplements. Its intent is parallel, nonetheless. In addition to strengthened FDA regulatory capacity, the committee acknowledged that science-based decision making is reliant on the availability of scientific data. Although there are ongoing efforts to collect and analyze biomarker data, the committee concluded that these efforts are uneven and not optimally organized within the U.S. Department of Health and Human Services (HHS). Recognizing the value of a well-coordinated, comprehensive effort to collect and share biomarker information in advancing public health, the committee sought to improve ongoing biomarker data collection efforts. Improved FDA information infrastructure and surveillance systems may also enhance the agency’s ability to interpret biomarkers and their relation to public health. Based on these findings, the committee made the following recommendation: Recommendation 6: 6a. The U.S. Department of Health and Human Services should facilitate a coordinated, department-wide effort to encourage the collection and sharing of data about biomarkers for all uses, including drugs, biologics, devices, and foods. 6b. The FDA in coordination with other federal agencies should build needed data infrastructure and surveillance systems to handle the information necessary to gain sufficient understanding of the effects of biomarker use. The second part of this chapter reviews the FDA’s infrastructure capacity, and ongoing biomarker data collection efforts. Opportunities to facilitate data collection and sharing, such as precompetitive collaboration, will also be highlighted. FDA REGULATORY AUTHORITY Several federal agencies have responsibility for public health. In addition to the FDA and the other 10 agencies that comprise HHS, HHS also collaborates with units within the Departments of Defense, Veterans Affairs, Agriculture, and Education in carrying out its public health responsibilities. The FDA’s mission is as follows: The FDA is responsible for protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, our nation’s food supply, cosmetics, and products that emit radiation. The FDA is also responsible for advancing
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Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease the public health by helping to speed innovations that make medicines and foods more effective, safer, and more affordable; and helping the public get the accurate, science-based information they need to use medicines and foods to improve their health. (FDA, 2008a) The FDA’s task is large. The FDA regulates products that comprise about 25 percent of consumer spending in the United States, which comes to more than $1 trillion in spending (Subcommittee on Science and Technology, 2007). The FDA’s 2008 budget authority was $1.87 billion; with user fees added to this number, the FDA’s total 2008 budget was $2.42 billion (Office of Budget, 2009). As stated by Wood (2008) in his article Playing “Kick the FDA”—Risk-free to Players but Hazardous to Public Health, Between 1988 and 2007, additional FDA responsibilities were imposed by 137 specific statutes, 18 statutes of general applicability, and 14 executive orders (Subcommittee on Science and Technology, 2007). At the same time, the FDA received a 2007 federal appropriation of only $1.57 billion—less than 75% of the budget for the school district in its home county in Maryland. For another comparison, Coca-Cola’s advertising budget in 2008 was $3 billion (Coca-Cola, 2009). The money spent to promote one company’s products in one year is greater than the money spent to ensure the safety of products purchased with one out of every four consumer dollars in the United States. Recommendation 7.1 from the Institute of Medicine (IOM) report The Future of Drug Safety stated that “to support improvements in drug safety and efficacy activities over a product’s lifecycle, the committee recommends that the Administration should request and Congress should approve substantially increased resources in both funds and personnel for the Food and Drug Administration” (IOM, 2007b). Food safety is also a challenge because responsibilities are spread over multiple agencies (IOM, 1998). IOM reports on food safety have also pointed out the need for sufficient funding to support a science-based food safety system (IOM, 1998). The call for adequate resources to protect food and drug safety has also been sounded by the FDA’s Science Board in its report FDA Science and Mission at Risk (Subcommittee on Science and Technology, 2007). The challenges facing the FDA as its duties expand and its resources shrink have also been noted by IOM committees and workshops (IOM, 2007a, 2007b) as well as other entities (GAO, 2009b; IOM, 2007a, 2007b; Wood, 2008). With its large task and small budget, the FDA faces criticism from many directions: when there is an outbreak of illness caused by a foodborne pathogen, when there are pervasive safety problems in food plants,
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Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease when medical and food products imported from other countries are adulterated, when new life-saving drugs are not approved fast enough, and when unsafe drugs are taken by patients for years before their risks are recognized. Criticism comes from the public, industry, and government. Decisions from case law modify laws and regulations; these decisions do not always consider their impact beyond a particular case. Changing administrations and priorities within the executive branch also complicate the FDA’s ability to be successful in protecting public health. The FDA derives much of its regulatory authority from the Food, Drug, and Cosmetic Act (FDCA), which was originally passed in 1938 and has been amended over time (Box 5-1). From a relatively modest portfolio of activities in 1938, the responsibilities of the agency have continued to expand. In the past two decades, Congress has enacted more than 100 statutes that directly impact the FDA’s regulatory responsibilities—an average of 6 statutes per year, in addition to its core objectives. All of these statutes require some type of FDA action, such as the development or implementation of regulations or guidance documents, or the establishment of new regulatory programs. Although the FDA’s purview of responsibilities continue to expand, the FDA gained through appropriation only 646 employees, an increase of 9 percent, and lost more than $300 million to inflation (Subcommittee on Science and Technology, 2007). Figure 5-1 illustrates the scope of the FDA’s regulatory responsibilities, as outlined in 2006. In terms of dollars, the Center for Devices and Radiological Health (CDRH) regulated manufacturers with industry sales of $110 billion; the Center for Food Safety and Applied Nutrition (CFSAN) regulated $417 billion worth of domestic food, $49 billion in imported food, $60 billion in cosmetics, and $18 billion in dietary supplements; and the Center for Drug Evaluation and Research (CDER) regulated $275 billion in pharmaceutical sales (Subcommittee on Science and Technology, 2007). The most recent amendment to the FDCA was the Food and Drug Administration Amendments Act of 2007 (FDAAA). The law expanded FDA authority and reauthorized the Prescription Drug User Fee Act (PDUFA), the Medical Device User Fee and Modernization Act, the Best Pharmaceuticals for Children Act, and the Pediatric Research Equity Act (FDA, 2009c). FDAAA requires more FDA involvement in ensuring that clinical trials are incorporated into ClinicalTrials.gov and provides the FDA with additional requirements, authorities, and resources related to pre- and postmarket drug safety, including the ability to require postmarketing studies, clinical trials, safety labeling changes, and Risk Evaluation and Mitigation Strategies (REMS). In addition, FDAAA requires new reporting of adverse events related to food (FDA, 2009b). The traditional tools of regulatory agencies include regulation, approval or disapproval of applications, and enforcement (Hamburg and
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Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease BOX 5-1 Expanding FDA Responsibilities The modern regulatory functions of the Food and Drug Administration (FDA) began with the passage of the 1906 Pure Food and Drug Act, which prohibited interstate commerce in adulterated and misbranded food and drugs. The Food, Drug, and Cosmetic Act (FDCA), passed by Congress in 1938, overhauled the public health system by authorizing the FDA to require evidence of safety for new drugs, set standards for food, and conduct factory inspections. Since 1938, the FDA’s role has expanded enormously. Enactment of a series of statutes, beginning in the 1950s and continuing into the 1970s, provided the FDA with a much broader mandate. For example, the Kefauver-Harris Amendments of 1962 strengthened rules for drug safety and required manufacturers to demonstrate effectiveness of drugs. In 1976, the FDCA was amended to apply safety and effectiveness safeguards to new medical devices. Significant amendments to the FDCA since 1980 are included below: Infant Formula Act of 1980 and as amended in 1986 Drug Price Competition and Patent Term Restoration Act of 1984 Nutrition Labeling and Education Act of 1990 Safe Medical Devices Act of 1990 Medical Device Amendments of 1992 Prescription Drug User Fee Act of 1992 Dietary Supplement Health and Education Act of 1994 FDA Export Reform and Enhancement Act of 1996 Food Quality Protection Act of 1996 Animal Drug Availability Act of 1996 The Food and Drug Administration Modernization Act of 1997 Best Pharmaceuticals for Children Act of 2002 Pediatric Research Equity Act of 2003 The Minor Use and Minor Species Animal Health Act of 2004 Dietary Supplement and Nonprescription Drug Consumer Protection Act of 2006 Food and Drug Administration Amendments Act of 2007 SOURCES: FDA (2009e, 2009f); Subcommittee on Science and Technology (2007). Sharfstein, 2009). Prior to the 1970s, FDA functions were primarily related to law enforcement (e.g., issues of adulteration and misbranding). Current regulatory responsibilities are science based, as most of the FDA’s work has moved away from the court to regulatory decisions involving scientific competencies and technical knowledge. Across all centers, the core regulatory functions can be roughly divided into three categories: (1) premarket review, (2) marketed product adverse event surveillance and
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Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease FIGURE 5-1 Food and Drug Administration—Regulatory Industry (FY2006): The people, science, and information needed to sup-port innovation, grow industries, and protect the public both in our country and around the world. SOURCE: Subcommittee on Science and Technology (2007).
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Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease BOX 5-2 Core FDA Regulatory Functions Premarket review involves reviewing and assessing sponsor applications and submissions and developing and/or implementing a Food and Drug Administration (FDA) response Examples include Biologic License Applications, New Drug Applications, Pre-Market Notifications, Health Claim Petitions, Generally Recognized as Safe Notices; responses include approval, complete response, non-acceptance, non-approval, clearance, an information/advice letter, and other actions Marketed product adverse event surveillance and efficacy/safety assessment, which involves identifying or receiving information about marketed product safety or efficacy issues, assessing the information, and developing and/or implementing an FDA response Examples include postmarket safety reports from sponsors or individuals; population-based surveillance studies; responses include inspections, follow-up and work with product sponsors, local public health agencies, recalls, label changes, issuance of health alerts, product recalls and withdrawals, and other legal action Ensuring marketed product quality and safety involve identifying or receiving information about a marketed product or a manufacturing or distribution facility, assessing this information, and developing or implementing an FDA response Examples include information obtained from facility and product quality inspections; responses can include inspections, intensive follow-up and work with product sponsors or distributors, work with import agencies, product recalls and withdrawals, and legal action SOURCE: Subcommittee on Science and Technology (2007). efficacy/safety assessment, and (3) ensuring marketed product safety and quality (see Box 5-2) (Subcommittee on Science and Technology, 2007). Drugs and Biologics Two centers, CDER and the Center for Biologics Evaluation and Research (CBER), are responsible for assessing the safety and effectiveness of drugs and biologics, respectively. CDER is the largest of the FDA’s five centers, and has responsibility for both prescription and over-the-counter drugs. CBER ensures the safety, purity, potency, and effectiveness of biological products, including vaccines, blood and blood products, cells, tissues, and gene therapies. The premarket review responsibilities of these
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Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease centers include reviewing and assessing sponsor applications and developing and/or implementing an FDA response for new, supplemental, or change-in-use products. Premarket applications related to these centers include Investigational New Drugs, New Drug Applications, and Biologic License Applications. In addition to premarket review responsibilities, these centers are involved in adverse event surveillance and efficacy and safety assessment of marketed products. The FDA receives and analyzes reports of adverse events, participates in active surveillance and signal detection activities, takes action on safety and efficacy problems, and implements and evaluates risk communications. Particular concerns have been raised over the FDA’s drug safety system, and a large component of the FDA’s drug safety system consists of postmarketing surveillance activities. Previous reviews of the FDA, such as the IOM report The Future of Drug Safety (IOM, 2007b), suggest that the FDA has unclear and insufficient regulatory authorities related to enforcement. The following section outlines the limitations of current postmarking activities and the corresponding lack of FDA authority. Postmarketing Surveillance in FDA Regulation of Drugs and Biologics Phase I through III clinical trials are dedicated to demonstrating safety and effectiveness for FDA approval, and usually involve a few hundred to a few thousand individuals. However, many more individuals may ultimately receive the intervention post-FDA approval, and tracking clinical experience, through phase IV (postmarketing) studies is important for identifying relatively rare adverse events and determining effectiveness within different populations and circumstances. However, some evidence suggests that drug sponsors are not fulfilling their postmarketing obligations efficiently, and that the FDA lacks authority to hold drug sponsors to their commitments after drug approval. Postmarketing surveillance may evaluate safety, efficacy, pharmacology, toxicology, and manufacturing controls, among other factors. The FDA requires drug applicants to conduct these studies in several situations. First, if a drug is approved under accelerated approval on the basis of a surrogate rather than clinical endpoint, then the FDA requires that postmarketing studies verify the safety and efficacy of the drug after it is on the market. If postmarketing studies do not substantiate clinical benefits, or raise safety concerns, the FDA may withdraw the drug. Second, in deferred pediatric studies, drugs approved in adults may be used in children with required postmarketing studies substantiating safety and efficacy in the pediatric populations. Third, when it is unethical to conduct clinical trials in humans, the FDA can approve drugs on
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Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease the basis of animal data, but also requires efficacy and safety data after approval. Finally, the FDA can request that the drug applicant conduct postmarketing studies prior to drug approval. Drug applicants agree to these commitments in writing, which the FDA then lists in its final drug approval letters. The Food and Drug Administration Modernization Act of 1997 expanded the FDA’s authority to oversee postmarketing study commitments. The legislation requires drug sponsors to report on the status of certain postmarketing studies (via annual status reports) and establishes that some information contained in these reports is considered public information. The FDA requires annual status reports for postmarketing studies that address clinical safety, clinical efficacy, clinical pharmacology, and nonclinical pharmacology.1 In the annual status report, drug sponsors indicate the status of their postmarketing commitments, marking studies as pending (study has not started, but is not behind schedule), ongoing (ahead or on schedule), delayed, terminated (study ended before completion, but a final report has not been submitted to the FDA), or submitted. There is concern that the current postmarketing surveillance system is inadequate in ensuring that drugs are safe and effective. The primary concern with the current system is that drug manufacturers are responsible for the collection, evaluation, and reporting of data from postmarketing studies of their own products. Statistics reveal that drug manufacturers are not efficiently fulfilling their postmarketing obligations; in 2004, fewer than half of promised postmarketing commitments had been initiated (Psaty et al., 2004). From 2004 to 2008, the number of open postmarketing commitments has remained relatively stable, at around 1,100–1,200, while the number of commitments met each year has also remained relatively stable, at around a much lower 100–160 each year.2 Drug manufacturers have little incentive to conduct timely postmarketing studies because these studies may reveal safety problems or other concerns that could result in more constrictive drug labeling, or withdrawal from the market, even though these studies may be a condition of drug approval. Drug manufacturers may also be tempted to conceal available data that suggest a drug has major risks. Examples of such concealment include unpublished data suggesting absence of benefit—or even risk of harm—of selective serotonin reuptake inhibitors in teens (Drummond, 2004), and data showing the interaction of cerivastatin with gemfibrozil and the risk of rhabdomyolysis. Although Bayer Corporation, 1 21 C.F.R. § 314.81(b)(2)(vii) (2003). 2 73 Federal Register 22157–22159 (2008), 72 Federal Register 5069–5070 (2007), 71 Federal Register 10978–10979 (2006), 70 Federal Register 8379–8381 (2005).
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Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease the manufacturer of cerivastatin, was aware of the risks of rhabdomyolysis as early as 4 months after the launch of the drug, the contraindication was not added to the package insert for more than 18 months3 (Fontanarosa et al., 2004; Psaty et al., 2004). Beyond the disincentives of drug manufacturers to reveal possible drug risks postapproval, there are also concerns that the FDA is ill equipped to oversee postmarketing activities and lacks regulatory recourse to ensure drug manufacturer compliance. In 2006, HHS conducted a review of the FDA’s monitoring of its postmarketing study commitments, and came to two conclusions: first, the FDA cannot readily identify whether, or how timely, postmarketing study commitments are progressing toward completions; and second, that monitoring postmarketing study commitments are not a top priority at the FDA (Office of Inspector General, 2006). The report found that one-third of annual status reports were missing or incomplete and contained information with little utility, while the management information system supporting postmarketing activities was found to be ineffective. Compared to other priorities, postmarketing surveillance was also found to be of lower priority. Although PDUFA provided additional funding to the FDA to meet new time lines for drug approval, it prohibited the agency from using the user fees on postmarketing surveillance or other drug safety programs (Psaty et al., 2004), and FDA officials noted that PDUFA-associated activities (e.g., reviewing drug applications and documenting FDA/industry meetings) are of higher priority (Office of Inspector General, 2006). Furthermore, a Government Accountability Office (GAO) study found that there is a lack of criteria for determining which safety actions to take in response to postmarketing findings, and when they should occur (GAO, 2006).4 In reviewing FDA postmarketing surveillance activities, the IOM report The Future of Drug Safety showed that the FDA lacks clear, unambiguous authority to enforce drug sponsor compliance with regulatory requirements. The committee recommended that Congress ensure that the FDA has the ability to require postmarketing risk assessment and risk management programs, and is equipped with better enforcement tools to ensure drug sponsor compliance (IOM, 2007b). 3 Eventually Bayer voluntarily withdrew cerivastatin from the U.S. market in August 2001 due to the high rates of rhabdomyolysis. 4 Also, a 2009 GAO analysis found that FDA has taken a passive approach to enforcing confirmatory study requirements and has never exercised its authority to withdraw a drug it approved based on surrogate endpoints under the accelerated approval process, even when such studies have been outstanding for nearly 13 years. This analysis found that two-thirds of postmarketing studies for drugs based on surrogate endpoints through the accelerated approval process have been closed from the creation of accelerated approval in 1992 to November 20, 2008 (GAO, 2009d).
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Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease In September 2007 FDAAA was enacted. Among its provisions were new authorities to require postmarket studies and clinical trials, safety labeling changes, and REMS. As a result of FDAAA, between March 25, 2008, and September 14, 2009, CDER and CBER issued 74 letters with postmarketing requirements to assess safety issues for drugs and biologics (FDA, 2009a). Whereas these kinds of studies would have had to have been undertaken voluntarily, they are now required with enforceable time lines. In addition, in 2008, the FDA introduced the Sentinel Initiative, a national integrated electronic database to detect adverse events of drugs and other medical products. It is hoped that the system will eventually monitor as many as 100 million individuals, and will be built from participating electronic health records and claims databases (IOM, 2009; Platt et al., 2009). The Sentinel System will be a distributed network, where all clinical data remains within the source systems’ databases, with centralized software to query approved network questions. Devices The FDA Center for Devices and Radiological Health is responsible for regulating medical devices as well as radiation-emitting electronic products. CDRH categorizes devices into three classes, depending on this risks they pose. Class I devices, which include items such as tongue depressors, toothbrushes, and bedpans, have the lowest regulation and do not require review by the FDA prior to marketing. Class II devices face an intermediate level of regulation, including a clearance process that usually does not require submission of clinical data to the FDA. Class III devices, including implants and other high-risk devices, are the most regulated device category and require submission of clinical evidence of safety and effectiveness to secure FDA approval prior to marketing. Regulation of medical devices tends to lag behind the regulation of pharmaceuticals (IOM, 2005). In addition to establishing the three categories of devices, The Medical Device Amendments Act of 19765 also gave the FDA authority to create a system for reporting adverse events associated with devices. In 1984 the FDA issued regulations requiring manufacturers and importers of devices to report information indicating that a device might have caused or contributed to a death or serious injury. The Safe Medical Devices Act of 1990 added requirements that hospitals and other facilities report to the FDA and manufacturers any events indicating that a device caused or contributed to an event. Additionally, the legislation established new requirements for manufacturers to track specific types of high-risk medical devices and gave the FDA authority 5 Public Law 94-295.
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Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease BOX 5-4 Role of NIH in Biomarker Data Collection The NIH has played an instrumental role in the development and qualification of biomarkers for all purposes. NIH has initiated a number of efforts aimed at improving collaboration between stakeholders and increasing the amount of publicly available information on promising biomarkers. These efforts include workshops on the state of the science for various biomarkers, the Biomarkers Consortium, and the Oncology Biomarker Qualification Initiative. NIH-led workshops on use of biomarkers for purposes with regulatory impact have been held via the Office of Dietary Supplements, NHLBI, and others. In 1999, the NIH and the FDA held a workshop on “Biomarkers and Surrogate Endpoints: Advancing Clinical Research and Applications” (Abstracts of the NIH-FDA conference, 1998). Topics ranged from definitions to needs and applications in disease areas from cardiovascular to psychiatric conditions. While this report does not describe the contributions of NIH and its separate institutes and offices in detail, these cannot be underestimated. The expertise, leadership, and resources of the NIH enable much rigorous science, interagency and inter-sector collaboration, and the public availability of biomarker data that would otherwise not occur. The NIH may also help play a role in prioritizing the development of biomarkers in underdeveloped areas, such as food and nutrition. protect integrity in its basic processes” (Hamburg and Sharfstein, 2009). According to a 1998 report from the U.S. House of Representatives Committee on Science, a necessary step toward evidence-based decision making is ensuring access to sound scientific data. The report recommends that sufficient resources are committed to science that informs policy decisions so that research, whenever possible, precedes policy decisions (Committee on Science, 1998). However, there are concerns that the FDA’s science capacity is at risk, threatening the agency’s ability to meet current and emerging regulatory responsibilities (Subcommittee on Science and Technology, 2007). The Subcommittee on Science and Technology concluded that: “science at the FDA is in a precarious position: the Agency suffers from serious scientific deficiencies and is not positioned to meet current or emerging regulatory responsibilities” (Subcommittee on Science and Technology, 2007). According to the subcommittee, three areas requiring improvement include strengthening mission-supportive scientific research programs, excellent staff with appropriate scientific expertise, and an information infrastructure and processing capability to ensure the FDA has access to the best data and information necessary to support regulatory science. The subcommittee found significant deficiencies in the ability of FDA
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Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease regulatory programs to assess and use information. Although the FDA is dependent on accurate and timely information to deliver its regulatory mission, the information crisis is putting their mission at risk. The subcommittee found that there is evidence of important, but slow, progress to improve information sciences and technology at the FDA over the past few years, yet significant gaps remain. In particular, the subcommittee concluded that the FDA cannot fulfill its surveillance mission because of inadequate staff and IT resources to implement cutting-edge approaches to modeling, risk assessment, and data analysis (Subcommittee on Science and Technology, 2007). The FDA is in the process of implementing a number of initiatives to improve its capacity to collect and interpret surveillance data. The following section describes these efforts and other efforts undertaken that may be important resources to the FDA as it collects outcome data on FDA-regulated products. Efforts to Collect Information on Outcomes The committee recommends that the FDA ensures that appropriate data infrastructure and surveillance systems are in place to gain sufficient understanding of the effects of biomarker use. There are a number of ongoing efforts to collect information on outcomes related to FDA-regulated products. These include the Sentinel Initiative, MedWatchPlus, and the Observational Medical Outcomes Partnership. In addition, the International Serious Adverse Events Consortium, the Cardiac Safety Research Consortium, and ClinicalTrials.gov may provide important information on outcomes. Information on outcomes will need to be linked to biomarkers, so that the FDA can gain sufficient understanding of the use of biomarkers in regulatory decision making. Sentinel Initiative As mentioned previously, the Sentinel Initiative aims to develop and implement a proactive system to track reports of adverse events linked to the use of the FDA’s regulated products (FDA, 2010c). It is hoped that the Sentinel Initiative will be a national electronic system that will transform FDA’s ability to track the safety of drugs, biologics, medical devices—and ultimately all FDA-regulated products once they reach the market. The Sentinel Initiative will be developed and implemented in stages. Currently, the FDA is working on the mini-Sentinel program, or developing a Sentinel prototype. Two aspects of this prototype include developing a coordinating center for a distributed system and evaluating emerging methods in safety science (Platt, 2010). Mini-Sentinel will include drugs, biologics, and devices; data sources include administrative
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Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease claims databases, outpatient and impatient electronic medical records, and registries. MedWatchPlus The FDA is currently developing MedWatchPlus, an electronic system for receiving, processing, storing, and analyzing adverse event reports and other safety-related information for all FDA-regulated products. This system will combine the FDA’s various safety reporting processes and systems and will provide a single point of entry for reporters. Additionally, the FDA and the NIH are collaborating to develop a “rational questionnaire” to ensure that submitting adverse events and problem reports are easier, more complete, and more consistent (FDA, 2009h). FAERS (FDA Adverse Event Reporting System) will be FDA’s new repository with enhanced analytic methods to enable staff to efficiently analyze thousands of safety reports and identify potential safety problems. Observational Medical Outcomes Partnership The Observational Medical Outcomes Partnership (OMOP) is a public–private partnership designed to help improve the monitoring of drugs for safety. The OMOP is funded and managed through the FNIH and draws on the expertise of the FDA, other federal agencies, the pharmaceutical industry, and non-profit organizations. The partnership is conducting a 2-year initiative to research methods that are feasible and useful to analyze existing healthcare databases to identify and evaluate safety and benefit issues of drugs already on the market (FNIH, 2010). In particular, the partnership is evaluating whether multi-source observational data can improve the ability to assess drug safety and benefits (Ryan, 2010). International SAE Consortium The International Serious Adverse Events Consortium (iSAEC) is a nonprofit organization comprised of pharmaceutical companies, the Wellcome Trust, and academic institutions that receives scientific and strategic input from the FDA and international regulatory bodies. This consortium attempts to identify DNA variants that may be useful in predicting the risk of drug-related serious adverse events (iSAEC, 2010). The iSAEC phase 1 objectives include creation of a publicly available knowledge base of cross drug safety pharmacogenomics markers for predicting key serious adverse events and supporting the execution of the Critical Path Initiative (Holden, 2010).
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Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease Cardiac Safety Research Consortium The Cardiac Safety Research Consortium (CSRC) is a public–private partnership of the Critical Path Initiative that focuses on cardiac safety and new medicine product development. Duke University’s Clinical Research Institute manages the CSRC, which involves industry, academics, and regulators. The CSRC has developed a model for precompetitive data sharing in which electronic ECG submissions to the FDA are made available for research by the consortium, with an initial focus on QT interval issues. Additional areas of focus include using the ECG library to qualify new ECG biomarkers for cardiac risk and developing additional research and regulatory evaluation tools to facilitate clinical decision making and future medical product development (CSRC, 2010). Clinicaltrials.gov ClinicalTrials.gov was created in 1997 after passage of the Food and Drug Administration Modernization Act (FDAMA). As a result of FDAMA and FDAAA, Congress has required that the FDA implement registration prior to recruitment of all clinical trials that fall under the regulatory authority of the FDA and, within 1 year of completion, the reporting of results in a database. These databases have been developed by the National Library of Medicine (NLM) at the NIH in collaboration with the FDA. Drug, device, and biologic trials are included in the legislative mandates; nutritional and supplement studies are not mandated for registration or reporting, nor are observational studies covered. Nonetheless, the databases accept and encourage registration of observational studies, and about 15 percent of the registry consists of observational studies. An unknown proportion of studies are nutritional, behavioral, or health services; again, these are voluntary. Overseas trials are registered if the sponsor intends to register the drug in the United States or has U.S. study sites. More than 80,000 trials are registered and about 500 results are available. Clinical trial results for trials initiated after September 2007 are to be provided even if the trial findings remain unpublished, as occurs in about 30 percent of trials; such reporting remains uneven. NIH and other publicly funded trials are also required to be registered and reported, but there is some confusion about the requirements. Noncompliance carries substantial penalties, so registration levels are high, with a possible exception in the device area. Individuals or researchers can use search terms that permit rapid and effective identification and aggregation. The database also links to PubMed and publications. This database has been used to scan all potential informative trials and is used in meta-analyses, which could inform qualification and validation/interpretation.
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Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease This database is built on a robust platform with public access and many links to related sources. Although the database was created and is maintained with the input of the FDA, the capability and staff necessary to administer the database reside at the NLM. Legislation is required to make changes in this reporting system, and a directive is needed regarding the implementation within the legislation. Congress has been aggressive in seeking transparency of results and their use. A major caveat is that the reporting is by investigators and sponsors, and the NLM has responsibilities for archiving, not validating, reports. Therefore, no interpretation of individual study findings is provided at the site, although the FDAAA requires an examination of whether this information can be included in an unbiased way. Reaction to ClinicalTrials.gov has been mixed. Companies feared that disclosure of clinical trial results would put them at a competitive disadvantage and impact the viability of the pharmaceutical development enterprise (Drazen and Wood, 2005). For a period of time, some companies failed to include meaningful data in their registry entries. However, efforts on the part of the medical research community resulted in improved data submissions (Drazen and Wood, 2005, 2006). Editors of medical journals supported the database, eventually requiring authors to have registered clinical trials in the database or be barred from publication in many medical journals (Drazen and Wood, 2005). It is not yet clear how beneficial the database will be for patients and the public, due to challenges of implementation and the short time that the database has been available (Hirsch, 2008; Zarin et al., 2007). REFERENCES Abstracts of the NIH-FDA conference “Biomarkers and Surrogate Endpoints: Advancing Clinical Research and Applications.” 1998. Disease Markers 14(4):187-334. Barker, A. 2006. Oncology Biomarker Qualification Initiative: NCI-FDA-CMS collaboration to speed development of cancer therapies. Presentation to the National Cancer Advisory Board June 14, 2006. Bethesda, MD. Barker, A., C. C. Siggman, J. K. Kelloff, N. M. Hylton, D. A. Berry, and L. J. Esserman. 2009. I-SPY 2: An Adaptive Breast Cancer Trial Design in the Setting of Neoadjuvant Chemotherapy. Clinical Pharmacology and Therapeutics 86(1):97–100. Borra, S. 2006. Consumer perspectives on food labels. American Journal of Clinical Nutrition 83(5):1235S–1235S. C-Path (Critical Path Institute). 2008. Predictive Safety Testing Consortium (PSTC). http://www.c-path.org/pstc.cfm (accessed September 28, 2009). C-Path. 2010a. Sharing knowledge that leads to innovation. http://www.c-path.org/programs.cfm (accessed March 13, 2010). C-Path. 2010b. Coalition Against Major Diseases. http://www.c-path.org/CAMD.cfm (accessed March 13, 2010).
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Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease Wood, A. J. 2008. Playing “kick the FDA”—Risk-free to players but hazardous to public health. New England Journal of Medicine 358(17):1774–1775. Yang, S. X., S. Kummar, S. M. Steinberg, A. J. Murgo, M. Gutierrez, L. Rubinstein, D. Nguyen, G. Kaur, A. P. Chen, V. L. Giranda, J. E. Tomaszewski, J. H. Doroshow, and The National Cancer Institute Phase 0 Working Group. 2009. Immunohistochemical detection of poly(ADP-ribose)polymerase inhibition by ABT-888 in patients with refractory solid tumors and lymphomas. Cancer Biology and Therapy 8(21)2004–2009. Yetley, E. A. 2007. Science in the regulatory setting: A challenging but incompatible mix? Novartis Foundation Symposium 282:59–68; discussion 69–76, 212–218. Zarin, D. A., N. C. Ide, T. Tse, W. R. Harlan, J. C. West, and D. A. Lindberg. 2007. Issues in the registration of clinical trials. Journal of the American Medical Association 297(19):2112– 2120.
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