Regulatory Decision-making Process Research Articles

Tissue‐based risk assessment of cyclic volatile methyl siloxanes

Cyclic volatile methyl siloxanes (cVMS) are important consumer materials that are used in personal care products and industrial applications. These compounds have gained increased attention in recent years following the implementation of chemical legislation programs worldwide. Industry-wide research programs are being conducted to characterize the persistence, bioaccumulation, and toxicity (PBT) properties of cVMS materials. As part of this larger effort, a tissue-based risk assessment was performed to further inform the regulatory decision-making process. Measured tissue concentrations of cVMS compounds in fish and benthic invertebrates are compared with critical target lipid body burdens (CTLBBs) as estimated with the target lipid model (TLM) to evaluate risk. Acute and chronic toxicity data for cVMS compounds are compared with data for nonpolar organic chemicals to validate application of the TLM in this effort. The analysis was extended to estimate the contribution from metabolites to the overall cVMS-derived tissue residues using a food chain model calibrated to laboratory and field data. Concentrations of cVMS materials in biota from several trophic levels (e.g., invertebrates, fish) are well below the estimated CTLBBs associated with acute and chronic effects. This analysis, when combined with the limited biomagnification potential for cVMS compounds that was observed in the field, suggests that there is little risk of adverse effects from cVMS materials under present-day emission levels.

Integration of Pharmacogenetics and Pharmacogenomics in Drug Development: Implications for Regulatory and Medical Decision Making in Pediatric Diseases

This article aims to provide an overview of the current situation regarding pharmacogenetic and pharmacogenomic (PG) studies in pediatrics, with a special focus on the role of PG data in the regulatory decision-making process. Despite the gap in pharmacogenetic research due to the lack of translational studies in adults and children, several technologies exist in drug development and biomarkers validation, which could supply valuable information concerning labeling and dosing recommendations. If performed under strict good clinical practice quality criteria, such findings could be included in the submission package of new chemical entities and used as additional information for prescribers, supporting further evaluation and understanding of the efficacy and safety profile of new medicines. Even though regulatory authorities may be aware of the potential role of PG in medical practice and guidances are available about the integration of PG in drug development, most data obtained from PG studies are not used by prescribers. The challenge is to better understand whether PG markers can be used to assess potential differences in drug response during the clinical program, so PG data can be integrated into the regulatory decision-making process, enabling the introduction of labeling information that promotes optimal dosing in the pediatric population.

Identification and Elucidation of the Biology of Adverse Events: The Challenges of Safety Assessment and Translational Medicine

There has been an explosion of technology-enabled scientific insight into the basic biology of the causes of adverse events. This has been driven, in part, by the development of the various "omics" tools (e.g., genomics, proteomics, and metabolomics) and associated bioinformatics platforms. Meanwhile, for decades, changes in preclinical testing protocols and guidelines have been limited. Preclinical safety testing currently relies heavily on the use of outdated animal models. Application of systems biology methods to evaluation of toxicities in oncology treatments can accelerate the introduction of safe, effective drugs. Systems biology adds insights regarding the causes and mechanisms of adverse effects, provides important and actionable information to help understand the risks and benefits to humans, focuses testing on methods that add value to the safety testing process, and leads to modifications of chemical entities to reduce liabilities during development. Leveraging emerging technologies, such as genomics and proteomics, may make preclinical safety testing more efficient and accurate and lead to better safety decisions. The development of a U.S. Food and Drug Administration guidance document on the use of systems biology in clinical testing would greatly benefit the development of drugs for oncology by communicating the potential application of specific methodologies, providing a framework for qualification and application of systems biology outcomes, and providing insight into the challenges and limitations of systems biology in the regulatory decision-making process.

INTEGRATED APPROACHES TO POSTHARVEST DISEASE MANAGEMENT IN CALIFORNIA CITRUS PACKINGHOUSES

INTEGRATED APPROACHES TO POSTHARVEST DISEASE MANAGEMENT IN CALIFORNIA CITRUS PACKINGHOUSES

A tale of three labels: translating the JUPITER trial data into regulatory claims

Whether a pivotal randomized trial will be interpreted in a similar and consistent manner by different regulatory agencies is uncertain as policy perspectives may play a role in data interpretation and the translation of trial results into clinical practice. Using a contemporary example, to compare and contrast regulatory claims in the United States, Europe, and Canada that derive from a pivotal clinical trial. The recently completed JUPITER trial of rosuvastatin as compared to placebo conducted among 17,802 men and women with LDL-C <130 mg/dL and hsCRP ≥ 2 mg/L, provides the only available data on rosuvastatin for primary prevention of cardiovascular disease. Thus, the JUPITER trial provides an opportunity to compare and contrast how regulatory agencies in the United States, Canada, and Europe chose to interpret an identical database. Labeling indications based on earlier statin trials of primary and secondary prevention were also reviewed. JUPITER demonstrated a 44% reduction (p < 0.000001) in the trial pre-specified primary endpoint (nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, coronary revascularization, or cardiovascular death) with no evidence of heterogeneity across geographic regions. In response to these data, the US Food and Drug Administration label for rosuvastatin in primary prevention came closest to the actual JUPITER trial population by stipulating that those eligible for treatment should be older men and women with hsCRP >2 mg/L, plus one additional risk factor for heart disease. The Canadian label is silent on age and hsCRP (the major trial inclusion criterion), stipulating instead that treatment can be considered for those with 'at least two conventional risk factors for cardiovascular disease,' a group more inclusive than that studied. In contrast, the European Medicines Agency label limits treatment only to 'high risk individuals' ignoring hsCRP and using instead a post hoc definition of 'high risk' that comprised a subgroup of less than 10% of the study population who contributed but 67 events to the study total and did not show statistical significance when compared to placebo. None of the regulatory labels included the trial primary endpoint; instead, each focused on separate and different components of the primary endpoint. Similar discrepancies were found between European and North American regulatory agencies with regard to earlier pivotal trials of statins for primary prevention, but not for secondary prevention. The JUPITER experience represents a case study and is not a systematic review of the regulatory decision process. Labeling indications can vary widely in different regulatory environments even when based on the same trial data.

Conflicting advocacy coalitions in an evolving modern biotechnology regulatory subsystem: policy learning and influencing Kenya's regulatory policy process

In many countries in Africa, the twin processes of modern biotechnology transfer and development of a regulatory regime have co-evolved. This provides a rich context in which to evaluate the underlying social and institutional factors that confront an evolving regulatory subsystem. This paper uses Kenya's biosafety regulatory system for the management of biotechnology as a case study to analyse such coevolution. Drawing some insights from the Advocacy Coalition Framework, this politically charged subsystem reveals empirically two advocacy coalitions which influenced the regulatory decision process trajectory. This has had significant implications for emerging regulatory instruments where different sources of knowledge informed the process. Thus, any innovation system with governance issues should reconceptualise how the tacit knowledge emanating from the complex relationships built around different advocacy coalitions is managed. Copyright , Beech Tree Publishing.

Missing Data Issues at the FDA Center for Biologics Evaluation and Research

Missing data in clinical trials pose a tremendous problem in the regulatory setting. The U.S. Food and Drug Administration relies on statistically rigorous evidence of safety and efficacy as a precondition for granting marketing approval for drugs, biologics, and many devices. The presence of missing data can compromise the integrity of any statistical analysis, further complicating a regulatory decision-making process with significant public health, legal, and financial implications. We review the unique missing data challenges faced by the Center for Biologics Evaluation and Research and discuss limitations in our current approach to these issues and potential directions for improvement.

Current and Future Regulation Challenges for the Chinese Telecommunications Sector

Current and Future Regulation Challenges for the Chinese Telecommunications Sector

Real-time PCR Detection of Sorghum Ergot Pathogens Claviceps africana, Claviceps sorghi and Claviceps sorghicola

Sorghum ergot is a serious disease that has caused major losses in sorghum growing regions worldwide. Claviceps africana, originally reported from Zimbabwe, is now the most widely distributed species causing ergot in many countries including the United States of America, whereas both C. africana and Claviceps sorghi exist in India. A third species (Claviceps sorghicola) has been described causing sorghum ergot in Japan. As the three species show morphological similarities, a DNAbased assay is desirable for rapid identification in cases where ergot-infected sorghum is found by regulatory authorities. We designed PCR primers and probes from the intron 3 region of the b-tubulin gene (for C. africana and C. sorghi) and the intron 4 region of EF-1a (for C. sorghicola) and tested them by real-time PCR with purified DNA and ergot samples from the field and greenhouse. The primer and probe sets specifically amplified DNA from the respective species with a detection limit of c. 1 pg DNA. Genomic DNA from six other Claviceps species did not amplify in any of the three ergot species-specific assays. The assays we describe will provide useful tools for detecting sorghum ergot pathogens in seed and grain shipments and for determining which species are present in the samples, thereby aiding in the regulatory decisionmaking process.

A Personal Perspective on the Initial Federal Health-Based Regulation to Remove Lead from Gasoline

ObjectiveThis article describes the personal experience and perspective of the authors, who had primary responsibility for drafting the initial health-based regulation limiting lead content of gasoline during the early 1970s while employed by the U.S. Environmental Protection Agency (EPA).Data sourceInformation used by the U.S. EPA in developing the initial health-based regulation limiting lead content of gasoline in December 1973 and studies documenting the impact of that and subsequent actions.Data extractionAmong the lessons learned from this experience is the importance of having input from independent scientists to the regulatory decision-making process. This also demonstrates the critical role of independent peer-reviewed research, such as that supported by the National Institutes of Health, as well as research conducted by scientists from the Centers for Disease Control and Prevention, in delineating the consequences of lead exposure in the population.Data synthesisRemoval of lead from gasoline in the United States has been described as one of the great public health achievements of the 20th century, but it almost did not happen. The experience of the authors in developing this regulation may be helpful to others involved in developing health-based regulatory policy in the future.ConclusionThe initial U.S. EPA health-based regulation to remove lead from gasoline is clearly an example where science successfully affected public policy. The leadership of the U.S. EPA at that time deserves much credit for establishing an atmosphere in which this was possible.

Reconciling public opinion and WTO rules under the SPS Agreement

AbstractThe WTO Agreement on the Application of Sanitary and Phytosanitary Measures (the SPS Agreement) allows Members to enact SPS measures necessary to protect health so long as they are based on scientific evidence. This scientific evidence requirement has attracted controversy among academics, policy-makers, and civil society. The argument has been advanced that the requirement inappropriately excludes the consideration of public opinion in the domestic risk regulatory decision-making process. The article addresses the question of whether it is possible to reconcile the SPS Agreement's requirement for scientific evidence with concerns regarding exclusion of the public voice in the domestic regulatory process. It responds positively to this query, subject to certain caveats to ensure that trade liberalization goals are not undermined. It argues that the scientific evidence requirement is not only the most appropriate means available for advancing the SPS Agreement's objectives, but that it provides countries with more flexibility than critics contend, including to respond to public sentiment in cases of scientific uncertainty. Recommendations are made as to how panels and the Appellate Body should proceed in disputes under the SPS Agreement, and how governments can comply with their trade obligations while remaining responsive to public concerns.

Application of in vitro neurotoxicity testing for regulatory purposes: Symposium III summary and research needs

Prediction of neurotoxic effects is a key feature in the toxicological profile of many compounds and therefore is required by regulatory testing schemes. Nowadays neurotoxicity assessment required by the OECD and EC test guidelines is based solely on in vivo testing, evaluating mainly effects on neurobehavior and neuropathology, which is expensive, time consuming and unsuitable for screening large number of chemicals. Additionally, such in vivo tests are not always sensitive enough to predict human neurotoxicity and often do not provide information that facilitates regulatory decision-making processes. Incorporation of alternative tests ( in vitro testing, computational modelling, QSARs, grouping, read-across, etc.) in screening strategies would speed up the rate at which compound knowledge and mechanistic data are available and the information obtained could be used in the refinement of future in vivo studies to facilitate predictions of neurotoxicity. On 1st June 2007, the European Commission legislation concerning registration, evaluation and authorisation of chemicals (REACH) has entered into force. REACH addresses one of the key issues for chemicals in Europe, the lack of publicly available safety data sheets. It outlines a plan to test approximately 30,000 existing substances. These chemicals are currently produced in volumes greater than 1 ton/year and the essential data on the human health and ecotoxicological effects are lacking. It is estimated that approximately 3.9 million test animals (including 2.6 million vertebrates) (Hartung T, Bremer S, Casati S, Coecke S, Corvi R, Fortnaer S, et al. ECVAM's response to the changing political environment for alternatives: consequences of the European Union chemicals and cosmetics policies. ATLA 2003;31:473–81) would be necessary to fulfill the requirements of REACH if the development and establishment of alternative methods is not accepted by regulatory authorities. In an effort to reduce animal use and testing costs within this tonnage band, the European Commission has advocated the use of alternative approaches. Neurotoxicity testing is not directly addressed within REACH, however when alerts are observed based on organ specific toxicity studies then neurotoxicity assessment has to be performed. This session at the 11th International Neurotoxicology Association Meeting provided a forum to openly discuss and debate the potential of in vitro testing strategies that could be relevant for neurotoxicity evaluation in the context of regulatory requirements. The EU FP6 project A-Cute-Tox was presented as an example of a possible in vitro testing strategy for prediction of human acute systemic toxicity. Other presentations focused on the characterization of the available in vitro models (cell lines and primary culture) and neuronal specific endpoints, with a special emphasis on electrical activity, metabonomics and modulation of vesicular neurotransmitter release as possible neuronal endpoints relevant for in vitro neurotoxicity testing. Finally, it was underlined that in vitro systems (strategies) that have the potential to be applied for neurotoxicity assessment have to be formally validated under standardised conditions that have been recognised by national and international validation bodies.

Product Quality Research Institute reports

The mission of the Product Quality Research Institute (PQRI) is to serve as a forum for academia, industry, and regulators to work cooperatively in conducting pharmaceutical product quality research and to support development of public standards and regulatory policy. PQRI was founded in 2001 under the guidance of the American Association of Pharmaceutical Scientists (AAPS). Within PQRI, scientists from FDA, industry, academia and USP come together to address urgent and challenging problems, and conduct research that would inform parties involved in the regulatory policy and decision-making processes. A PQRI Aerodynamic Particle Size Distribution (APSD) working group was established in 1999 to assess the chi-square ratio statistical test method for comparing particle size distribution profiles of pharmaceutical aerosols.

Impact of microarray data quality on genomic data submissions to the FDA

How can microarray data best be exploited and integrated into the regulatory decision-making process?

Understanding Regulatory Fit

The authors focus on three critical areas of future research on regulatory fit. First, they focus on how regulatory orientation is sustained. The authors argue that there are two distinct approaches that bring about the “just-right feeling”: (1) a process-based approach that involves the interaction between regulatory orientation and decision-making processes and (2) an outcome-based approach that involves the interaction between regulatory orientation and the framed outcomes offered. Second, the authors discuss possible boundary conditions of regulatory fit effects, highlighting the apparent paradoxical role of involvement. They suggest that the antecedents that give rise to regulatory fit (e.g., lowered motivation) can differ from its consequences (e.g., increased motivation). Third, the authors discuss broader implications of regulatory fit, proposing three possible mechanisms by which regulatory fit can lead to improved physical health and discussing the degree to which the just-right feeling plays a role in goal-sustaining experiences related to subjective well-being (e.g., flow).

The COX-2 inhibitors: a reasoned review of the data.

The recent press coverage of the issues surrounding non steroidal anti-inflammatory drugs and the selective COX-2 inhibitors has not allowed for an informed debate to take place regarding the therapeutic risk to benefit ratio of these drugs. The overall discussions that have taken place within the context of the regulatory decision process has been mostly proprietary and thus not made public and the resultant decisions have not been prominently featured in the popular press so have not gotten the attention of the practicing clinician or the patients who use these drugs. This paper will review the evidence that has been accumulated and highlight the decisions that have been made by some of the regulatory groups to address the issues surrounding overall benefit to risk of the NSAIDs inclusive the COX-2 selective inhibitors.

The COX-2 inhibitors: a reasoned review of the data.

The recent press coverage of the issues surrounding non steroidal anti-inflammatory drugs and the selective COX-2 inhibitors has not allowed for an informed debate to take place regarding the therapeutic risk to benefit ratio of these drugs. The overall discussions that have taken place within the context of the regulatory decision process has been mostly proprietary and thus not made public and the resultant decisions have not been prominently featured in the popular press so have not gotten the attention of the practicing clinician or the patients who use these drugs. This paper will review the evidence that has been accumulated and highlight the decisions that have been made by some of the regulatory groups to address the issues surrounding overall benefit to risk of the NSAIDs inclusive the COX-2 selective inhibitors.

Performance-Based (Risk-Informed) Regulation: A Regulatory Perspective

Performance-based regulation (PBR) has been mandated at the national level in the United States and at the agency level, where appropriate, at the U.S. Nuclear Regulatory Commission (USNRC). Guidance has been developed that implements the USNRC’s definitions of PBR and other such conceptual regulatory improvements. This paper describes why PBR is important, what constitutes PBR in the context of direction provided at the USNRC, and how PBR can be implemented using a five-step process. The process steps articulate questions to be posed by the analyst regarding various aspects of a regulatory issue so that a suitably performance-based resolution can be developed. A regulatory alternative thus developed can be included among other options to be considered as part of the regulatory decision-making process.

Risk Assessment in the European Food Safety Regulation: Who is to Decide Whose Science is Better?Commission v. Franceand Beyond…

The outbreak of bovine spongiform encephalopathy (hereinafter BSE) in Europe has brought about serious tensions and fears – not only among consumers, but also among the national and European authorities responsible for risk management. Faced with the incapacity of the existing system to control the situation, on the one hand, and the need to restore consumers’ confidence on the other, the EU and national regulators felt obliged to repair the weaknesses as soon as possible. However, remedial actions undertaken at the time of the BSE crisis were not always the product of thorough consultations and they were often not well coordinated. Thus, they became a source of disagreement among the various actors in play. The caseCommission v. France, which I will examine more closely in this paper, illustrates such a conflict among the national and European scientific authorities. The judgment was delivered in 2001, but the problem of the successful integration of science into the regulatory decision-making process of the EU still remains unsettled. In this paper I will present suggestions as to how the situation could be influenced by the outcomes of recent reforms of European food safety law and the establishment of the European Food Safety Authority.

Cooperation and the Capacity for Control: Regulatory Styles and the Evolving Influence of Environmental Regulations in the UK

This paper seeks to contribute to the broader debate on how to promote ‘better regulation’ by examining the origins and influence of different regulatory styles. More particularly it examines the extent to which economic theories of cooperation can help to explain the presence of the cooperative regulatory style that has long been associated with the implementation of environmental regulations in the United Kingdom. After reporting the results of empirical research that focused on these issues, it concludes that cooperative regulatory styles are likely to depend upon: (a) the presence of inter-dependencies between regulators and firms; and either (b) the presence of trust amongst stakeholders; or (c) the effective exclusion of those stakeholders from influence in the regulatory decisionmaking process. Highlighting the importance of recent changes in each of these three areas in the United Kingdom, it explains the factors that have led to a shift away from a purely cooperative approach towards what has been termed a more ‘responsive’ or ‘risk-based’ approach. Recognising that such changes have been driven by a desire to enhance the efficacy and the efficiency of environmental regulation, and by concerns about the lack of transparency and accountability in the regulatory process, it concludes that such evolutions represent an important contribution to the debate on regulation and its reform.