2
Defining Regulatory Science

The concept of regulatory science is not a new one. The FDA Science Board’s 2007 Science and Mission at Risk report (FDA Science Board, 2007) describes regulatory science as a science-based decision-making process needed to fulfill the responsibilities of a public health agency: “FDA must have the scientific staff and resources to undertake the regulatory research that will provide a basis to: (1) improve capacity for safety and efficacy evaluations and monitoring of candidate and licensed products, (2) modernize current regulatory pathways, and (3) develop new regulatory pathways where there are currently none.” According to the report, this capacity is important because “decisions made in regulation development, pre-market approvals, legal actions and related public health emergencies must be based on understanding of contemporary and emerging science within the context of the risk analysis paradigm” (FDA Science Board, 2007, p. 14).

While a number of descriptions of regulatory science have been put forth, no formal definition exists. Some alternative definitions of regulatory science are presented in Box 2-1. The following general definition was submitted to the IOM Drug Forum for discussion at this workshop by Carl Peck, Professor of Bioengineering and Therapeutic Sciences at the University of California, San Francisco, Center for Drug Development Science, and former Director of FDA’s CDER (1988–1993) (Peck, 2010, p. 1):

Regulatory science is a broad term concerning drug and other product regulations, regulatory standards, law and procedures across many disciplines. It is a systemized body of knowledge (practiced by FDA and



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2 Defining Regulatory Science The concept of regulatory science is not a new one. The FDA Science Board’s 2007 Science and Mission at Risk report (FDA Science Board, 2007) describes regulatory science as a science-based decision-making process needed to fulfill the responsibilities of a public health agency: “FDA must have the scientific staff and resources to undertake the regulatory research that will provide a basis to: (1) improve capacity for safety and efficacy evaluations and monitoring of candidate and licensed products, (2) modernize current regulatory pathways, and (3) develop new regula- tory pathways where there are currently none.” According to the report, this capacity is important because “decisions made in regulation develop- ment, pre-market approvals, legal actions and related public health emer- gencies must be based on understanding of contemporary and emerging science within the context of the risk analysis paradigm” (FDA Science Board, 2007, p. 14). While a number of descriptions of regulatory science have been put forth, no formal definition exists. Some alternative definitions of regula - tory science are presented in Box 2-1. The following general definition was submitted to the IOM Drug Forum for discussion at this workshop by Carl Peck, Professor of Bioengineering and Therapeutic Sciences at the University of California, San Francisco, Center for Drug Development Sci- ence, and former Director of FDA’s CDER (1988–1993) (Peck, 2010, p. 1): Regulatory science is a broad term concerning drug and other product regulations, regulatory standards, law and procedures across many dis- ciplines. It is a systemized body of knowledge (practiced by FDA and 5

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6 ESTABLISHMENT OF REGULATORY SCIENCE FOR DRUG DEVELOPMENT BOX 2-1 Some Definitions of Regulatory Science While no official definition of regulatory science has been promulgated by any U.S. regulatory agency or standards-setting body, the following definitions highlight a common theme: drawing science and policy together for the benefit of public health and safety: • …the science and tools we use to assess and evaluate a product’s safety.” “ Margaret Hamburg, FDA Commissioner (FDA, 2009) • The development and use of new tools, standards and approaches to “ more efficiently develop products and to more effectively evaluate product safety, efficacy and quality.” Announcement of NIH−FDA Collaboration to Fast-Track Innovations to the Public (FDA, 2010c) • The acquisition and analysis of data sufficient to inform decision mak- “ ing pertinent to the approval of safe and effective therapeutics, devices and cosmetics and ensuring the safety and nutritional value of the food supply.” Garret FitzGerald, University of Pennsylvania School of Medicine (FitzGerald, 2010) • Regulatory science is a unique application of science, at all levels, to the “ societal decision process.” Alan Moghissi, President, Institute for Regulatory Science (The Scientist, 2009) • Regulatory Science relates the regulatory and legal requirements of bio- “ medical product development to the scientific research needed to ensure the safety and efficacy of those products.” Academic website for the Univer- sity of Southern California School of Pharmacy (USC, 2010) similar regulatory agencies world-wide) comprising public protection- oriented medical product regulations, policy and decisions using scien- tific methods employing empirical and causal evidence utilized in the evaluation and approval of all the products that FDA regulates. Thus the role of regulatory science is inherent in FDA’s functioning as a scientific agency. It plays a critical role in all aspects of the agency’s mission, including: • review and assessment of laboratory data; • review and assessment of animal and human clinical data; • methods development; • facilities inspection; and • evelopment of technical and scientific standards for preclinical d

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 DEFINING REGULATORY SCIENCE assessment, product development, postmarket surveillance, manu- facturing, packaging standards, food safety standards, and food processing technologies. Garret FitzGerald, Professor of Translational Medicine and Therapeu- tics, University of Pennsylvania School of Medicine, offered the following guidelines for determining what the term does not denote: • a new set of regulations; • an approach to speeding up the approval process; or • an attempt to establish cutting-edge biomedical science at FDA. Nevertheless, regulatory science can aid in the above areas by boost - ing scientific capacity. It is not a cure-all for the shortfalls in drug regula - tion, yet is critical to FDA’s accomplishment of its complex goals. Box 2-2 summarizes FDA Commissioner, Margaret Hamburg’s talk on regulatory science, which encapsulates these intricacies. Workshop participants sug - gested that, because it lies beyond the traditional domain of biomedical science, the practice of making regulatory decisions on the basis of the best science possible is an emerging area of meta-science. Jeffrey Drazen, Editor-in-Chief of the New England Journal of Medicine and Co-Chair of the Drug Forum, described regulatory science as “a sci- ence that has been evolving and is continuing to evolve, but it’s not as hard a science as we would like.” Thus, enhancement of the regulatory science discipline today represents a concerted attempt to systemize and standardize daily regulatory processes and bolster regulatory decision- making capabilities with a sound scientific base. The following chapter explores why such efforts are necessary.

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8 ESTABLISHMENT OF REGULATORY SCIENCE FOR DRUG DEVELOPMENT BOX 2-2 Excerpts from the Commissioner’s Speech FDA Commissioner, Margaret Hamburg, provided an overview of regulatory science priorities at the agency. Commissioner Hamburg referred to regulatory sci- ence as “vital to enhance the quality and integrity of FDA’s regulatory decisions.” The Commissioner’s speech defined the need for and application of regula- tory science; discussed collaborative efforts to advance regulatory science; and described models and initiatives that, if adequately funded, could significantly advance the field of regulatory science. The Commissioner emphasized that “[o]utreach and collaboration are central to regulatory science efforts. When suc- cessful, these collaborative efforts will help predict which discoveries will succeed or fail as actual products, thereby reducing product development costs and get- ting better products to patients faster.” She remarked that FDA should actively participate in research and development by partnering with academia, industry, and other government agencies. The following excerpts represent topical highlights from the Commissioner’s presentation at the workshop: • Definition and Application of Regulatory Science “[Regulatory] science that underlies the development and utilization of new tools, standards, and approaches for the assessment of medical product efficacy, safety, and quality, is the critical bridge between basic scientific research discoveries and new marketed medical products. Regula- tory science comprises an array of disciplines and approaches. Regulatory science not only takes place in laboratories, but it also may involve clinical, epidemiological, and statistical tools and information-gathering systems. “Unlike work performed by specific sponsors, regulatory science is im- portant for multiple products and stakeholders. The knowledge generated from such studies informs a whole class of potential products rather than a single product. It informs, in some instances, whole new ways of thinking about the potential of science.” • egulatory Science’s Potential for Supplementing Biomedical R Innovation “…[A]n important regulatory science problem might be how to character- ize the immune response that alters or blocks the effect of recombinantly produced proteins or antibodies used to treat many diseases, like cancer or rheumatoid arthritis. The knowledge generated from such studies would inform a whole class of potential products, a whole class of recombinant proteins, rather than a single product. So you go from what is an important and interesting question in science to something that actually makes the difference in the ability to move that science into the marketplace.

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9 DEFINING REGULATORY SCIENCE “…[R]egulatory science is essentially a goldmine that we must continue to excavate. For example, promising research is under way using stem cells to restore brain function lost in patients with Parkinson’s Disease. But before these treatments can reach patients, we must develop scientifically valid standards and manufacturing processes for stem cell therapies so they can be produced reliably and safely. “Regulatory science may help us bring promising platforms and multiuse technologies online. Some could be adapted to aid in our preparedness against some of the most important biological threats that we face as a global community, from pandemics, such as H1N1, to the emerging threat of bioweapons. These efforts should incorporate a systems biology approach, where data and knowledge is shared across multiple pathogens and used to translate basic discoveries into clinical application. “[The lifecycle approach to drug development] is a very important new and growing emphasis within FDA. It is an area where I think we can and will bring important advances in regulatory science to bear, improving our understanding of pharmacoepidemiology as we address postmarketing sur- veillance, better use of bioinformatics in this regard, and, importantly, devel- oping the science of comparative safety trials, which I think is an important gap in the work that we do.” • Regulatory Science Initiatives at FDA “…[C]ollaboration between NIH and FDA scientists led to a new method, using gene biomarkers, to assess ‘stemness’—that is, the extent of differen- tiation in several lines of stem cells. These methods are a first step in setting standards for ensuring that undifferentiated stem cells do not contaminate the final, more differentiated stem cells that are administered to patients. “…[I]n 1997, the FDA, along with representatives from pharmaceutical companies and academia, came together to create the structure for the development of clinical data standards that could be used across the phar- maceutical industry without bias towards any one company or organization. These standards allowed for better and more efficient data analysis and faster approval of important medications. “FDA has led several collaborative efforts with our European counter- parts to identify and qualify novel biomarkers for assessing drug-induced kidney toxicity. These biomarkers, originally detected in microarrays, have led to a noninvasive strategy for detecting kidney toxicity in animal models and are more sensitive and specific than the test traditionally used, and … allow us to make assessments early on to prevent the investments of time and money in what may prove to be scientific dead-ends.” • Areas of Need for Enhancing Regulatory Science at FDA “Our regulatory scientists must be able to understand therapies that are being developed using the most recent scientific advances, they must have continued

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10 ESTABLISHMENT OF REGULATORY SCIENCE FOR DRUG DEVELOPMENT BOX 2-2 Continued the right tools to evaluate these therapies, and they must be a partner with the greater scientific community as they work to bring these therapies to people. “[FDA must foster] a culture where multiple perspectives and opinions are sought and brought to bear on complex regulatory science problems. FDA must support and enhance its workforce, from clinical and scientific reviewers to lab and expert manufacturing, scientists, and inspectors, so that we can ably and effectively engage in the broader biomedical research and development enterprise, and so that we can effectively undertake our vital regulatory oversight and review work.” • artnerships to Build and Sustain a Regulatory Science P Infrastructure “[On February 24, 2010,] we announced a first-of-its-kind collaboration between NIH and FDA. We have established a joint leadership council to en- able our agencies to work together to improve regulatory science, beginning with what I think is a small but very important program of grants to advance important research in regulatory science. It’s … an important first step[] to strengthen regulatory science as an organized research endeavor and as a catalyst to advance science at FDA more broadly. Moreover, as Secretary Sebelius noted at the announcement, collaboration between NIH and FDA, including support for regulatory science, will go a long way towards fostering access to the safest and most effective therapies for the American people. “With our Critical Path Initiative, FDA will continue to partner with aca- demic groups, patient advocacy groups, and industry to bring innovation to fields such as genomics, imaging, and informatics, so they can be applied to gaps in drug and diagnostic development. “…[T]hrough a competitive application process, and resources willing, FDA hopes to support the notion of centers of excellence in regulatory science… These centers would perform research independently and col- laboratively with FDA scientists to address unmet scientific needs in regu-

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11 DEFINING REGULATORY SCIENCE latory science and try to bridge the gap between research, discovery, and innovation and the evaluation and development of new safe and effective products. “…[S]cience is a global enterprise. There are enormous opportunities to collaborate with scientific colleagues around the world on matters of mutual concern, but also to engage with sister regulatory agencies to address the sharing of important information and strategies and to harmonize standards and approaches.” In looking forward, the Commissioner said, achieving an enhanced regulatory science at FDA and beyond will require not only a concrete, coordinated plan, but also resources. She reported that, for the first time in history, the President’s fiscal year 2011 budget included a targeted initiative to advance regulatory science for public health. She reported that FDA “will support scientific excellence by recruit- ing, training, and retaining FDA scientists through meaningful career ladders, fellowship programs, scientific collaborations, exchanges, and other professional development activities.” In addition to the collaboration with NIH, the Commissioner announced, other interagency partnerships will be explored, such as with the National Institute of Standards and Technology (NIST) regarding areas of standards development and qualification, and with the Defense Advanced Research Products Agency (DARPA) to help provide regulatory input on novel products at the early development stage in its programs. She also noted that FDA will continue to engage outside advisory groups, such as the FDA Science Board, to gather information to help define regulatory science priority areas and foster and support the work necessary to address them. In closing, the Commissioner stated, “I think we really have the opportunity to lay out an important set of ideas and actions and also to help … shape this emerg- ing field of regulatory science as a discipline. We are living in a century where the advances in biology are astounding and ripe for action. With our collective effort, these advances can be transformed into therapies that will alleviate suffering and products that will enhance our quality of life.”

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