Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease (2010) / Chapter Skim
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5 Strengthening Evidence-Based Regulation
5 Strengthening Evidence-Based Regulation
Pages 197-234
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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.
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. 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.
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. 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)
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. 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)
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marketed product adverse event surveillance and
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Radiological Health ( CDRH) • ~ $ 40 billion investment s per year CDRH protec ts the health of the public by assuring the safety • ~8 00 new produc ts per year and ef fectiveness of medical devices and the safety of • ~1.6 million tissue transplantations radiological produc ts marketed in the US.
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CBER ensures the safety, purity, potency, and effectiveness of biological products, including vaccines, blood and blood products, cells, tis sues, and gene therapies. The premarket review responsibilities of these
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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 obliga tions efficiently, and that the FDA lacks authority to hold drug sponsors to their commitments after drug approval.
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. 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.
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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.
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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)
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While this Act increased the scope of device regulation, it also enabled certain medical devices for small user populations without requiring substantial clinical evidence of effectiveness through a Humanitarian Device Exemption. The 1997 FDA Modernization Act reversed some provisions of the 1990 legislation, such as eliminating certain requirements for adverse event reporting, and ended provisions for mandatory postmarketing surveillance.
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The following section describes the FDA's regulatory authority related to foods, while Box 5-3 discusses FDA regulatory authority related to dietary supplements. 6 Legislative mandates and legal action have influenced the way foods are regulated in the United States.
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Qualified health claims require FDA review and approval. statements that describe the relationship between a substance and disease in labeling of foods, including dietary supplements, after the statements have been reviewed and authorized by the FDA (CFSAN, 2009)
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. Legal action challenged the SSA standard and resulted in a process to allow claims with lesser scientific evidence, with qualifying language (qualified health claims)
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EVALUATION OF BIOMARKERS AND SURROGATE ENDPOINTS BOX 5-3 Dietary Supplements Adding to the complexity of the FDA's regulatory authority, the FDA regulates dietary supplements under a different set of regulations than those covering con ventional foods. Dietary supplements are defined in the Dietary Supplement Health and Education Act of 1994 (DSHEA)
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STRENGTHENING EVIDENCE-BASED REGULATION identify dietary supplement safety concerns is hindered by a lack of information (GAO, 2009a)
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. Additional research was conducted on consumer understanding of health claims after the introduction of qualified health claims in the marketplace.
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. Research also indicates that consumers have difficulty understand ing the "qualifying language" that is intended to help consumers dis tinguish among the four levels of scientific evidence in authorized and qualified health claims.
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an authorized health claim for the relationship of calcium and osteoporosis -- authorized health claims require strong evidence New Figure 9 and FDA review; (B) a nutrient content claim -- these require substantiating data to be kept by the company and FDA notification but do not require FDA review; (C)
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The violations cited include unauthorized health claims, unauthorized nutrient content claims, and the unauthorized use of terms, such as "healthy," which have strict regulatory definitions (FDA, 2010a)
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Efforts to collect biomarker data are currently underway, and involve collaborations among government, industry, academic, and phil anthropic stakeholders. The following section outlines ongoing efforts to collect information about biomarkers and discusses HHS' important role in facilitating and coordinating these efforts.
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It has four disease/therapeutic focus areas: can cer, immunity and inflammation, metabolic disorders, and neuroscience. The founding partners of The Biomarkers Consortium include the NIH, the FDA, the Pharmaceutical Research and Manufacturers of America, and FNIH.
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Most projects are launched within 4–6 months, with four to five funders supporting the study.10 One of the Consortium's projects includes an evaluation of the performance of adiponectin as a biomarker predictive of glycemic efficacy. Using a statistical analysis of combined data from multiple phase II clinical trials performed by four pharmaceutical companies, the project assessed the relationship between adiponectin and glucose lowering in response to PPAR (peroxisome proliferator-activated receptors)
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, the Life Science Consortium envi sions a new precompetitive environment that enables drug companies to 11As mentioned in Chapter 1, the Critical Path Initiative is the FDA's national strategy to drive innovation in the scientific processes through which FDA-regulated products are developed, evaluated, manufactured, and used (FDA, 2010b)
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Role of HHS in Biomarker Data Collection These ongoing efforts to collect and share information about biomarkers will provide necessary information for the effective application of the committee's proposed evaluation framework. Recognizing the value of a well-coordinated, comprehensive effort to collect and share biomarker
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Other manufacturers may use an authorized health claim on their products, which decreases the incentives to collect biomarker or clinical outcome data on the food substance in their food products. In addition, HHS coordination may ensure that biomarker data collection efforts are effective and that they leverage the stakeholders' strengths and capacities.
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. 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)
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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.
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. 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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. 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.
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. REFERENCES Abstracts of the NIH-FDA conference "Biomarkers and Surrogate Endpoints: Advancing Clinical Research and Applications." 1998.
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2005. Questions and answers: Quali fied health claims in food labeling.
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http://www.fda.gov/Food/Dietary Supplements/ConsumerInformation/ucm110417.htm#what (accessed November 6, 2009)
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Washington, DC: The National Academies Press. iSAEC (International Serious Adverse Events Consortium)
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2009. Utility of adino pectin as a biomarker predictive of glycemic efficacy is demonstrated by collaborative pooling of data from clinical trials conducted by multiple sponsors.
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2007. Issues in the registration of clinical trials.
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