nanotechnology · 3 nanotechnology is on its way to america’s supermarkets, drugstores, and...

Project on EmergingNanotechnologies

Project on Emerging Nanotechnologies is supported by THE PEW CHARITABLE TRUSTS

Michael R. Taylor

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PEN 5OCTOBER 2006

Does FDA Have the Tools It Needs?

REGULATING THE PRODUCTS OFNANOTECHNOLOGY

ForewordAuthor's Preface

Executive SummaryAbout the Author

IntroductionNanotechnology and FDA

Potential Risks: What is New about Nanotechnology? FDA’s Regulatory Role: Principles from Current Law

Evolution of the FDC ActKey Features of the Current Law

Regulatory Principles from Current Law Key Elements of a Regulatory Framework

for Nanotechnology ProductsPre-Market Oversight

Post-Market OversightOverview and Analysis of FDA's Legal Tools for Regulating

Nanotechnology ProductsCosmetic Ingredients and Products

Whole FoodsDietary Supplements

GRAS Food IngredientsFood Additives

Food Packaging Medical Devices

OTC DrugsNew Drugs

FDA Resources: Current Status and Importance for Safety What FDA Needs To Do

FDA's Growing Budget GapWhat FDA Is Doing

The Consequences of Scarce ResourcesConclusion: Gaps in the Tool Kit

RecommendationsNear-Term Actions

Long-Term Legal and Policy ActionsResource Needs

Concluding ObservationTable 1 Endnotes

CONTENTS135111313161818202122

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The opinions expressed in this report are those of the author and do not neces-sarily reflect views of the Woodrow Wilson International Center for Scholars orThe Pew Charitable Trusts.

REGULATING THE PRODUCTS OFNANOTECHNOLOGY:Does FDA Have the Tools It Needs?

Michael R. Taylor

PEN 5 OCTOBER 2006

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In 2006, the Food and Drug Administration (FDA) made two important announcements.First, it announced that the agency was holding its first major public meeting on FDA-regulated products containing nanotechnology materials on October 10th in theWashington, DC area. Second, FDA said that it had set up an internal task force to studyhow to regulate nanotechnology products—focusing on understanding possible adversehealth effects from FDA-regulated nanotechnology products and addressing ways to closeany knowledge or policy gaps in this area.

Nanotechnology is the ability to do things—measure, see, predict and make—on ascale of atoms and molecules, usually in the realm of 1-100 nanometers. A nanometer isa billionth of meter and a human hair is about 100,000 nanometers in width. As FDAnoted in the announcement of its October meeting, due to their small size and extreme-ly high ratio of surface area to volume, nanotechnology materials often have chemical,physical or biological properties that are different from those of their larger counterparts.Because of these novel properties, nanotechnology materials have great potential for usein a vast array of exciting products. However, these special properties may also pose newand different risks for humans and the environment.

According to Lux Research, the nanotechnology industry is expected to grow to $2.6trillion in manufactured goods by the year 2014.1 It is a technology which promises tochange every facet of people’s lives—including important areas under FDA oversight: theprescription drugs, medical devices and therapeutics people rely on; the food and dietarysupplements they eat; and the cosmetics they apply.The 2005 market size for nanotechnol-ogy drug delivery systems alone is estimated at $980 million, and expected to grow 54%annually over the next five years.2 Sales of nanotherapeutics, like nanosilver-based wounddressings, were $28 million last year and are expected to increase every year by 62% through2010.3 Food industry experts project that nanotechnology will be incorporated into $20 bil-lion worth of consumer products globally by 2010.4

With government and industry investing billions of dollars a year in nanotechnologyR&D, the stakes involved in FDA “getting it right” in its oversight of nanotechnology arehigh.The recent and critical assessment by the Institute of Medicine (IOM) of the Americandrug safety system opened with a quote from business writer Matthew Herper, saying“…FDA has become synonymous with drug safety. In a sense, ‘FDA approved’ is the brandthat the entire $216 billion U.S. drug market is founded upon. Dilute the confidence of thepublic in the agency, and many billions of dollars in current and potential sales vanish

Foreword

1.The Nanotech Report 4th Edition. New York, NY: Lux Research, Inc., 2006, p. iii.2.The Nanotech Report 4th Edition. New York, NY: Lux Research, Inc., 2006, p. 106.3.The Nanotech Report 4th Edition. New York, NY: Lux Research, Inc., 2006, p. 124.4.“Study: Nanotechnology in Food and Food Processing Worldwide 2003-2006-2010-2015.”Tübingen,

Germany: Helmut Kaiser Consultancy, 2006.Available at http://www.hkc22.com/nanofood.html, accessedSeptember 27, 2006.

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overnight.”5 The public will expect FDA to likewise ensure the safety of nanotechnology-based products, and these products are already here.

Michael Taylor’s report, Regulating the Products of Nanotechnology: Does FDA Have theTools It Needs?, is an extremely important and thoughtful step in helping to ensure thatFDA has the strategy, expertise and resources it needs in the area of nanotechnology to“get it right” now.

David RejeskiDirector, Project on Emerging Nanotechnologies

5. Institute of Medicine.The Future of Drug Safety: Promoting and Protecting the Health of the Public.Washington, DC:The National Academies Press, 2006, p. 15.

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Nanotechnology is on its way to America’s supermarkets, drugstores, and hospitals, promis-ing great benefits to consumers, patients and the economy. Like any new technology, how-ever, the very properties that make nanotechnology different and exciting may pose safetyquestions that society will demand be addressed.

And, so, nanotechnology is also on its way to the Food and Drug Administration (FDA)– the 100-year-old public health institution on which Americans rely to ensure the safety ofmany of the products to which nanotechnology is being applied, including cosmetics, foodsand food packaging, drugs, and medical devices.

FDA is not “nano ready.” This study asks whether FDA is ready, today, for the productsof nanotechnology. Does FDA have the tools it needs – legal, resource and scientific – tooversee the introduction of nanotechnology in a way that meets public expectations? Theshort answer is, unavoidably, no. FDA is missing some of the legal tools it needs, but its readi-ness for nanotechnology is most seriously hampered by the lack of resources required torespond promptly to products in the market and in the development pipeline.

Gaps exist in FDA’s legal tool kit. FDA implements a venerable old consumer protec-tion law, the Federal Food, Drug and Cosmetic (FDC) Act, that has stood the test of time inmany respects and has retained its resilience through significant amendments since first beingenacted in 1938. Nanotechnology does reveal gaps in FDA’s legal tool kit.While there is nota need to start from scratch in providing FDA the legal tools it require to regulate the prod-ucts of nanotechnology, those gaps do need to be filled if FDA is to provide the oversightpeople expect. The report analyzes the FDC Act with nanotechnology in mind, identifiesgaps, and recommends ways to close them.

FDA lacks necessary resources. The larger issue affecting FDA’s readiness for nanotech-nology is resources. For the past decade or more, FDA’s resource base and overall capacityhave been eroded by the pressure of increasing demands and costs of doing business coupledwith the failure of Congress and successive administrations to adequately fund even baseoperations. Just to be able to do what it was doing in 1996 and continue the new activitiesmandated for it since then, FDA’s 2006 budget would have to be 49% greater than it is.Under the President’s proposed 2007 budget for FDA, the funding gap between responsibil-ities and capacity will grow again, to 56%.

This harsh budget reality is a real threat to FDA’s ability to effectively oversee nanotech-nology. It means among other things that FDA lacks the resources it needs to build its ownexpertise, to develop the safety-testing protocols and detection methods needed to evaluatenew nanotechnology products, to conduct its own risk research, to gather the necessary pre-market data required to get ahead of commercialization and to oversee products after theyhave entered the market.

The potential consequences of not adequately funding these FDA needs are at leasttwofold. First, FDA may miss potential safety problems or discover them too late to pre-vent harm, thereby jeopardizing public health and public confidence in nanotechnology.

Author’s Preface

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And second, FDA may lag in providing regulatory guidance and prompt regulatory reviewsto product developers, thereby impeding innovation that benefits all.

Neither outcome will be acceptable to the public at large or the regulated industry, butFDA’s funding dilemma is stark: devoting resources to nanotechnology means takingresources away from other programs and priorities. I hope the public interest and high stakessurrounding nanotechnology will help prompt action to address FDA’s underlying budgetcrisis. Society cannot fairly hold FDA accountable for delivering on the dual goals of ensur-ing safety and fostering innovation if it withholds from FDA the means to do the job.

Even within its current authority and resources, FDA can and should take some immediatesteps to address the first wave of nanotechnology products now entering the market, includingperhaps the most fundamental one of setting the criteria for determining when a nanoscalematerial is “new for legal and regulatory purposes” and “new for safety evaluation purposes.”The distinctive properties of nanomaterials mean that some will pose novel safety questionsthat are not adequately addressed by safety testing and evaluations performed on convention-al versions of the same material. FDA thus should take some immediate steps to prepare itselffor regulating nanotechnology products and to deal with cosmetic, sunscreen and food-relat-ed applications that are already entering the market.To accomplish this task and to preparemore broadly for its oversight role, FDA needs better access to information about applicationsof nanotechnology that are in the development pipeline; this report suggests some targetedsteps FDA could take to obtain such information.

Though I make a number of recommendations in this report, it will be obvious that I donot have all the answers. I offer an evaluative framework and my own analysis in this reportas a starting point. I hope the report will stimulate discussion and debate among FDA offi-cials and FDA’s many stakeholders who aspire to effective and efficient regulation of nan-otechnology products. Further analysis and active dialogue will be required to get FDA reg-ulation right in this new arena.

Finally, I would like to thank the Project on Emerging Nanotechnologies (“theProject”)—a joint initiative of the Woodrow Wilson International Center for Scholars andThe Pew Charitable Trusts. I am particularly grateful to its leaders, David Rejeski and JuliaMoore, for commissioning this study.They posed the question and turned me loose to beginanswering it, leaving responsibility for the content of the report solely in my hands. Likewise,I thank FDA for providing me information on its programs, the people I interviewed for pro-viding their perspectives, and the Project staff and two long-time colleagues of mine, FredDegnan and Terry Medley, for reviewing it. Finally, the Project’s Shilpa Deshpande and EvanMichelson provided crucial research assistance, but they and all others I have mentioned bearno responsibility for the result.

M.R.T.

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Nanotechnology and the Need for Oversight

The question addressed in this paper is whether the Food and Drug Administration (FDA) hasthe tools it needs to regulate the products of nanotechnology.This question is important becauseFDA will be charged with overseeing the safety of some of the earliest and most visible applica-tions of nanotechnology – including cosmetics, sunscreens, food packaging, drugs and medicaldevices – and will be expected to do so in a manner that protects public health, fosters benefi-cial innovation and provides the basis for public confidence in nanotechnology products.

The extremely tiny, engineered particles of material made possible by nanotechnologyare not necessarily hazardous, but they have sufficiently different properties that their safe-ty cannot be assumed based on what’s known about the safety of the conventional-size ver-sions of the material.

It is thus reasonable to adopt the presumption that engineered nanomaterials are “newfor safety evaluation purposes,” which means that until evidence indicates otherwise, theymerit careful regulatory oversight by FDA, both before and after entering the marketplace.

Regulatory Principles from Current Law

FDA has a long history of regulating new technologies under the 1938 Federal Food, Drug,and Cosmetic Act (FDC Act), which has been amended many times in response to newtechnological and public health challenges. The FDC Act remains a resilient legal tool kitfor FDA and the source of regulatory principles that properly apply to oversight of nan-otechnology products, including these:

• Protecting and promoting public health and the welfare of consumers are the proper driv-ers of all FDA decision-making, with product safety being FDA’s first duty.

• Technological innovation is a valued means to the ends of both protecting and promotingpublic health and, thus, FDA has a duty to manage its programs in ways that facilitate inno-vation, consistent with its duty to ensure product safety.

• Public confidence in FDA and the safety and effectiveness of FDA-regulated products areimportant goals of the regulatory process.

• The public health principle of prevention, implemented through FDA pre-market safetyreview, properly governs when a product involves intended exposure to a substance thathas no prior history of exposure to human beings and no widely accepted and scientifi-cally established demonstration of safety.

Executive Summary

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• Post-market oversight of FDA-regulated products is just as essential to protecting and pro-moting public health as pre-market oversight.

Key Elements of FDA Oversight for Engineered Nanomaterials

Based on the above principles drawn from current law, and considering what is known sci-entifically about engineered nanomaterials, the FDA regulatory system for ensuring the safe-ty of nanotechnology products should be capable of performing certain key functions, pre-market and post-market, including the ability to:

Pre-market Oversight• Obtain early and adequate information on nanotechnology products under development.

• Define and enforce safety standards for nanomaterials, including the nature and extent of thetesting required to satisfy them.

• Place the initial and continuing burden to demonstrate safety on the nanotechnology product’ssponsor.

• Review the nanotechnology product’s safety prior to marketing and impose conditions asneeded to ensure safety.

Post-market Oversight• Require post-market monitoring and testing as needed to ensure nanotechnology product safety.

• Require timely adverse event reporting.

• Inspect manufacturing establishments and examine records related to nanotechnologyproduct safety.

• Remove from the market nanotechnology products that appear to pose a significant safetyhazard or no longer meet the applicable safety standard.

There need not be a “one size fits all” approach to performing these functions; in fact, dif-ferent approaches can be used for different product categories, as under the current FDC Act.These desired functional elements comprise a useful framework, however, for analyzing theadequacy of FDA’s legal tools for regulating nanotechnology products.

The Adequacy of Current Law for Performing Key Functions

Using this framework, the report analyzes the strength of current law as applied to nine cate-gories of nanotechnology-based products that will come under the agency’s jurisdiction—

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cosmetic ingredients and products, whole foods, dietary supplements, generally recognized assafe (GRAS) food ingredients, food additives, food packaging, medical devices, over-the-counter (OTC) drugs and new drugs.

The results of this analysis, which are summarized in Tables 1 and 2, show that the legaltools provided by the FDC Act vary widely from category to category, with cosmetics andwhole foods being subject to generally weaker statutory authorities and medical devices anddrugs being regulated under provisions that are stronger in terms of accomplishing the frame-work’s pre-market and post-market functions. Many of these differences reflect implicit con-gressional judgments about (1) the degree of potential risk posed by various categories – withcosmetics deemed inherently less risky and new drugs inherently more risky – and (2) thenature of the pre- and post-market oversight required to assure safety. Many of these judg-ments and differences in regulatory approach continue to make sense, while others are chal-lenged by new technologies, such as nanotechnology.

Based on the report’s analysis of current law, gaps in FDA’s legal authority with respect tonanotechnology products include (1) the lack of pre-market oversight tools for cosmetics, (2)FDA’s inability to acquire information about nanotechnology products early enough in theirdevelopment to prepare properly for their regulation and (3) inadequate authority for post-market adverse event reporting.

The Adequacy of FDA’s Resources for Oversight of Nanotechnology

Even more so than legal authority, the issue affecting FDA’s readiness to regulate nanotechnolo-gy products is resources. For the past decade and more, FDA’s resource base and overall capacityhave been eroded by the dual pressures of increasing demands and costs of doing business and thefailure of Congress and successive administrations to adequately fund even base operations.

Just to be able to do what it was doing in 1996 and continue the new activities mandatedfor it since then, FDA’s 2006 budget would have to be 49% greater than it is. Under thePresident’s proposed 2007 budget for FDA, however, the funding gap between responsibilitiesand capacity will grow once more, to 56%.

This harsh budget reality threatens FDA’s ability to effectively oversee nanotechnology. Itmeans among other things that FDA lacks the resources it needs to build its own nanotech-nology expertise, to develop the safety testing protocols and detection methods needed toevaluate new nanotechnology products, to conduct its own risk research, to gather the nec-essary pre-market data required to get ahead of commercialization and to oversee productsafter they have entered the market.

The potential consequences of not adequately funding these FDA needs are at leasttwofold: (1) in products areas where FDA lacks strong pre-market authority, such as cosmet-ics and dietary supplements, FDA may miss potential safety problems or discover them toolate to prevent harm, thereby jeopardizing public health and public confidence in nanotech-nology; and (2) for products going through FDA pre-market approval systems, FDA may lagin providing regulatory guidance and prompt regulatory reviews to product developers, there-by impeding innovation that benefits all.

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Recommendations

Over the long-term, Congress must address the gaps in FDA’s legal authority and resources.In addition, however, there are steps FDA could take now under current law to address nan-otechnology products that are already entering or appear close to entering the market.Thesenear-term actions are outlined first, followed by recommendations for longer-term legislativeand resource improvements.

Near-Term Actions• Establish Criteria for “New for Legal and Regulatory Purposes” and “New for Safety Evaluation

Purposes.”The single most important step that FDA should take immediately is to establish cri-teria and provide guidance to the industry for classifying some nanoscale materials as “new” forlegal, regulatory and safety purposes. For nanotechnology products that do not require individ-ual product review and approval by FDA, manufacturers often have to make a threshold deter-mination of whether the product poses a new safety question or otherwise should be consid-ered a new or different material, compared with the conventional form.The conventional formmay, for example, have been listed in FDA regulations as a “generally recognized as safe”(GRAS) food substance or as an approved food additive or food contact material. If the man-ufacturer judges the nanotechnology version to be the same as the listed one, there is no legalrequirement to seek FDA pre-market review, and FDA may not become aware of the productuntil after it enters the market.The burden would then rest on FDA to determine after the factwhether there is a safety or regulatory concern warranting action.

To guide companies in making what amount to market-entry decisions for their partic-ular products, FDA should promptly establish criteria for judging when a nanomaterial is“new” for legal and regulatory purposes, i.e., for purposes of distinguishing it from versionsthat are already listed in FDA’s GRAS, food additive and food packaging regulations or thathave been reviewed through the Cosmetic Ingredient Review (CIR).The criteria might bebased solely on material size, surface-volume ratios or other physical characteristics, or theycould include other properties that FDA might judge relevant.The point is to have a basisfor companies to know when they need to come to FDA prior to marketing, versus whenthey can rely for legal and regulatory purposes on the existing approval, GRAS affirmationor CIR review of the conventional form of the material.

A necessary extension of clarifying what is “new” for legal and regulatory purposeswould be to establish criteria for determining when a nanomaterial should be considered“new for safety evaluation purposes.”These criteria presumably would include functionalproperties that relate to the likelihood that the safety profile of the nanotechnology versionwould be different from the conventional one. Such criteria would be helpful for all cate-gories of FDA-regulated products as a guide to decisions about the need for toxicity testingbeyond what already exists on the conventional form. Another application of such criteriamight be to narrow the “new” category so that FDA review of nanotechnology versions ofalready-approved conventional forms would be required when there is a scientific basis forjudging that such review is needed to ensure safety.

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• Resolve the Meaning of “Micronized” in the Over-the-Counter (OTC) Sunscreen Monograph.FDA’s regulation authorizing the use of “micronized” titanium dioxide does not preciselydefine the term, and some sunscreen product labels claim that nanomaterials are being used.By defining the term “micronized” and clarifying the extent to which the monographembraces the full range of nanomaterials, FDA would help resolve the status of one of themore visible early products of nanotechnology to enter the market and build confidencethat FDA is on top of its regulatory task.

• Request Cosmetic Companies to Submit Safety Substantiation Data. An FDA regulation requirescosmetic companies to compile safety substantiation data on their ingredients, but it doesnot give FDA access to review such data. In order to better inform FDA about the nan-otechnology cosmetic products on the market today and the basis for their safety, FDAshould request the voluntary submission of substantiation data on all cosmetic productsmaking nanotechnology claims or containing nanomaterials.

• Provide the Cosmetic Industry Guidance on What Constitutes “Adequate” Substantiation. WhileFDA does not currently have legal authority to access a company’s substantiation data, theprovision of guidance on what constitutes “adequate” substantiation for nanomaterialswould at least provide the industry with a common starting point and could contribute tothe establishment of a de facto standard of care for the industry.

• Provide Guidance on When the Use of Engineered Nanomaterials and Their Associated Claims TurnCosmetics into Drugs. The labels of some cosmetic products make explicit or implied claimsthat the products contain nanomaterials that affect the structure or function of the body,which is the legal basis for classifying a product as a “drug.” By providing guidance on whenthe use of engineered nanomaterials and their associated claims in cosmetics make the prod-uct a drug, FDA will be asserting its traditional regulatory authority and responsibility fordrugs and providing assurance that “cosmetic” ingredients having biological impact receiveappropriate review.

• Call for Data on Food Uses. In the absence of clear authority to access food industry data onpipeline products, FDA should attempt to access at least some of the food industry’s safety-related data by collaborating with industry, perhaps through a trade association, on a volun-tary call for data on food uses of nanotechnology.

Legal Authority• Call for Data Authority. To address its need to be informed, FDA should have administrative

authority to call for the submission of specified information on emerging technologies andproducts under its jurisdiction, including products in the development pipeline.The legisla-tion granting such authority should carefully define the purposes for which FDA may callfor data and establish criteria and a process so that the requests are focused and targeted.

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• Discretionary Pre-Market Notification Authority. FDA should be provided rule-making author-ity to establish interim pre-market notification mechanisms to address emerging and noveltechnologies. FDA would have the discretion to identify product categories for which pre-market notification would be required, the circumstances that trigger notification and thedata that would have to be submitted; a sunset provision should be included.

• Records Access. Records access could be achieved by expanding FDA’s general inspectionauthority to include access to safety substantiation data and other safety information, and bygranting FDA the ability to request submission of such information in its new authority tocall for data.

• Post-Market Monitoring Authority. FDA should have authority to require post-market moni-toring and surveillance, if needed, to assure the long-term safety of the product.

• Adverse Event Reporting. FDA should be given broad authority to devise mandatory adverseevent reporting systems that are appropriate for each product category and least burdensometo achieve the legitimate oversight purpose.

Resource Needs• Early Warning Information Collection. Congress should consider funding within the FDA

Office of the Commissioner, and in each of the operating centers, focal points for the gath-ering of “scientific intelligence” to keep FDA abreast of technological developments and tokeep the agency involved in discussions occurring within the greater scientific community.

• FDA Regulatory Research. FDA’s research responsibility is to ensure that proper toxicity-test-ing protocols are available and that the agency has the scientific knowledge and technicaltools, including analytical methodologies, to play its product review and post-market mon-itoring roles.The $1 million FDA has invested in such research is noteworthy and admirable,but it is not sufficient in light of the array of applications of nanotechnology the agency canexpect to confront in coming years.

• Building FDA’s Scientific and Regulatory Staff. Effective, science-based oversight of nanotechnol-ogy products – oversight that understands the safety issues well enough to prevent problemswhile not unduly slowing innovation – will require specialized scientific expertise and focusedeffort by regulatory policy makers in all of FDA’s programs. Congress should provide FDA theresources to acquire the needed scientific expertise and to bolster the agency’s regulatorycapacity across all of its programs, at both the policy-making and field oversight levels.

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Michael R.Taylor is a Professor at the University of Maryland School of Medicine, wherehe conducts research on policy, resource and institutional issues that affect the success of pub-lic health agencies in carrying out their prevention missions. Previously, he was a SeniorFellow and Director of the Risk, Resource, and Environmental Management Division atResources for the Future. While at Resources for the Future, Taylor co-founded the FoodSafety Research Consortium, which he chairs. Prior to Resources for the Future, Taylorserved in government, practiced law in Washington and worked in private industry. He wasAdministrator of the United States Department of Agriculture’s Food Safety and InspectionService from 1994 to 1996; Deputy Commissioner for Policy at the Food and DrugAdministration (FDA) from 1991 to 1994; and an FDA staff lawyer and Executive Assistant tothe FDA Commissioner from 1976 to 1981. He practiced food and drug law as a partner inthe law firm of King & Spalding for 10 years and served as Vice President for Public Policyat Monsanto Company. Taylor has served on several committees of The National Academyof Sciences and currently serves on the Advisory Committee of the Partnership to CutHunger and Poverty in Africa and the Board of Trustees of Resolve, Inc. He received his lawdegree from the University of Virginia and his B.A. in political science at Davidson College.

About the Author

Nanotechnology and FDA

The question I address in this paper iswhether the Food and Drug Administration(FDA) has the tools it needs—legal, resourceand scientific—to regulate the products ofnanotechnology.This question is of increasingimportance and timeliness for the many ele-ments of American industry that are investingin this amazing new technology. It is also cru-cial for the millions of consumers and patientswho stand to benefit from the innovativeproducts nanotechnology makes possible andwho will want to know that any potentialrisks are well understood and addressed.

In simple terms, “nanotechnology” is theability to engineer matter in ways that takeadvantage of their special properties at thenanoscale.6 Nanotechnology has far-rangingapplications in cosmetics, foods and foodpackaging, medical products and a host ofother areas of great importance to consumers,public health, the economy and the environ-ment. An inventory of manufacturer self-identified consumer products, compiled bythe Project on Emerging Nanotechnologies,has identified over 300 such products alreadyavailable on the market worldwide.

Lux Research, Inc., a commercialresearch organization, estimates that over$32 billion in products incorporating nan-otechnology were sold in 2005, with globalresearch and development spending reaching$9.6 billion.7 In its 2006 Nanomedicine, Device& Diagnostics Report, NanoBiotech Newsestimates that there are currently 130 nano-based drugs and delivery systems and 125devices or diagnostic tests in preclinical, clin-ical, or commercial development—anincrease of 68% since last year.8 Over thelonger term, Lux Research projects that $2.6trillion in global manufactured goods willincorporate nanotechnology,9 or about 15%of total manufacturing output.

The very properties that make engi-neered nanomaterials beneficial, however,may present novel risks, or at least raise newsafety questions—questions that must beunderstood and addressed if the benefits ofthe technology are to be fully realized andpublic health and the environment are to beprotected.

As the agency charged with regulatingthe safety of some of the earliest and mostvisible applications of nanotechnology—incosmetics, sunscreens, food packaging, drugs

13Regulating the Products of Nanotechnology

Introduction

6. FDA has not formally defined “nanotechnology” but it participates in the National Nanotechnology Initiative(NNI), a White House-led program that coordinates federal agency efforts in nanoscale science, engineering, andtechnology, and cites the NNI’s definition, which considers an activity to be “nanotechnology” if it involves allof the following elements: (1) research and technology development at the atomic, molecular or macromolecularlevels, in the length scale of approximately 1-100 nanometers; (2) creating and using structures, devices and sys-tems that have novel properties and functions because of their small and/or intermediate size; and (3) ability tocontrol or manipulate on the atomic scale. Lux Research, Inc. offers this succinct definition of nanotechnology:“The purposeful engineering of matter at scales of less than 100 nanometers (nm) to achieve size-dependentproperties and functions.” The Nanotech Report 4th Edition. New York, NY: Lux Research, Inc., 2006, p. 1.

7.“Nanotechnology in $32 Billion Worth of Products: Global Funding for Nanotech R&D Reaches $9.6 Billion.”New York, NY: Lux Research, Inc., May 8, 2006.Available atwww.luxresearchinc.com/press/RELEASE_TNR4.pdf, accessed September 27, 2006.

8. 2006 Nanomedicine, Device & Diagnostics Report.Atlanta, GA: NanoBiotech News, 2006.9. The Nanotech Report 4th Edition. New York, NY: Lux Research, Inc., 2006, p. iii.

and medical devices, all of which will direct-ly affect consumers—FDA will be at the“heart of the action,” as it will bear consid-erable responsibility for answering questionsabout product safety and potential risks. Aswith past revolutions in genomics and othertechnological fields, FDA will be expectedby society to ensure the safety of nanotech-nology products without impeding innova-tion or blocking the public’s access to thepromised benefits. Clearly, the stakes arehigh: the products FDA regulates account forabout 25 cents of every dollar consumersspend.10 If FDA is successful, we all win. IfFDA fails, we all lose.

The extraordinary pace of innovation innanotechnology makes it timely, if noturgent, to examine FDA’s preparedness toplay this vital oversight role. Research andproduct development are proceeding withgreat speed, and neither science nor themarketplace will wait for years of delibera-tion over how nanotechnology productsshould be regulated. Rather, at an accelerat-ing pace, new products will be challengingFDA to set policies and make product-spe-cific decisions that will have a lasting impacton how the safety of nanotechnology is reg-ulated and on how the products of nan-otechnology are seen and accepted by thepublic. This is not an easy challenge, espe-cially since current knowledge about thepotential risks of new engineered nanoma-terials is limited.11 FDA will, nevertheless, beexpected to acquire knowledge and deployits regulatory tools in ways that detect andprevent risks while not impeding beneficialinnovation.

The timeliness of this report’s topic—inFDA’s centennial year as a public healthregulatory agency—is heightened bybroader questions about whether FDA isequipped today to meet the public’s highexpectations. FDA has a long record andtraditionally strong reputation as a science-based public health regulatory agency, withextensive experience overseeing the intro-duction of new technology. In some ways,nanotechnology is just another in a longline of new technological challenges FDAhas faced using the legal tools and resourcesat its disposal.

But today, FDA is an agency under enor-mous stress. Its job is being made more diffi-cult every year, not only by promising newtechnologies in biomedicine and many otherfields but also by new public health chal-lenges, from bird flu to bioterrorism, and bythe growing and globalizing marketplace forthe products FDA regulates.As the job growslarger and more difficult every year, howev-er, the agency’s resources are shrinking andits public credibility is eroding.

In relation to the job it is expected to do,FDA has been under-funded for many years.FDA’s 2006 budget would have to be 49%greater than it is just to maintain its 1996base level of activity and continue the initia-tives Congress has directed it to undertake.This funding shortfall would continuegrowing, to 56%, under FDA’s proposedbudget for 2007.

Public confidence in FDA is also on thedecline. A recent Harris poll showed thatbetween 2004 and 2006, the share of theAmerican population holding a positive

10.“An FDA Overview: Protecting Consumers, Protecting Public Health.” Rockville, MD: United States Food andDrug Administration,August 2004.Available at http://www.fda.gov/oc/opacom/fda101/fda101text.html,accessed September 27, 2006.

11.Andrew Maynard. Nanotechnology:A Research Strategy for Addressing Risk. Washington, DC: Project on EmergingNanotechnologies,Woodrow Wilson International Center for Scholars, 2006.

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view of FDA’s efforts to ensure the safety, aswell as the effectiveness, of new prescriptiondrugs dropped from 56% to 37%.12 Thisquestion of public trust in FDA is not a smallmatter for nanotechnology companies. Inrecent congressional testimony, a leadingnanotechnology industry analyst from LuxResearch noted that firms developing prod-ucts using engineered nanomaterials couldfind commercial feasibility blocked by thepublic perception that these materials aredangerous—even if they are proved safe.13

Against this backdrop, nanotechnologyprovides a revealing and very timely lensthrough which to examine the bigger pic-ture of FDA’s ability to do the job societyexpects it to do, as affected by the interac-tion of the agency’s legal authority, resourcesand scientific tools. And this bigger pictureis directly relevant to nanotechnology. FDA’slegal tools, virtually all of which pre-datenanotechnology by decades, are the essentialstarting point, but legal authorities are of lit-tle value without adequate resources toapply them. Scarce resources also impedeFDA’s ability to assemble the new scientificknowledge and tools that will be needed toeffectively regulate the products of nan-otechnology. To really understand andimprove FDA’s preparedness to regulate inthis new arena, it is necessary to look atFDA’s legal, resource and scientific tools asan integrated whole.

A truly complete analysis of FDA’s toolsfor regulating the products of nanotechnol-ogy is, to put it mildly, a daunting task. FDA

implements a voluminous compilation oflaws that regulate widely diverse products:lipstick and sunscreens, artificial sweetenersand food packaging, artificial hips and heartvalves, cancer drugs and AIDS vaccines, toname a few. FDA regulates the safety andproper labeling of all products within itsjurisdiction in widely diverse ways, as wellas the therapeutic effectiveness of medicaldevices, drugs and vaccines. Complicatingmatters further, judgments about the ade-quacy of FDA’s tools necessarily hinge onthe particular product category and appli-cation of nanotechnology under considera-tion and a complex mix of legal, policy, sci-entific, agency resource and social-valueconsiderations.

It is beyond the scope of this paper totackle all of these issues. As a first step intothe thicket, however, I examine in this paperFDA’s legal tools and resources for regulatingthe safety of nanotechnology products. I willanalyze the legal tools based on principlesthat are embedded in the law FDA current-ly administers—as it has evolved over thepast 70 years—as well as my perspective onwhat the public expects from FDA and whatI think is needed to achieve three goals crit-ical to the success of nanotechnology:

• protecting public health;

• fostering innovation; and

• providing the basis for public confidence inthe products of nanotechnology.

Regulating the Products of Nanotechnology

12. Beckey Bright.“Americans Growing Less Confident in FDA’s Job on Safety, Poll Shows” The Wall Street JournalOnline, May 24, 2006.Available at http://online.wsj.com/public/article_print/SB114831296787359612-uW9Ve_ZtSkQ20zMT5k2fNvR14Uw_20060622.html, accessed September 27, 2006.

13. Matthew M. Nordan.“Nanotech Commercialization Has Advanced, but Government Action to Address RiskHas Not.”Testimony before the United States House of Representatives Committee on Science,“Research onEnvironmental and Safety Impacts of Nanotechnology:What are the Federal Agencies Doing?” September 21,2006.Available at http://www.house.gov/science/hearings/full06/Sept%2021/nordan.pdf, accessed September27, 2006.

15

I will also review the status of FDA’sresources and how that affects the agency’sability to achieve these central goals of regula-tion in the area of nanotechnology. On thebasis of this analysis, I will identify gaps inFDA’s legal and resource tool kit and makerecommendations for filling them.

Some of my recommendations are directedat FDA, which certainly has a leadership roleto play in preparing to regulate in this newtechnological arena.The primary audience forthe analysis and recommendations in thispaper lies, however, outside FDA, in the polit-ical, business, public health and consumercommunities that share an interest in seeingthat FDA can effectively regulate the productsof nanotechnology. After all, the people whowork at FDA are keenly aware of what theirstatutes and resources permit them to do and,from my experience,FDA staff throughout themany centers and offices involved in nan-otechnology will work hard to make the bestuse of the tools they have to carry out theirassigned mission.

The question is whether society, actingthrough Congress and politically accountableofficials of the executive branch, has givenFDA the tools it needs. I conclude that FDAhas many of the legal tools it needs but lacksothers, and that it is severely lacking in theresources required to prepare scientifically andotherwise for effective regulation of nan-otechnology products and to mount a pro-gram in which the public will have confi-dence. FDA can and should participate inidentifying these gaps, but it is for others insociety to address them.

Potential Risks: What is Newabout Nanotechnology?

The starting point for thinking about FDA’stools for regulating the safety of nanotechnol-ogy products is an understanding of (andsome assumptions about) their potential risks.Much has been written about the specialproperties of nanomaterials and the state ofour knowledge and uncertainty about theirpotential adverse health effects. The RoyalSociety & The Royal Academy ofEngineering in the United Kingdom, theEuropean Commission’s Scientific Com-mittee on Emerging and Newly IdentifiedHealth Risks and the International LifeSciences Institute in the United States haveaddressed the issue, as have many others.14

I will not recap that growing literaturehere. As a lay policy analyst, I take this liter-ature at face value and draw the followingunderstandings and assumptions from it:

• Manufactured nanomaterials have physical,chemical and other properties that typical-ly differ from larger-scale materials of thesame substance in ways that may affect theway nanomaterials interact with thehuman body, such as differing absorptionpatterns and differing abilities to reach cer-tain organs and penetrate cell walls.

• The different properties and behaviors ofengineered nanomaterials do not meanthey are necessarily hazardous, but they domean that the body of evidence used toassess the safety of larger materials cannot

14. See: Nanoscience and Nanotechnologies: Opportunities and Uncertainties. London, UK:The Royal Society & TheRoyal Academy of Engineering, July 2004; The Appropriateness of Existing Methodologies to Assess the PotentialRisks Associated with Engineered and Adventitious Products of Nanotechnologies. Brussels, Belgium: EuropeanCommission/SCHENIHR, March 10, 2006; Gunter Oberdorster, et al,“Principles for Characterizing thePotential Human Health Effects From Exposure to Nanomaterials: Elements of a Screening Strategy,” Particleand Fibre Toxicology 2005, 2:8.

16

be assumed to demonstrate the safety ofthe corresponding nanomaterials.

• Materials produced at the nanoscale varywidely in their properties and in theirapplications, with the likelihood that, asused, some engineered nanomaterials willpose hazards while others will not. Theability to engineer these materials withprecise nanoscale structures—includingsurface layers and diverse morpholo-gies—adds another layer of complexity todetermining which materials will be haz-ardous and which will be benign.

• For these reasons, judgments about thesafety of any particular engineered nano-material cannot be based either on thesafety of larger-scale versions of the samematerial or on easy generalizations aboutnanomaterials as a class; case-by-case safe-ty assessment is required.

• The one generalization that may beappropriate is that nanometer-diameterparticles (nanoparticles) bound in amatrix of other material are less likelythan unbound or free nanoparticles to besystemically absorbed and distributed andthus are less likely to pose a safety con-cern, though end-of-life disposal of suchbound nanoparticles could presentpotential risks.

• Finally, it is not clear that existing animaltoxicity-testing protocols, on which werely to assess the safety of most chemicals,can be used in their present form to assessengineered nanomaterials; for example,the traditional measure of dose in terms ofthe test substance’s mass may have to give

way to ratios between the surface area ofa nanomaterial and its volume or mass.

One way to distill and apply this state ofknowledge on the safety of engineerednanomaterials is to adopt the presumptionthat they are “new for safety evaluation pur-poses.”This is not meant to say that any par-ticular nanomaterial is unsafe. It does mean,however, that, a priori, we just do not know.This presumption is central to the discus-sion that follows, but it also raises an impor-tant definitional issue that FDA and othersmust address in considering how best toapply FDA’s current regulatory tools and todetermine whether there are gaps in thosetools that need to be filled.

I am using the terms “nanotechnology”and terms such as “nanomaterial” and “nan-otechnology product” to refer to tech-niques and applications that are encom-passed within the NNI’s definition of “nan-otechnology,” which includes manipulationand use of matter at the scale of 1–100nanometers to take advantage of novelproperties and functions that occur at thatscale. It is under these circumstances that itseems fair and necessary to establish thepresumption that an engineered nanomate-rial is “new for safety evaluation purposes.”Terms such as “nanotechnology” and“nanomaterial” are often used loosely, how-ever, to apply to a broad range of techniquesand resulting materials, many of which areproperly presumed new for safety evalua-tion purposes while others may not be.Making clear this distinction, including thecriteria for drawing it, should be one ofFDA’s high-priority tasks, because it is adistinction that does and should play a crit-ical role in FDA’s regulatory program.

Regulating the Products of Nanotechnology 17

Evolution of the FDC Act

In analyzing the adequacy of FDA’s legal toolsfor regulating nanotechnology products, it isneither necessary nor wise to start fromscratch. FDA has been regulating the applica-tion of new and advancing technologies fordecades, under a series of congressional enact-ments going back to 1938, and as FDA’s rolehas evolved over the years, some key principleshave emerged concerning FDA’s regulatoryrole and approach.Certainly, each new wave oftechnology challenges existing principles andapproaches and may warrant revising them, ashas happened many times over the years, butthe proper starting point for this paper’s analy-sis is the role FDA plays under current law.

Constitutionally and functionally, FDA andits mission are creatures of Congress.Established in 1906, FDA is an expert, science-based, regulatory agency whose job is to carryout the public health mission assigned to it byCongress, using the legal tools and resourcesCongress provides. As an executive branchagency, FDA properly operates within a recog-nized range of discretion and autonomy, but itsjob is to implement laws passed by Congress.The principal law under which FDA operatesis the Federal Food,Drug, and Cosmetic Act of1938 (FDC Act), as amended dozens of timesin the nearly 70 years since its enactment.

The history of the FDC Act and its manyamendments is germane to nanotechnologybecause it is largely a history of Congressresponding to evolving food and medical tech-nologies, to demands from consumers andindustry for FDA to oversee the introductionof these technologies and to occasional “crises”that catalyze the politics of legislative reform.

As a result, the current FDC Act reveals as wellas, or better than, any other source the accu-mulated and evolving expectations of theAmerican public concerning FDA’s role indealing with the public health consequences ofnew technology.

The original 1938 law, for example, estab-lished the first federal requirements for pre-market safety testing and FDA approval ofnew drugs in response to the famous ElixirSulfanilamide disaster, in which the poisonoussolvent glycol was used in a cough medicineand killed 107 people, including many chil-dren. The 1938 act also gave FDA newauthority to establish legal limits on pesticideresidues in food in response to public healthconcerns raised by the wider use of chemicalpesticides in agriculture. It also establishedFDA’s first regulatory authority over cosmet-ics, authorizing FDA to remove a cosmeticproduct from the market if the agency couldprove it was hazardous.

Other instructive examples of society,through Congress, responding to new technol-ogy and to evolving public expectationsinclude:

•The Food Additive Amendment of 1958. Thisamendment was enacted in response to theurging of the food industry, which was con-cerned about public acceptance of theexpanding use of chemicals in food process-ing.Congress required pre-market safety test-ing and approval of food additives unless theywere already “generally recognized as safe”(GRAS) by scientists.

•The Kefauver-Harris Drug Amendments of1962. These amendments were enacted in

FDA’s Regulatory Role: Principles from Current Law

18

response to the growing sophistication ofdrug development and marketing andsparked by the discovery that the new sleep-ing pill thalidomide could cause severe birthdefects. Congress strengthened the pre-mar-ket testing and evaluation of new drugs byrequiring that they be tested for effective-ness as well as safety.

•The Medical Device Amendments of 1976.These amendments were enacted as medicaltechnology was advancing rapidly to pro-duce sophisticated and life-saving devicesand in response to the Dalkon Shieldepisode, in which many women wereinjured from use of an intrauterine contra-ceptive device that had not been adequate-ly tested and was lawfully marketed withoutFDA approval. Congress required that med-ical device manufacturers and products beregistered with FDA, that FDA be notifiedprior to any new product entering the mar-ket and that new products go through acomplete pre-market testing and approvalprocess for safety and effectiveness, unlessthe sponsor could demonstrate that theproduct is substantially equivalent to a prod-uct marketed prior to 1976.

•The Dietary Supplement Health and EducationAct of 1994. This act was passed in responseto concerns of the dietary supplement indus-try and its customers that FDA intended torequire supplement companies to prove thesafety of supplements that already had a his-tory of marketing. Congress classified a widearray of supplements as foods and precludedshifting to the supplement manufacturer theburden of proof on safety with respect toproducts marketed prior to enactment of the1994 law. But, Congress also required thatingredients used in a supplement product forthe first time after 1994 either have a history

of use in food in the same chemical form asthose being used in the supplement productor be submitted to FDA prior to marketingalong with information substantiating thesafety of those ingredients.

•The Food and Drug Administration Modern-ization Act of 1997. This act was passed, inpart, in response to concerns that FDA’sapproval processes for drugs and devices wereunduly slowing innovation and market entryof beneficial new products. Congress stream-lined the process in various ways whileretaining established standards for producttesting and FDA’s pre-market evaluation ofsafety and effectiveness.

The foregoing components of the FDC Actdeal primarily with FDA’s pre-market over-sight of the products it regulates. Equallyimportant to FDA’s public health role are theinspection, adverse event reporting andenforcement provisions of the law, whichempower FDA to discover safety problemswith marketed products, to take action toremove specific versions of a product from themarket or to ban the product entirely asrequired to protect consumers and patients.The inherent inability of pre-market testing toreveal all there is to know about the safety andeffectiveness of innovative new technologiesand applications means that FDA’s regulationand oversight is best understood as a continu-um, which includes pre-market review andapproval but also encompasses FDA’s responseto problems identified and experience gainedthroughout the product’s lifetime of use.

As with its pre-market authorities, FDA’spost-market authorities vary across productcategories. For example, during inspections ofdrug and many medical device manufacturingfacilities, FDA has broad access to records relat-ing to the safety and proper manufacturing of


products, while FDA’s access to similar recordsregarding foods is generally conditioned onFDA having a reason to believe that a productposes a serious health hazard. In contrast, FDAhas no authority to inspect records related tothe safety of a cosmetic product.Similarly,FDAcan require drug and medical device manufac-turers to report side effects, malfunctions orother adverse events associated with theirproducts, but it has no such authority for foodsand cosmetics.

Key Features of the Current Law

What does the history of the FDC Act teachus about its key features? The first, overarchingobservation suggested by the evolution of theFDC Act is that Congress has built a frame-work that tailors regulatory standards andprocesses for new technologies in accordancewith broad assumptions about the risks posedby particular product categories and the per-ceived need for pre-market review andapproval of products by government.Importantly, this framework is not builtaround the underlying technologies them-selves. FDA does not regulate polymer chem-istry, bioengineering or genomics per se. Itregulates the products produced through theapplication of these technologies.And this is awise approach, because the safety of productsfor consumers rests on how the technology isapplied to produce particular products and theresulting properties of those products.

While this approach and the current struc-ture of the law have clear strengths, they alsohave limitations that become most evidentwhen dramatically new technologies comealong. For example, most cosmetic ingredi-ents are not subject to any FDA pre-marketreview for safety based on the assumption, in1938, that lotions, creams and other materialsapplied externally to improve appearancepose little safety concern. In 1960, in response

to concerns about the safety of coal tar hairdyes, Congress required that color additivesused in cosmetics and all other FDA-regulat-ed products be tested for safety and approvedby FDA prior to marketing.These broad cat-egorical assumptions about potential risk—pre-market review for colors but none forother cosmetic ingredients—may be sound asa general matter, but do they hold true whenengineered nanomaterials are used toenhance the functional properties of non-color cosmetic ingredients?

Similarly, the regulatory structure for foodingredients and food packaging materialsestablished in 1958 is built around the recogni-tion that many natural and manmade materialshave a long history of safe use in food or oth-erwise are generally recognized to be safe.Thepolicy idea is that subjecting every new use ofthese materials to an FDA pre-market safetyreview is not necessary to assure safety and nota good use of resources. Does this assumptionhold when such materials are manufacturedand used at the nanoscale?

Therapeutic drugs and medical devicesare generally subject to more comprehensivepre-market safety regulation than cosmeticsand foods, but they, too, are regulated in waysthat reflect categorical assumptions about riskand the extent of pre-market oversightrequired to ensure safety. Most over-the-counter (OTC) drugs are regulated under anFDA monograph system that lists drug ingre-dients that are “generally recognized” byexperts to be safe and effective for specificuses, based on a history of safe use or scien-tific evidence. Products comprised of theseingredients are exempt from the definition of“new drug” and from the individual productlicensing requirement that applies to newdrugs. For medical devices, the pre-marketnotification option for “substantially equiva-lent devices” provides a means to avoid a full-blown pre-market review of a device’s safety

20


and effectiveness based on the assumptionthat, for these devices, such a review isunnecessary. Does nanotechnology challengethese approaches?

These features of the FDC Act and the law’shistory give rise to a second broad observation:there is an inherent tension between theimperative to protect the public’s health fromharm and the goal of promoting public healthand consumer welfare in general, by fosteringaccess to innovative new products.This tensionis manifest in the complex, highly varied legalframework Congress has created for the widearray of products FDA regulates. It is anythingbut a “one size fits all” regulatory system.And,in general, this approach makes sense. It reflectsthe scientific and public health reality thatproducts differ widely in the degree of riskthey pose, as well as the political reality thatCongress will always seek to balance the needto protect public health and the need to avoidundue restraints on innovation, business activi-ty and consumer choice. Consumers benefitfrom both careful regulation to ensure productsafety and ready access to innovative and ben-eficial new products.

Regulatory Principles from Current Law

With this background in mind, several regula-tory principles emerge from the current FDCAct that I believe should inform FDA’s regula-tion of the products of nanotechnology.

• First, protecting and promoting public healthand the welfare of consumers are the proper

drivers of all FDA decision-making, withproduct safety being FDA’s first duty.15

• Second, technological innovation is a valuedmeans to the ends of both protecting andpromoting public health and, thus, FDA has aduty to manage its programs in ways thatfacilitate innovation, consistent with its dutyto ensure product safety.

• Third, public confidence in FDA and thesafety and effectiveness of FDA-regulatedproducts are important goals of the regulato-ry process because they help ensure that thebenefits of innovation will be available andaccepted in the marketplace withoutunfounded concerns about product safetyand effectiveness.

• Fourth, the public health principle of preven-tion, implemented through FDA pre-marketsafety review,properly governs in cases wherea product involves intended exposure to asubstance that has no prior history of expo-sure to human beings and no widely accept-ed and scientifically established demonstra-tion of safety.

• Fifth, and finally, post-market oversight ofFDA-regulated products is just as essential toprotecting and promoting public health aspre-market oversight.

Now let’s consider how these principlesapply to nanotechnology.

15. It is important to note that, in the FDC Act and in good public health policy,“safety” is not an absolute. Congresshas established a range of safety standards that vary by product category. For food additives, the standard is “reason-able certainty of no harm,” with the burden on the sponsor to prove the additive meets this standard. For drugsand medical devices, all of which pose some degree of risk, judgments about safety balance risks and therapeuticbenefits. For cosmetics, whole foods, and food contaminants (as opposed to intentional additives)—articles that arenot subject to FDA pre-market review—the “safety” standard is in fact a risk standard (e.g.,“reasonable possibilityof harm”) that FDA must prove has been violated in order to remove a product form the market. In all these cases,FDA’s job is to implement and enforce the safety standards established by Congress.

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The final preliminary step before analyzingthe adequacy of FDA’s legal tools for regu-lating nanotechnology products is to estab-lish a normative framework for the analy-sis—to explain what I mean by “adequate.”I will do this by laying out the key func-tional elements of an effective FDA regula-tory framework for nanotechnology-derived products, drawing on current lawand the principles embedded in it.The ele-ments of the framework are the things Ithink FDA should be able to do to achievethe three primary goals of ensuring productsafety, fostering innovation and maintainingpublic confidence in the products of nan-otechnology.

The importance of spelling out such anormative framework cannot be overstated.A clear understanding of FDA’s goals and ofwhat FDA should be able to do to achievethem is essential to analyzing the adequacyof FDA’s legal tools, and it should drive anypublic policy debate about whether toexpand or contract FDA’s tool kit.Describing this framework is also a way ofexpressing my judgment about what FDAneeds to be able to do to meet the public’sexpectations concerning government over-sight of nanotechnology products. This isultimately a subjective and political ques-tion, of course, to be resolved by Congress,and, like most such questions, it is prone tocontroversy. By being explicit about myperspective, I hope to stimulate thoughtand debate, as well as to frame the analysisto follow.

The framework I propose includes pre-market and post-market elements.

Pre-Market Oversight

The common justification for any govern-ment pre-market oversight of a new technol-ogy is that it is needed to (1) ensure productsafety (and possibly effectiveness) in fact, and(2) maintain public confidence in the prod-uct’s safety based on the assumed objectivityof the government safety review. These twojustifications are closely linked.

Without a pre-market review by govern-ment or some other objective body, thedetermination of product safety is left, in thefirst instance, to the judgment of the compa-ny that developed the product and has acommercial interest in marketing it. Mostcompanies take their safety responsibilitiesvery seriously. However, because the inter-pretation of safety data and the application ofsafety standards are inherently judgmentalaffairs, the public has long insisted on pre-market review of health-sensitive products,such as food ingredients, drugs and medicaldevices, that involve substances having noprior history of exposure to human beingsand no widely accepted and scientificallyestablished demonstration of safety. Such areview both increases the likelihood thatsafety issues will be identified and addressedprior to marketing, and it helps maintainpublic confidence in the product’s safety.

I think this justification for pre-marketreview applies, in general, to the FDA-regu-lated products of nanotechnology that arefairly considered “new for safety evaluationpurposes.”This does not mean that there is a“one size fits all” solution for pre-marketoversight and review of nanotechnology

Key Elements of a Regulatory Frameworkfor Nanotechnology Products

22


products, as I will discuss later in this paper.It does suggest, however, that FDA shouldhave sufficient pre-market authority to carryout the following activities for nanotechnol-ogy products:

1. Obtain early and adequate information onnanotechnology products in the developmentpipeline. Companies that are developingnew technologies and product applica-tions always know more about them earlier in the process than FDA does. Toprepare for effective and efficient over-sight—including making informed deter-minations on such matters as whether anapplication is “new for safety evaluationpurposes”—FDA needs access to infor-mation on products in the developmentpipeline under conditions that informFDA while protecting the company’slegitimate proprietary interests.

2. Define and enforce safety standards for nano-materials, including the nature and extent ofthe testing required to satisfy them. One pur-pose and value of pre-market oversight isthat it establishes a level and clearlydrawn playing field with respect to safetyand a basis for judging that all marketedproducts satisfy a safety standard that isknown to and accepted by society.Typically, Congress expresses safety stan-dards for FDA-regulated products inbroad terms, leaving it to FDA to fleshout their operational meaning, includingtesting requirements.

3. Place the initial and continuing burden todemonstrate safety on the nanotechnology prod-uct’s sponsor. This means the product spon-sor must marshal evidence sufficient todemonstrate that its product is safe, inaccordance with the applicable safety stan-

dard, and respond with data to any signifi-cant new safety questions.This is in lieu ofthe government having to prove that theproduct falls short of the standard or is haz-ardous.This element is essential if the goalis to prevent harm rather than react to andcorrect safety problems after they occur.

4. Review the nanotechnology product’s safetyprior to marketing and impose conditions asneeded to ensure safety. A pre-market safetyreview by FDA provides an objectiveassessment of whether the product meetsthe applicable safety standard, therebyincreasing the likelihood that the productwill, in fact, be safe, and provides a strongbasis for public confidence in the product’ssafety.The procedural nature of the reviewcould range from pre-market notificationto a full-blown approval and productlicensing regime, but inherent in any cred-ible pre-market review is FDA’s ability toimpose conditions on the marketing anduse of the product, such as compliancewith good manufacturing practices(GMPs), as needed to ensure safety.

Post-Market Oversight

As noted earlier, one of the key principlesdrawn from current law is that post-marketoversight of FDA-regulated products is justas essential to protecting and promotingpublic health as pre-market oversight. Noamount of pre-market testing can rule outthe possibility of unanticipated safety prob-lems occurring from the actual use of theproduct. Even the large-scale clinical trialsused to assess drug safety and efficacy, whichmay involve hundreds or even thousands ofsubjects, are not capable of detecting everylow- incidence adverse effect that couldoccur and be of great public health signifi-

23

cance when the drug is administered overlong periods to millions of people. Forhealth-protection reasons alone, FDA musthave the tools to detect and promptly cor-rect such problems.

The ability to deal effectively with safetyconcerns that might arise post-market is alsoimportant to achieving the public health ben-efits of innovation. Absent that ability, FDAwould, in prudence, likely impose more strin-gent pre-market testing requirements andtake an even more cautious approach to itspre-market evaluation, which could substan-tially delay access to beneficial new products.

With these concerns in mind, FDA shouldhave authority to carry out the followingpost-market oversight for products of nan-otechnology:

1. Require post-market monitoring and testingof nanotechnology products as needed toensure safety. In light of the limitations ofpre-market testing and the novelty of theissues that may be posed by certain appli-cations of nanotechnology, FDA shouldhave the authority to require sponsors toactively monitor post-market experiencewith the product or to undertake formaldata collection when needed to providean adequate assurance of safety.This is inkeeping with the on-going responsibilityof the sponsor to demonstrate the prod-uct’s safety.

2. Require timely adverse event reporting. Evenwhen special post-market monitoring or

testing is not justified, adverse events maywell occur after a product enters the mar-ket. FDA will never have the resources todetect all such safety-related problems,but, in the normal course of their busi-ness, product sponsors are typically thefirst to learn about them. Significantadverse events should be reportedpromptly to FDA.

3. Inspect manufacturing establishments andexamine records related to nanotechnologyproduct safety. The safety of a nano-enabled product may hinge on its quality,purity or other attributes that are affectedby how it is manufactured, which is whymarketing of most FDA-regulated prod-ucts is conditioned on compliance withGMPs.To prevent, detect and investigatemanufacturing-related safety problems,FDA needs full access to facilities andsafety-related records.

4. Remove from the market nanotechnology prod-ucts that appear to pose a significant safety haz-ard or no longer meet the applicable safety stan-dard. When FDA has reason to believe thata safety problem poses a significant hazardto health, the agency should be able torecall the product through an expeditiousadministrative process pending final reso-lution of the safety issue. If FDA concludesupon further analysis that the product nolonger meets the applicable safety standard,the sponsor’s authorization to market theproduct would be revoked.

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This section provides a brief overview andsummary analysis of FDA’s legal tools for regulating nanotechnology products. Theanalysis is organized around the functionalelements of pre-market and post-marketoversight described in the preceding section,which I believe are the key elements of a sys-tem needed to achieve the goals of protect-ing public health, fostering innovation andproviding the basis for public confidence innanotechnology products.

A couple of methodological points are inorder. First, in this section, the focus of theanalysis is on the legal tools themselves andhow they contribute to performing eachfunction. I provide my perspective, drawnfrom experience, concerning the practicaleffectiveness of FDA’s program in each area,but I have not formally evaluated the per-formance of any program. I also do not con-sider the impact of scarce resources on theeffectiveness of FDA’s regulatory programs. Iwill do that in the next section.

Second, I have used a simplified, four-levelrating system—none, weak, moderate, strong—to describe FDA’s legal capacity to per-form key regulatory functions for nanotech-nology products.This will, as intended, pro-voke debate, and, no doubt, disagreement.My purpose is to provide a succinct basis forcomparison of the relative strength of FDA’slegal tools across the range of product cate-gories and a starting point for discussion.

As a reference point for the analysis to fol-low, Table 1 provides an overview of FDA’ssafety-related legal authorities (pre-market

and post-market) for nine categories of prod-ucts: cosmetic ingredients, whole foods,dietary supplements, GRAS food ingredi-ents, food additives, food packaging, medicaldevices, OTC drugs and “new” (generallyprescription) drugs. This is by no means acomplete catalog of product categories regu-lated by FDA—color additives, animal drugs

and biologics, to name a few, are not includ-ed—but it includes products that seem mostlikely to be affected early on by nanotechnol-ogy. Table 1 illustrates the diversity ofapproaches adopted by Congress for regulat-ing these categories of products, rangingfrom the largely post-market approach for

Overview and Analysis of FDA’s Legal Tools for RegulatingNanotechnology Products

“Nano-Labels: The Tower of Babel““Ingredient or packaging labels found on a selection

of cosmetic, personal care and dietary supplementproducts:

“On a skin cream:“optimizes cellular energetic balance using ananocomplex of multiple intra-cellular transmitters”

“On a dietary supplement:“Nano Calcium Gluconate, Nano CalciumCarbonate, Nano Magnesium Carbonate”

“On a sunscreen: “Our anti-aging ingredients are nano-zinc oxide…”

“On a face cream:“…the first to harness the power of Fullerene C60 inthe field of cosmetics”

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TABLE 1. FDA’S SAFETY-RELATED LEGAL AUTHORITIES

CosmeticIngredienti

WholeFood

DietarySupplement

GRASFoodIngredient

FoodAdditive

FoodPackaging

MedicalDevice

OTCDrug

NewDrugii

FDA Judicial Remedies toRemove Risky Productsxv Yes Yes Yes Yes Yes Yes Yes Yes Yes

Continuing Sponsor Burden to DemonstrateSafety

No No No No Yes Yes Yes Yes Yes

Post-MarketMonitoring and Testing No No No No Limitedxvi Limitedxvii Yesxviii No Limitedxix

Mandatory Adverse Event Reporting No No No No No No Yes No Yesxx

EstablishmentInspection Yes Yes Yes Yes Yes Yes Yes Yes Yes

Access to Safety Records No Limitedxxi Limitedxxii Limitedxxiii Limitedxxiv Limitedxxv Yesxxvi Yes Yes

Voluntary Recall Yes Yes Yes Yes Yes Yes Yes Yes Yes

Mandatory Recall No No No No No No Yesxxvii No No

Pre-Market Tools

Establishment Registration Voluntary Yes Yes Yes Yes No Yes Yes Yes

Product Registration Voluntary No No No No No Yes Yes Yes

Safety Substantiationwithout Pre-MarketNotificationiii

Optionaliv No No Nov No No No No No

Pre-Market Notification No Novi Limitedvii No No Yesviii Yesix No No

Pre-Market Safety Reviewand ApprovalBy Regulation

No No No No Yes Yesx No Yesxi No

Pre-Market Safety Reviewand ApprovalBy Product License

No No No No No No Yesxii No Yes

Mandatory GoodManufacturingPractices (GMPs)

No Noxiii Yesxiv No No No Yes Yes Yes

Post-Market Tools

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TABLE 2. CAPACITY OF FDA’S LEGAL AUTHORITY TO ACHIEVE THE PRIMARY GOALS OF REGULATORY OVERSIGHT FOR NANOTECHNOLOGY PRODUCTS

cosmetics and whole foods to the moreintensive combination of pre-market andpost-market approaches for medical devicesand drugs.

The following analysis briefly describesFDA’s approach for each category and thebasis for my judgment about the relativestrength of FDA’s legal capacity to performthe key oversight functions.These judgmentsare summarized in Table 2.

Cosmetic Ingredients and Products

OverviewCosmetics are of particular interest for thisanalysis. As reported in the Project onEmerging Nanotechnologies nanotechnolo-gy consumer products inventory,16 cosmeticproducts claiming use of nanomaterials areamong the most prominent early entries intothe U.S. consumer marketplace.Additionally,


CosmeticIngredient

WholeFood

DietarySupplement

GRASFoodIngredient

FoodAdditive

FoodPackaging

MedicalDevice

OTCDrug

NewDrug

Pre-Market

Obtain EarlyInformation on Pipeline None None None Weak Weak Weak Mod-

erate Weak Mod-erate

Enforce Safety and Testing Requirements Weak None Weak Moderate Strong Strong Strong Strong Strong

Place Burden To ProveSafety on Sponsor Weak None Weak Moderate Strong Strong Strong Strong Strong

Review SafetyPrior to Marketing None None Weak Weak Strong Strong Strong Mod-

erate Strong

Post-Market

Require NeededMonitoring and Testing Weak None None None Weak None Strong Weak Mod-

erate

Require Timely AdverseEvent Reporting None None None None Weak None Strong None Strong

Inspect Facilities and Safety Records Weak Mod-

erate Moderate Moderate Mod-erate Moderate Strong Strong Strong

Remove UnsafeProducts from Market Moderate Mod-

erate Moderate Strong Mod-erate Strong Strong Strong Strong

16. See http://www.nanotechproject.org/consumerproducts, accessed September 27, 2006. Unless otherwise noted,subsequent examples of nanotechnology products are drawn from this website, which is maintained by theProject on Emerging Nanotechnologies and contains an inventory of manufacturer self-identified consumerproducts that make express or implied claims for the incorporation of engineered nanomaterials or other appli-cations of nanotechnology.

27

preliminary data from Japan indicate an addi-tional 87 cosmetics are on the market in thatcountry alone, some of which are sure to endup in global commerce and be subject to theU.S. regulatory system.17 On the other hand,as was analyzed in J. Clarence Davies January2006 report Managing the Effects ofNanotechnology, FDA’s legal tools for regulat-ing cosmetics are among the most limited.

The ensuing analysis of FDA’s approach tonanotechnology cosmetics is complicated,however, by FDA’s creative use of its legaltools and a longstanding industry self-regula-tory program for cosmetic ingredient safety.With the exception of color ingredients, theFDC Act gives FDA no explicit authority forpre-market oversight of cosmetic ingredientsor cosmetic products.18 FDA has only thestandard post-market authorities, includingthe right to inspect manufacturing facilitiesand seek court action against unsafe or oth-erwise unlawful products, and can take courtenforcement action if a product’s labeling isfalse, misleading or otherwise misbranded.This level of oversight and grant of legalauthority occurred in the1938 FDC Act and

was based on the assumption that cosmetics(defined to include only products thatcleanse, beautify, promote attractiveness oralter appearance) are products that are prima-rily applied externally, do not affect the“structure or function” of the body in adrug-like way and thus are not likely to posesignificant safety concerns.

In the 1970s, as the array of cosmeticingredients expanded, the potential for der-mal absorption, allergic responses and otherpossible hazards was recognized. FDA madecreative use of the aforementioned misbrand-ing authority to establish a “backdoor” safetysubstantiation requirement for cosmetics.FDA issued a regulation declaring that ingre-dients and products that had not been “ade-quately substantiated for safety prior to mar-keting” would be deemed misbranded unlessthey bear this warning statement:“Warning –The safety of this product has not beendetermined.”19 Few if any marketed cosmeticproducts bear such a warning, implying thattheir safety has been substantiated based onappropriate testing or other relevant data.FDA does not, however, have authority toaccess or review the company’s substantiationdata or other safety-related records.

To support industry compliance with thesubstantiation requirement, the Cosmetic,Toiletry, and Fragrance Association (CTFA),which is the principal cosmetic industrytrade association, established the CosmeticIngredient Review (CIR) in collaborationwith FDA and the Consumer Federation ofAmerica.20 Funded by CTFA but independ-ently operated, the CIR conducts and pub-lishes scientific reviews on the safety of cos-metic ingredients. The CIR reported in

Nanotechnology Cosmetics in the Marketplace

As of October 2006, a search of the Project onEmerging Nanotechnologies nanotechnology consumerproduct inventory returned 58 specific and general nan-otechnology cosmetic products from nine countries,along with 40 products categorized as personal-careproducts. Many of these cosmetics are designed to beapplied to the hair, mouth, eyes, hands and body andare available in cream, spray, liquid and powder forms.

17. See http://staff.aist.go.jp/kishimoto-atsuo/nano/index.htm, accessed September 27, 2006.18. See 21 USC 361 et seq.19. See 21 CFR 740.10.20. See the CIR website at http://www.cir-safety.org/, accessed September 27, 2006.

28

August 2006 that 1,300 ingredients havebeen assessed to date, which it says coverstwo-thirds of the ingredients most com-monly used in cosmetics today. Ingredientspassing CIR review are deemed by FDA andthe industry to satisfy FDA’s safety substanti-ation requirement.

The CIR is generally regarded as a suc-cessful program, as far as it goes, and, as a cat-egory, cosmetics are not a major publichealth concern. The program is voluntary,however, and ingredients that have not gonethrough the process are beyond FDA’s over-sight unless and until they are suspected ofcausing harm.To date, no engineered nano-materials have gone through the process, butpresumably, they will be subject to it at somepoint in the future.

Another program that addresses safetyconcerns associated with cosmetics is theVoluntary Cosmetic Registration Program(VCRP).As noted on its website,VCRP is anFDA post-market reporting system for use bymanufacturers, packers and distributors ofcosmetic products that are in commercial dis-tribution in the United States. It involvesregistering cosmetic-manufacturing estab-lishments and ingredients using the CosmeticProduct Ingredient Statements (CPIS).21 InJanuary 2007, CTFA will launch a ConsumerCommitment Code, under which companiespledge to make their safety dossiers on cos-metic ingredients available to FDA upon theagency’s request.22

With this as background, I provide belowmy judgments about the relative strength of

FDA’s legal tools for regulating nanotechnol-ogy cosmetic products.

Pre-Market Functions• Capacity to Obtain Early Information on

Products in the Pipeline – None. Becausethere is no requirement for FDA pre-marketreview and no other incentive or require-ment for companies to disclose theirresearch or product development activity,FDA has no legal basis for obtaining thisinformation from them.23 This is an impor-tant issue in the nanotechnology cosmeticarena because of genuine uncertainty aboutthe actual composition and properties ofingredients that are claimed on cosmeticproduct labels to be produced through orotherwise incorporate the benefits of nan-otechnology.

• Capacity to Enforce Safety and Testing Require-ments – Weak. The cosmetic industrydeserves credit for the CIR, which is in parta response to FDA’s substantiation “require-ment.”As a matter of FDA’s legal authority,however, this functional element is ratedweak because the safety substantiation islegally optional, the CIR is voluntary andadministered beyond FDA’s legal controland cosmetic products bearing nanotech-nology claims are on the market withoutFDA review or knowledge about their actu-al composition or safety-related properties.

• Capacity to Place Burden to Prove Safety onSponsor – Weak. FDA’s authorities are


21. See http://www.cfsan.fda.gov/~dms/cos-regn.html, accessed September 27, 2006.22.“CTFA Launches Package of Consumer-Oriented Industry Initiatives at 2006 Annual Meeting.”Washington,

DC: Cosmetic,Toiletry, and Fragrance Association, March 2, 2006.Available at http://www.ctfa.org/, accessed September 27, 2006.

23. FDA is free to conduct its own research to discover this information, but its capacity to do so is heavily affectedby resource constraints, as discussed more fully below.

29

deemed weak on this element for the samereasons as above, as well as the fact that aproduct cannot be removed from the mar-ket unless FDA can prove that it is poten-tially injurious or that its safety has notbeen adequately substantiated.

• Capacity to Review Safety Prior to Marketing –None. FDA has no authority to obtain andreview cosmetic ingredient or product safe-ty data prior to market entry.

Post-Market Functions• Capacity to Require Needed Monitoring and

Testing – Weak. FDA has no explicitauthority to require post-market monitor-ing or testing for safety or any other pur-pose. FDA’s safety substantiation regulationcontemplates that when a safety questionarises post-marketing the company willconduct adequate studies to resolve thequestion, but FDA’s legal capacity in thisregard is weak for the same reasons that itscapacity to enforce safety and testingrequirements pre-market is weak.

• Capacity to Require Timely Adverse EventReporting – None. FDA has no legal author-ity for this purpose.

• Capacity to Inspect Facilities and Safety Records– Weak. FDA can inspect facilities, but it hasno access to records, other than as providedvoluntarily by companies.

• Capacity to Remove Unsafe Products from theMarket – Moderate. FDA has the standardjudicial enforcement tools to take a cosmet-ic product off the market if it can prove itcontains a substance that “may render it inju-rious to users.” FDA has no mandatory recall

authority for cosmetics, but, because ofFDA’s power to warn consumers and makeother use of publicity when it has concern,the agency typically has good success inobtaining the voluntary recall of productswhen it brings a safety concern to the atten-tion of a company.

Whole Foods

OverviewThis category includes whole food articlessuch as fruits, vegetables and fish, as opposedto ingredients or intentionally added sub-stances, such as oils, sweeteners, preserva-tives, color additives and animal drug andpesticide residues. It is included in thisanalysis not because the regulatory regimefor whole foods is likely to play a role in theoversight of engineered nanomaterials andproducts, but rather as the starting point forunderstanding the complicated range ofapproaches Congress and FDA have taken tothe regulation of substances in or affectingthe food supply.

Whole foods are subject only to post-market oversight and to two different safetystandards, depending on whether the sub-stance that raises a safety concern is natural-ly occurring in the food or “added” inadver-tently by some human activity.24 In the for-mer case, such as the naturally occurringtoxin solanine in potatoes, the food can beremoved from the market only if FDA canprove that it is “ordinarily injurious” tohealth. Added substances, such as dioxins,mercury and lead, make food “adulterated”and thus unlawful in commerce if FDA canprove that the substance is present at a levelthat “may render” the food “injurious tohealth.” This reflects the congressional

24. See 21 USC 342(a).

30

judgment that human interventions are sub-ject to a higher safety standard than nature,as will be illustrated further in the discussionbelow of GRAS food ingredients, food addi-tives and food packaging.

The one arguable exception to the lack ofpre-market oversight for whole foods is FDA’spolicy for regulating genetically modifiedwhole foods derived from plants,which is dis-cussed below under “GRAS FoodIngredients” and not included in the analysisthat follows.

Pre-Market Functions• Capacity to Obtain Early Information on Products

in the Pipeline – None.There is, of course, no“pipeline” for most whole foods and allunintentional contaminants and no legal toolfor obtaining “early warning” information.

• Capacity to Enforce Safety and TestingRequirements – None. FDA has no pre-mar-ket legal authority over whole foods.

• Capacity to Place Burden to Prove Safety onSponsor – None. FDA has no pre-marketlegal authority over whole foods.

• Capacity to Review Safety Prior to Marketing –None. FDA has no pre-market legal author-ity over whole foods.

Post-Market Goals• Capacity to Require Needed Monitoring and

Testing – None. FDA has no authority toimpose monitoring or testing requirementson parties marketing whole foods or other-wise bearing responsibility for the presenceof unintended contaminants in foods.

• Capacity to Require Timely Adverse EventReporting – None. FDA has no authority torequire adverse event reporting, althoughFDA’s Center for Food Safety and AppliedNutrition (CFSAN) operates a voluntaryAdverse Event Reporting System (CAERS).

• Capacity to Inspect Facilities and Safety Records– Moderate. FDA can inspect facilitieswhere whole foods are processed and stored,collect samples for testing and access safety-related records if it has a “reasonable belief”that the food “presents a threat of adversehealth consequences or death.”25

• Capacity to Remove Unsafe Products from theMarket – Moderate. FDA has the standardjudicial enforcement tools that work effec-tively when FDA can prove that the applica-ble safety standard has been violated. Therecall system, though voluntary, normallyworks well to remove products from themarket when FDA can demonstrate animmediate safety concern.

Dietary Supplements

OverviewThe nanotechnology consumer productinventory cites numerous examples of dietarysupplement products that claim the use ofnanomaterials or otherwise refer to nanotech-nology in their product claims. It is impossibleto know what these claims actually mean, butthe suggestion often is that the nanosize ofparticular materials enhances their absorbabil-ity or other functional properties.

Prior to 1994, the safety of dietary sup-plement ingredients was subject to


25. In the case of seafood and juice products, FDA has issued regulations requiring processors to implementHACCP (Hazard Analysis and Critical Control Points) systems. Based on those regulations, FDA has access tocertain records related to the design and operation of such systems. See 21 CFR Parts 120 and 123.

31

regulation by FDA on the same basis as anyintentionally added food substance, whichmeant that FDA could require pre-marketapproval as a food additive if the supplementingredient were not generally recognized assafe (or GRAS). Under the DietarySupplement Health and Education Act(DSHEA), Congress excluded supplementingredients from the definition of food addi-tive, shifting to FDA the burden of proofregarding the safety of a wide range of sup-plements on the market at the time, includ-ing vitamins, minerals, herbs and otherbotanicals, amino acids and any other sub-stance used to supplement the diet and con-sumed in pill or other supplement form.26

FDA has no pre-market authority over suchsupplements, but can take court enforcementaction to remove them from the market ifthe agency can prove they “present a signifi-cant or unreasonable risk of illness or injury.”

For supplements containing “new” ingre-dients—meaning ones with no history ofuse in supplement products and no presencein the food supply in the same chemical form—DSHEA requires the sponsor to submit apre-market notification providing informa-tion that the sponsor believes the products“will reasonably be expected to be safe.”

Pre-Market Functions • Capacity to Obtain Early Information on

Products in the Pipeline – None. FDA has nolegal tool for accessing information on newtechnologies and products under develop-ment in the supplement industry, and,because most new supplement products areformulated using ingredients that were usedin supplements prior to DSHEA, few com-panies have any need or incentive to bringsuch information to FDA.

• Capacity to Enforce Safety and TestingRequirements – Weak. FDA’s authority inthis regard applies only to new dietaryingredients and, even for these, does notempower FDA to establish testing require-ments or a true safety standard.

• Capacity to Place Burden to Prove Safety onSponsor – Weak. Likewise, the only pre-market safety burden applies to new ingre-dients, and the requirement is not todemonstrate safety but only to provide theinformation on the basis of which the man-ufacturer concludes that the product “willreasonably be expected to be safe.”

• Capacity to Review Safety Prior to Marketing –Weak. FDA’s receipt of pre-market notifi-cations provides FDA some informationbut it does not provide the basis for a fullFDA safety review, and FDA is not empow-ered to block marketing on the basis that itconsiders the notification inadequate.27

Post-Market Goals• Capacity to Require Needed Monitoring and

Testing – None. FDA has no authority to

Nanotechnology Dietary Supplements

As of October 2006, a search of the Project onEmerging Nanotechnologies consumer product invento-ry returned 16 dietary supplements that claim the use ofnanoscale calcium, magnesium and silver to increasethe bioavailability of supplements in the body.

26. See 21 USC 321(ff), 342 (f) and 350b.27. See 21 CFR Part 190.

32

require post-marketing monitoring and test-ing of dietary supplement ingredients orproducts.

• Capacity to Require Timely Adverse EventReporting – None. FDA has no authorityfor this purpose, though CFSAN’s volun-tary reporting system, CAERS, applies tosupplements.

• Capacity to Inspect Facilities and Safety Records– Moderate. FDA can inspect facilitieswhere supplements are processed andstored, collect samples for testing and accesssafety-related records if it has a “reasonablebelief ” that the food “presents a threat ofadverse health consequences or death.”DSHEA gave FDA authority to establishGMP requirements for supplements, whichpresumably would include some record-keeping and access requirements, but therequired regulations have not been issued.

• Capacity to Remove Unsafe Products from theMarket – Moderate. FDA’s legal capacityhere is similar to that for whole foods,which means FDA can go to court toremove a supplement product from themarket if it can prove a significant or unrea-sonable risk of illness or injury. For newdietary ingredients, FDA can go to court ifit can prove there is inadequate informationto provide reasonable assurance that theingredient does not present a significant orunreasonable risk.28 The voluntary recallsystem is also available.

GRAS Food Ingredients

OverviewThe Project on Emerging Nanotechnologiesconsumer products inventory lists products“powered by nanotechnology” or “utilizingthe incredible new nanotechnology” toimprove the properties of frying oil and the fla-vor of cocoa, and a September 2006 report byJennifer Kuzma and Peter VerHage,Nanotechnology in Agriculture and FoodProduction:Anticipated Applications, offers furtherdocumentation that nanotechnology is on itsway to the food supply. Similarly, the HelmutKaiser Consultancy estimates that the nan-otechnology food market is growing rapidly

and will reach over $20 billion by 2010—about three times its current size.29 A recentstudy by Cientifica found over 150 nanotech-nology applications currently in the foodindustry, with some of the world’s biggestcompanies—such as Altria, Nestle, Kraft,Heinz and Unilever—involved in nanotech-nology research and development.30 Thesefindings make the system for regulating


Nanotechnology and Food

An online database categorizing the anticipated applica-tions of nanotechnology in agriculture and food productionfound 160 projects that cover a wide range of researchareas, topics and techniques, including bioprocessing forfood, pathogen and contamination detection and smarttreatment and delivery systems. The database is availaibleat http://www.nanotechnology.org/inventories.

28. See 21 USC 342(f).29.“Study: Nanotechnology in Food and Food Processing Worldwide 2003-2006-2010-2015.”Tübingen,

Germany: Helmut Kaiser Consultancy, 2006.Available at http://www.hkc22.com/nanofood.html, accessedSeptember 27, 2006.

30. Nanotechnologies in the Food Industry. London, UK: Cientifica,August 2006.Available at http://www.cientifica.com/www/details.php?id=47, accessed September 27, 2006; Sean Roach.“Most Companies Will Have to Wait Years forNanotech’s Benefits.” FoodProductionDaily.com,August 21, 2006.Available at http://www.foodnavigator-usa.com/news/ng.asp?n=69974-nanotechnology-packaging-nano-applications, accessed September 27, 2006.

33

substances used in food processing and packag-ing, including GRAS substances, food additivesand food packaging, important to our analysisof FDA’s nanotechnology regulatory tools.

GRAS food ingredients are regulatedunder a legal system established by Congressin 1958 to ensure the safety of intentionalfood additives through careful pre-markettesting and FDA review, while avoiding time-consuming and costly FDA review of inten-tionally added substances whose safety isalready well established. It thus excludes fromthe definition of “food additive” and from thepre-market approval requirement intentional-ly added substances that are “generally recog-nized as safe” by scientists based on a historyof safe use in food prior to 1958 or “scientif-ic procedures,” which means the same quan-tity and quality of evidence required todemonstrate the safety of a food additive.

By law, there is no requirement for acompany that considers its food substanceGRAS to inform FDA of its marketingplans or seek any FDA review. If a companymarkets based on its “independent” GRASdetermination, however, FDA can challengethat determination in court on the groundsthat the substance is not GRAS and thus isan unapproved (and thereby unlawful) foodadditive. To help avoid such disputes, FDA,shortly after enactment of the food additivelaw, issued extensive lists of substances itconsiders GRAS,31 and, in the 1970s, initiat-ed a GRAS review program that involvedextensive literature reviews and the promul-gation of often detailed regulations, includ-ing chemical specifications, for additives thatFDA has affirmed as GRAS.32 In addition tothese FDA efforts, commercial customerstypically demand from their suppliers

documentation that an ingredient or foodsubstance is either FDA approved as a foodadditive or GRAS. In the absence of a spe-cific GRAS listing by FDA, companies fre-quently commission panels of scientists toreview the available evidence and render ajudgment about GRAS status.

This system generally works very well toassure the safety of substances intentionallyadded to food. One of its great strengths froma public health and public confidence per-spective is that it places the burden to provesafety on the sponsor rather than FDA.Thus,when challenging an independent GRASdetermination, FDA need not prove harmbut only that safety is not generally recog-nized; the approval of a food additive can berevoked based solely on an FDA showing thatthere is an unresolved safety question.

The 1958 food additive amendments tothe FDC Act were also intended to fosterinnovation in food technology by providinga basis for public confidence in the safety ofmarketed additives. The innovation goal isalso evident in the balance struck by inclu-sion of the GRAS concept. However, theGRAS concept raises an issue, at least from apublic confidence perspective, because of itsreliance on the judgment of the sponsor asto whether or not a new substance—or anew form or use of a substance—requiresFDA approval. Even when FDA has issuedGRAS (or food additive) regulations thatappear applicable to the substance, there isroom for the exercise of judgment as towhether the substance is covered. For exam-ple, the chemical specifications in FDA’s reg-ulations are typically written without regardto material size, leaving open the question ofwhether a nanoscale version would be

31. See 21 CFR Part 182.32. See 21 CFR Parts 184 and 186.

34

covered. In addition, it is almost certainly thecase that the safety evaluation underlying theregulation would not have considered theeffects at the nanoscale.

In the late 1980s, agricultural biotechnol-ogy presented FDA an analogous challengegrounded in the food additive-GRASregime’s inherent flexibility. In 1992, FDAestablished a policy for oversight of geneti-cally modified and other “novel,” plant-derived whole foods. The policy consistedlargely of scientific guidance concerning thedetermination of whether the genetic modi-fication resulted in a compositional changesufficient to trigger regulation as a food addi-tive.33 It also included a voluntary pre-marketnotification procedure under which develop-ers of such foods could submit informationto FDA supporting their judgment that nosuch change had occurred and thus that thenovel food was “substantially equivalent” toits traditional counterpart.

FDA’s biotechnology food policy was aneffort to clarify the pre-market safety assess-ment and approval obligations of productdevelopers and provide an incentive forcompanies to submit information to FDA inadvance of marketing, despite the lack ofany legal requirement that they do so forproducts they considered GRAS and thusnot food additives. This system has workedwell to provide FDA with informationabout genetically modified (GM) foodsentering the marketplace, none of which hasexperienced known safety problems. Thesystem does not, however, include a fullFDA safety review or conclusion about thesafety of new products, which has been afactor in the lack of confidence amongsome U.S. consumers and many in Europeabout the safety of GM foods.


Products in the Pipeline – Weak. FDA has nolegal tool for accessing information on newtechnologies and products under develop-ment in the food industry. FDA’s gatekeep-er role under the food additive-GRASregime gives companies some incentive toprovide information during their develop-ment process, but the flexibility of theGRAS concept reduces the incentive, andFDA typically gets detailed informationabout new technologies only when compa-nies are ready or close to ready to marketthem or submit them for approval.

• Capacity to Enforce Safety and TestingRequirements – Moderate. Even with theflexibility in the GRAS concept, the laws,andFDA’s enforcement leverage, if FDA disagreeswith an independent GRAS determination,it has reasonably good capacity to set andenforce safety and testing standards. Over theyears, FDA has provided considerable guid-ance on the testing required to show the safe-ty of GRAS substances and food additives.

• Capacity to Place Burden to Prove Safety onSponsor – Moderate. As the GRAS conceptis written and implemented, sponsors havethe ultimate burden to prove safety, whichmost take very seriously despite their legalflexibility to make an independent GRASjudgment.

• Capacity to Review Safety Prior to Marketing –Weak. By definition, GRAS substances arenot required to go through an FDA pre-mar-ket review, though in some cases sponsorshave sought GRAS affirmation from FDAprior to marketing.


33. See 57 Fed. Reg. 22984, May 29, 1992.

35


Testing – None. FDA has no authority torequire post-market monitoring and testingof GRAS food ingredients.

• Capacity to Require Timely Adverse EventReporting – None. FDA has no authority forthis purpose, though CFSAN’s voluntaryreporting system, CAERS, applies to GRASingredients.

• Capacity to Inspect Facilities and Safety Records– Moderate. FDA can inspect facilitieswhere GRAS ingredients are processed andstored, collect samples for testing and accesssafety-related records if it has a “reasonablebelief” that the substance “presents a threatof adverse health consequences or death.”

• Capacity to Remove Unsafe Products from theMarket – Strong. FDA’s capacity in thisregard is strong because, in addition to hav-ing all the standard enforcement tools, itneed only prove that a safety question existsor that safety is not “generally recognized.”

Food Additives

OverviewAs outlined above, substances intentionallyadded to food—such as spices, flavors, preser-vatives, emulsifiers and sweeteners—are foodadditives, unless they are GRAS, and arerequired to go through a formal FDA safetyreview and approval process.34 In this process,the burden of proof is on the sponsor to provesafety, FDA has full control over testingrequirements, and the safety standard is strict:

“reasonable certainty of no harm.” Theprocess culminates in a regulation setting theconditions under which the additive may belawfully used.This is a strong and effective sys-tem for ensuring additives are safe and forproviding the basis for public confidence insafety. Some argue, however, that it is a deter-rent to innovation because the standards arestringent and the process is cumbersome, cost-ly and legalistic.

It should be noted that there are othercategories of intentionally added substancesthat are regulated under different sections ofthe FDC Act, such as color additives,35 animaldrug residues36 and pesticide residues.37 Thestandards and procedures vary in detail butare substantially the same as for food addi-tives. Color additives and animal drugresidues are regulated by FDA. TheEnvironmental Protection Agency evaluatesthe safety of pesticide residues in food andsets tolerances (or legal limits) on the amountthat may be present; FDA enforces the pesti-cide tolerances.

Pre-Market Functions • Capacity to Obtain Early Information on Products

in the Pipeline – Weak. FDA has no legal toolfor accessing information on new technolo-gies and products under development in thefood industry, but FDA’s gatekeeper role forfood additives provides companies with someincentive to provide information during theirdevelopment process, especially when noveltechnologies are involved.

• Capacity to Enforce Safety and TestingRequirements – Strong. By virtue of its pre-market approval authority, FDA has clear

34. See 21 USC 348.35. See 21 USC 379e.36. See 21 USC 360b.37. See 21 USC 346a.

36

legal capacity to interpret and apply thestatutory safety standard, including establish-ing the testing requirements that give thesafety standard its functional meaning.

• Capacity to Place Burden to Prove Safety onSponsor – Strong. As a matter of law, theburden to prove safety is on the sponsor, anda food additive cannot be marketed untilFDA concludes that the sponsor has met thatburden.

• Capacity to Review Safety Prior to Marketing –Strong.This is a central attribute of the pre-market approval system for food additives.


Testing – Weak. FDA has no authority torequire post-marketing monitoring andtesting of food additives, but on a few occa-sions FDA has elicited agreements fromsponsors to conduct post-market monitor-ing as a condition of approval.The enforce-ability of these agreements is questionable.

• Capacity to Require Timely Adverse EventReporting – Weak. FDA has no authorityfor this purpose, though the occasionalpost-market monitoring noted above hasincluded adverse event reporting, andCFSAN’s voluntary reporting system,CAERS, applies to food additives.

• Capacity to Inspect Facilities and Safety Records– Moderate. FDA can inspect facilitieswhere food additives are processed andstored, collect samples for testing, and accesssafety-related records if it has a “reasonablebelief ” that the substance “presents a threatof adverse health consequences or death.”

• Capacity to Remove Unsafe Products from theMarket – Moderate. The strong point ofFDA’s legal capacity in this regard is that itcan revoke a food additive approval regula-tion based solely on a showing that newevidence raises an unresolved safety ques-tion.The weak point is that the administra-tive process involves formal, trial-like pro-ceedings that are resource intensive andtime- consuming.

Food Packaging

OverviewWith companies already claiming that theyare using silver “nanoparticles” in food stor-age containers to keep food fresher andlonger and, in the future, to signal whenfoods are spoiled, food packaging and otherfood contact materials are among the earlyapplications of nanotechnology that con-sumers will encounter directly in the market-place.The primary FDA regulatory concernin this arena is that components of the foodcontact material may migrate to the food,posing a safety concern or otherwiseadversely affecting the quality of the food.

Food packaging materials and other foodcontact substances that are not GRAS areincluded in the statutory definition of “foodadditive” and, for most of the years since1958, have been regulated through the foodadditive petition process. The result is anextensive and detailed list of regulations,including chemical specifications, prescribingthe conditions under which what FDA calls“indirect” food additives, in such categoriesas adhesives, polymers, adjuvants, productionaids and sanitizers, can be safely and lawfullyused.38 This system has all the strengths of thefood additive system as applied to direct


38. See 21 CFR Parts 172–178.

37

additives, but with typically a much lowerpossibility for human exposure to chemicalsand a lower level of possible safety concern.

Based on wide agreement that thisapproach was wasteful of both agency andindustry resources, Congress created, in the1997 FDA Modernization Act, an alternativepre-market notification process as an optionfor FDA and the industry in the typical caseof low migration and low toxicological con-cern.39 Under this approach, the sponsor sub-mits a food contact notification (FCN) con-taining information prescribed by FDA; FDAthen has 120 days in which to review andobject if it concludes that the food contactmaterial has not been shown to be safe. IfFDA does not object, The FCN is deemed“effective” and the material can be marketedunless FDA later determines that the materialis no longer safe, in which case FDA candeclare the FCN no longer effective, whichrevokes its marketing authorization. One dis-tinct feature of this system is that in contrastto a food additive regulation, which authoriz-es use by any manufacturer, a FCN covers useof a food contact material only by the entitythat submitted it.

Given the relatively small potential forfood safety problems associated with foodcontact materials, the old food additive regu-lation system and the new FCN system bothprovide a high degree of assurance that thesematerials are safe. Under the old food additiveregulation system, however, engineered nano-materials will raise the same issue presentedby GRAS substances and food additives:namely, whether the nanosize form of a pre-viously approved material is covered by theexisting regulation.This issue would not ariseto the extent manufacturers use the FCNprocess because each company must submit

its own FCN on the specific material itintends to market.

Independent determinations of GRASstatus remain an option for developers of newpackaging or food contact materials, thoughthe availability of the FCN route reduces theattractiveness of the GRAS option. If pur-sued, it raises the same issues as GRAS deter-minations for any other substance. The fol-lowing analysis applies to food packaging andcontact materials for which GRAS claims arenot made.


in the Pipeline – Weak. FDA has no legal toolfor accessing information on new technolo-gies and products under development by thefood packaging industry,but FDA’s gatekeep-er role under the food additive and FCNprovisions of law provide companies withsome incentive to provide information dur-ing their development process, especiallywhen novel technologies are involved.

• Capacity to Enforce Safety and TestingRequirements – Strong. Whether under theregulation or FCN route, FDA’s strong pre-market requirements give it clear legalcapacity to enforce the safety standard andset testing and other data requirements.

• Capacity to Place Burden to Prove Safety onSponsor – Strong. As a matter of law, theburden to prove safety rests clearly on thesponsor.

• Capacity to Review Safety Prior to Marketing –Strong. This is the purpose and clear con-sequence of the legal framework for foodpackaging and food contact materials.

39. See 21 USC 348(h) and 21 CFR 170.100 et seq.

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Testing – None. FDA has no authority torequire post-market monitoring and test-ing, and the voluntary agreement approachthat has worked for some direct additives isnot likely of practical relevance to packag-ing and food contact materials.

• Capacity to Require Timely Adverse EventReporting – None. FDA has no authorityfor this purpose, though CFSAN’s volun-tary reporting system, CAERS, applies tofood packaging and contact materials.

• Capacity to Inspect Facilities and Safety Records– Moderate. FDA can inspect facilitieswhere food additives are processed andstored, collect samples for testing and accesssafety-related records if it has a “reasonablebelief ” that the substance “presents a threatof adverse health consequences or death.”

• Capacity to Remove Unsafe Products from theMarket – Strong. As in the case of directfood additives, FDA can revoke a food addi-tive approval regulation for food contactmaterials or deem a FCN no longer effectivewithout proving harm, only that new evi-dence raises an unresolved safety question.Under the FCN route, FDA has the furtheradvantage of a simple process for deeming anFCN no longer effective, avoiding the cum-bersome process required to revoke a foodadditive approval regulation.

Medical Devices

OverviewMedical devices have particular potential tobenefit from advances in nanotechnology asstronger and more highly functional materials

become available for a range of implantabledevices, prostheses and diagnostics. As healthsignificance and therapeutic benefit increase,however, so too does the need for vigilance toassure safety, which for devices involves bal-ancing the risks and benefits of the device forthe patient.

The Medical Device Amendments of 1976establish a comprehensive regulatory schemethat actively addresses the goals of protectingpublic health, fostering innovation and pro-viding the basis for public confidence. Thedevice amendments provide FDA with a morecomplete arsenal of regulatory tools than it hasfor any other regulatory category (see Table 1),including the capacity to tailor the intensive-ness of pre-market oversight to the nature ofthe product, the degree of risk it poses and thenature of oversight FDA thinks the productneeds to assure safety and effectiveness.

This system is too complicated to describein detail here. In a nutshell, however, itrequires that any company seeking to marketa device product for the first time submit thatproduct for review to FDA unless FDA hasexempted that particular type of productfrom this requirement based on a determina-tion that pre-market review is not needed to


Nanotechnology Medical Devices

Using information provided by the NanoBiotech News2006 Nanomedicine, Device & Diagnostics Report, theProject on Emerging Nanotechnologies was also able toestimate commercialization time frames for two sets ofnanotechnology medical applications: cancer-relevantdrugs, diagnostic tests and devices; and general drugdelivery devices. In terms of drug delivery devices, theProject found 56 products in the pipeline, many of whichare in early-stage development or preclinical testing.

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assure safety and effectiveness. In general,only the best-understood and lowest-riskdevices are so exempted, and even for these,the manufacturer must register with FDAand list its products with the agency.

For all other device products, the sponsormust submit either a pre-market notificationor a full pre-market approval application,which, in either case, requires the sponsor toprovide FDA the information it needs toidentify issues of safety and effectiveness and,if needed, conduct a full-blown pre-marketreview of the product’s safety and effective-ness for its intended use. FDA approval ofnew devices, such as ones performing newfunctions or incorporating new materials orother new technology, typically requires clin-ical testing, which must also be reviewed inadvance by FDA. Under this comprehensiveset of pre-market authorities, the incorpora-tion of new nanomaterials to alter the func-tional properties of medical devices will besubject to careful pre-market review by FDA.

FDA also has extensive post-market regu-latory tools, including the traditional inspec-tion and enforcement tools available acrossthe board at FDA, as well as additionalauthorities, such as the authority to mandaterecalls in some cases, require adverse eventreporting and post-market surveillance, man-date GMPs and have extensive records access.

Many challenging issues have surroundedFDA’s implementation of the device amend-ments, many of which result from the largenumber of often small companies and theincredibly rapid pace of innovation. Using itsabundant tools in a way that achieves the dualgoals of protecting public health and foster-ing innovation is not easy and may well proveto be a challenge in the case of nanotechnol-ogy, but FDA does not lack legal tools.


Products in the Pipeline – Moderate.Though FDA has no explicit authority toaccess company information on technolo-gies and products under development, itsoversight of clinical investigations andstrong gatekeeper role provide companies astrong incentive to provide FDA withinformation on novel technologies wellahead of commercialization.

• Capacity to Enforce Safety and TestingRequirements – Strong. FDA’s strong andflexible pre-market oversight tools provideample authority and practical leverage tointerpret and enforce the risk-benefit safe-ty standard.

• Capacity to Place Burden to Prove Safety onSponsor – Strong. The burden to provesafety rests as a general matter on the spon-sor, unless FDA has made its own judgmenton the safety and effectiveness of a particu-lar type of device and exempted it from thepre-market submission requirements.

• Capacity to Review Safety Prior to Marketing –Strong. FDA has full but flexible authori-ty to conduct pre-market safety reviews asneeded.


Testing – Strong. FDA has explicit authori-ty to require post-market surveillance fordevices whose failure would be reasonablylikely to have serious health consequences.40

• Capacity to Require Timely Adverse EventReporting – Strong. FDA has explicit and

40. See 21 USC 360l and 21 CFR Part 822.

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broad authority to require adverse eventreporting for devices.41

• Capacity to Inspect Facilities and Safety Records– Strong. FDA has broad authority toinspect device manufacturers, including forcompliance with mandatory GMPs, and torequire the provision of agency access torecords related to assuring the safety andeffectiveness of devices.

• Capacity to Remove Unsafe Products from theMarket – Strong. FDA can effectively with-draw a company’s marketing authorization,whether granted under the pre-marketnotification or full pre-market approvalroute, based on new information raising asignificant safety question,42 and it has abroad range of other post-market remedies,including mandatory recall authority, to dealwith emergent safety problems.

OTC Drugs

OverviewIn general, FDA regulates human pharmaceu-tical products under a comprehensive set ofpre-market and post-market controls. TheFDC Act defines the term “drug” broadly toinclude products that diagnose, treat and pre-vent disease, as well as those that affect thestructure or function of the body for otherpurposes (not including food purposes). Any“new drug” must be approved on an individ-ual product basis prior to marketing. In a man-ner similar to the food additive provisions of

the FDC Act, however, products are excludedfrom the definition of “new drug” if they are“generally recognized as safe and effective”(GRAS/GRAE) for their intended use.43

To implement the GRAS/GRAE ele-ment of the FDC Act and address the regu-latory status of OTC drugs, FDA initiated in1972 a monograph system under which FDAreviews the safety and effectiveness of activeingredients and issues regulations listing—bycategory of intended OTC uses—the ingre-dients that can lawfully be incorporated indrug products based on FDA’s conclusionthat they are generally recognized as safe andeffective for their intended uses.44 Most OTCdrugs are regulated under this system.Products formulated using these “mono-graphed” active ingredients and “safe andsuitable” inactive ingredients, and labeled inaccordance with the monograph, are notconsidered “new drugs” and thus are not sub-ject to the requirement for a new drug appli-cation and the issuance of a product-specificapproval as a prerequisite for marketing. Onthe other hand, as a general rule, FDA con-siders any drug not covered by a monographto be a “new drug.”

Nanotechnology in Sunscreens

As of October 2006, a search of the Project on EmergingNanotechnologies Consumer Product Inventory contained18 specific and generic nanotechnology sunscreens fromthe United States, United Kingdom and Australia.

41. See 21 USC 360i and 21 CFR Part 803.42. FDA does not have explicit statutory authority to administratively revoke marketing authorizations granted

under the pre-market notification procedure, but it has on occasion issued revocation letters and has ampleother post-market authorities to remove such products from the market, including publicity, if it believes thereis a safety concern.

43. See 21 USC 321(g) and (p) and 21USC 355.44. See 21 CFR Part 330 et seq.

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In addition to these basic provisions defin-ing the terms of market access for drugs, theFDC Act gives FDA a range of other pre-market and post-market authorities (see Table1), including company registration and prod-uct listing, oversight of clinical trials, manda-tory GMPs, adverse event reporting for “newdrugs” and access to company records relatedto product safety.The drug provisions of theFDC Act lack some of the post-marketauthorities Congress has provided for med-ical devices, such as comprehensive authorityto require post-market surveillance, but, ingeneral, the legal tool kit for drug regulationis strong.

The GRAS/GRAE concept, as imple-mented through the OTC monograph pro-gram, gives rise, however, to at least one issuethat will be important to how engineerednanomaterials are regulated.Like FDA’s GRASaffirmation regulations for food substances, theOTC monographs typically list active ingredi-ents by name and may include purity and otherspecifications (often incorporating by referencestandards adopted by the U.S. Pharmacopeia),but ordinarily without reference to materialsize.Thus, it becomes a matter of interpretationwhether a nanoscale version of a listed ingredi-ent is properly considered within the mono-graph and thus lawful to market.

This issue has already arisen in a petition bythe International Center for TechnologyAssessment (ICTA) filed with FDA regardingthe sunscreen monograph, which lists titaniumdioxide as an active ingredient.45 Whenreduced to very small size, titanium dioxidecontinues to provide protection from ultravio-let light but it does not scatter light and thusbecomes clear on the skin (rather than white),which is cosmetically advantageous. Whilecompanies are using “micronized” materials of

titanium dioxide, which FDA has said fallwithin the monograph, they are also releasingproducts that are making “nano” claims.“Micronization” refers to a process of grindingmaterials down rather than a particle-size clas-sification, and may or may not lead to the pro-duction of nanosize particles. Since FDA hasnot precisely defined the term “micronize,” it isnot clear exactly what size materials are beingused in the marketplace or whether they posesafety questions different from those addressedin establishing the monograph.


Products in the Pipeline – Weak. FDA has nolegal tool for accessing information onnew technologies and products underdevelopment by the OTC drug industry,but the need to comply with the OTCmonograph system gives companies someincentive to provide information duringthe development process, especially whennovel technologies are involved.

• Capacity to Enforce Safety and TestingRequirements – Strong. The OTC mono-graph system, backed up by the FDC Act’snew drug authority, provides FDA ampleauthority to set and enforce safety stan-dards and testing requirements.

• Capacity to Place Burden to Prove Safety onSponsor – Strong. If FDA believes there isan unresolved safety question about anapproved OTC ingredient, it can proposeto amend the monograph on that basis,effectively shifting the burden to provesafety to the product sponsor(s) eitherthrough the OTC rule-making process ornew drug approval process.

45. See 21 CFR Part 352.

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• Capacity to Review Safety Prior to Marketing –Moderate. Individual OTC product formu-lations that are within a monograph are notrequired to be submitted for review by FDA,but “monographed” active ingredients haveall been reviewed for safety and effectivenessby FDA through the monograph process.


Testing – Weak. FDA has no explicit legalauthority to require post-market monitor-ing and testing of monographed OTC drugproducts, though, in the event of a safetyquestion, it can use the possibility ofremoving an ingredient from the mono-graph as a tool for eliciting informationfrom manufacturers.

• Capacity to Require Timely Adverse EventReporting – None. FDA has no explicitlegal authority to require adverse eventreporting by manufacturers of mono-graphed OTC drug products and does notdo so.

• Capacity to Inspect Facilities and Safety Records– Strong. FDA can inspect manufacturingfacilities, including for compliance withmandatory GMPs, and can access recordsrelated to product safety.

• Capacity to Remove Unsafe Products from theMarket – Strong. FDA can, through rule-making, remove an active ingredient fromthe monograph based solely on a showingthat available data no longer demonstratesafety.

New Drugs

OverviewNew drugs (both pioneer or brand nameand generic) require approval by FDAthrough the new drug application (NDA)process, or abbreviated NDA (ANDA) forgenerics.This process results in a company-and product-specific approval to market theproduct in accordance with conditions andunder a detailed label approved by FDA.FDA is empowered to oversee human-safetyand efficacy testing of new drugs and torequire prior to marketing the submission ofextensive information on all aspects of adrug’s composition, safety and effectiveness.FDA thus has ample legal authority toaddress any safety question that might arisepre-market with respect to the application ofnanotechnology.

FDA also has considerable post-marketauthority, as outlined in Table 1 and below,though its lack of broad authority to requirepost-market surveillance and testing has beencited recently by the GovernmentAccountability Office (GAO) as a gap inFDA’s authority that affects oversight of drugproduct safety.46

Nanotechnology in Pharmaceuticals

In its submitted comments to FDA, the Project on EmergingNanotechnologies has identified at least nine currentlyavailable nanotechnology drug and drug delivery prod-ucts that have already been approved for use by FDA.Many of these drugs are designed to more effectively tar-get and treat a range of diseases, from high cholesterolto breast cancer, and cause fewer side effects.


46. Drug Safety: Improvement Needed in FDA’s Postmarket Decision-making and Oversight Process. Washington, DC:United States Government Accountability Office, GAO-06-402, March 2006.Available athttp://www.gao.gov/new.items/d06402.pdf, accessed September 27, 2006.

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in the Pipeline – Moderate. Despite the lackof a specific legal tool for accessing informa-tion on new technologies and productsunder development by the drug industry,companies facing the NDA process have asignificant incentive to provide FDA with theinformation the agency needs to understandand efficiently review new products especial-ly when novel technologies are involved.

• Capacity to Enforce Safety and TestingRequirements – Strong. The NDA processgives FDA complete authority in this regard.

• Capacity to Place Burden to Prove Safety onSponsor – Strong. The NDA process placesthe burden of proof on safety on the appli-cant, and, if a safety question arises post-approval, the burden rests on the NDA hold-er to resolve it.

• Capacity to Review Safety Prior to Marketing –Strong. No new drug can enter the marketwithout FDA approval.


Testing – Moderate. As reflected in Table 1,

FDA has clear legal authority to require post-market testing for safety only in limited cir-cumstances, involving primarily follow-upon expedited approval of lifesaving drugsbased on surrogate end points and testing ofapproved drugs for use by children.Nevertheless, FDA’s strong leverage throughthe NDA process provides companies anincentive to produce data FDA thinks arenecessary to sustain continued approval of amarketed drug.

• Capacity to Require Timely Adverse EventReporting – Strong. FDA has clear authori-ty to require adverse event reporting fornew drugs.

• Capacity to Inspect Facilities and Safety Records –Strong. FDA can inspect manufacturingfacilities, including for compliance withmandatory GMPs, and can access recordsrelated to product safety.

• Capacity to Remove Unsafe Products from theMarket – Strong. FDA can revoke approvalof an NDA based on a showing that safetyand effectiveness are no longer demonstrat-ed, and NDA holders typically respond vol-untarily once FDA concludes revocation isnecessary.

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FDA’s legal tools are essential to its success, butthey are not sufficient in and of themselves.They need to be well implemented, whichtakes human and financial resources.The harshbudget reality at FDA, however, is that theagency’s resources are in steady decline in rela-tion to the responsibilities it has been given todo, and the resources it does have are spokenfor, mostly by programs and activities that arecommanded by law or public health priority.FDA simply lacks any significant cushion ofresources it can draw upon when new chal-lenges arise.To its credit, FDA is doing thingsto prepare for and respond to the challenge ofnanotechnology,but the scarcity of resources isa severe constraint on the agency’s ability todo what it needs to do to meet the public’sexpectations.

In this section, I will outline some of thethings FDA needs to be doing now and inthe near future to prepare for and effectivelyoversee the coming wave of nanotechnologyproducts; describe the current state of FDA’sbudget and what FDA is doing within thatbudget; and make a few points about theconsequences of not having enoughresources to do the job.

What FDA Needs To Do

Meeting public expectations regarding theregulation of nanotechnology or any noveltechnology requires both preparation andaction. The preparatory steps FDA shouldtake involve, generally, building its knowl-edge base, expertise and technical tool kit,and, on that basis, developing guidance forcompanies that will be seeking to understand

and meet FDA’s requirements. Examples ofsuch preparatory activities include:

• Learning more about applications of nanotech-nology that are in the pipeline or market. Thepurpose here is to be able to understand forplanning purposes the kinds of nanotech-nology applications that are likely to becoming so that safety and regulatory issuescan be identified and prepared for and theagency can assure the public that it is ontop of this emerging field. This couldinvolve scientific intelligence gatheringthrough public sources, surveys of firms andacademic researchers, tracking and analysisof products on the market and direct out-reach to leading companies. It shouldencompass all areas covered by theagency—drugs, biological products, cos-metics, medical devices and foods.

• Developing the necessary in-house scientificexpertise to understand and evaluate the productsof nanotechnology. FDA already has muchgeneral expertise in fields related to nan-otechnology—in chemistry, physics, mate-rial science and engineering—but the nov-elty of the technology and its rapid advancewill demand specialized expertise FDAdoes not have in-house. Meeting this needwill require a combination of training andnew hiring, both of which are expensive.

• Developing the safety evaluation and analyticaltools required to assess particular nanotechnologyproducts. This may be FDA’s most resourceintensive and critical need. It will beresource intensive because these tools will


FDA Resources: Current Status andImportance for Safety

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have to be built on a foundation of researchand experimentation. For example, the cur-rent battery of in vitro models, animalbioassays and clinical trial methods used forchemical safety testing assume convention-al and much larger material size, with dosesbeing measured in mass per unit of bodyweight or similar measures. For nanoscalematerials, which are thought capable ofgoing places in the body that conventionalmaterials cannot reach and behaving differ-ently as a function of their small size, cur-rent toxicology tools may not be adequate.Likely, some are and some are not.Someone has to do the work to know thedifference.

• Developing necessary scientific and regulatoryguidance. In all product categories, clarity byFDA internally and with product develop-ers about criteria for product testing, datasubmission and review is essential to mak-ing good public health decisions and facili-tating innovation. Nanotechnology, like anynew technology, will involve learning bydoing and an evolution in FDA’s under-standing and requirements. Early effort, incollaboration with the external scientificcommunity, to develop guidance that is asclear as possible will pay big dividends.

In addition to supporting these preparato-ry activities, FDA needs resources so that itcan take action in the near term to get infront of future regulatory issues, as well asaddress products that are already entering themarket. As discussed in the Recommend-ation section of this report, cosmetic, sun-screen and food packaging applications ofnanotechnology are in the market today and

present regulatory issues that flow fromFDA’s lack of an airtight pre-market handle.FDA could take steps using current legalauthority to get ahead of these issues, thoughthat would require management and stafftime that are in short supply.

Longer term, as more products emerge andgo through the pre-market approval systems atFDA, highly expert staffing will be needed inheadquarters and the field if FDA is to providemeaningful post-market oversight on suchmatters as responding to adverse event reportsand conducting GMP inspection.

FDA’s Growing Budget Gap

Where will FDA get the funds for thepreparatory and regulatory actions outlinedabove? That question is hard to answer in lightof FDA’s extremely difficult budget situation.

The simple fact is that for at least the pastdecade, FDA’s annual appropriation has fallenshort of what the agency would need just tokeep doing what it had been doing the yearbefore, including continuing the newly man-dated activities that the administration andCongress regularly put on FDA’s plate.According to analyses prepared by FDA,47 theagency’s 2001 budget would have had to be26% greater than it was just to stay even withits 1996 budget. By 2006, this budget gap hadgrown to a stunning 49%, meaning that justto be able to do what it was doing in 1996and to continue the new activities mandatedsince then, FDA’s 2006 budget would have tohave been 49% greater than it is. Under thePresident’s proposed 2007 budget for FDA,the gap grows again to 56%.

This harsh budget reality stems from thefact that about 80% of FDA’s budget goes for

47.Table presented in connection with FDA briefing for consumer groups on “FDA Financial Realities,” March 10,2006 (copy on file with author).

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costs directly associated with personnel,including salary, benefits and rent for officespace and other facilities.These costs rise onaverage 5.8% per year for reasons beyondFDA’s control, such as congressionally man-dated pay raises and increasing health insur-ance, rent and other facility costs. Congress,however, routinely fails to fully fund theseincreases, which means that to cover them,FDA must either reduce staffing levels orreduce already tight operating budgets—themoney for research, grants and contracts, trav-el and other activities through which FDAstaff do their current jobs and prepare for newchallenges, such as nanotechnology.

The impact of this resource erosion at FDAis seen most acutely at its Center for FoodSafety and Applied Nutrition (CFSAN),which oversees cosmetics as well as the dietarysupplement, food packaging and other food-related applications of nanotechnology thatare already entering the market. Just since2003, CFSAN’s total staff has declined from950 to 850, with a further decline to 817 pro-jected in 2007.48 At the same time, CFSAN’soperating budget, which covers a vast array offood safety and nutrition activities, as well ascosmetics, has declined from an already-mod-est $47.5 million to $30 million and is project-ed to be $25 million in 2007.

As documented in a recent Institute ofMedicine report, FDA’s drug safety programis another important activity that is ham-pered by FDA’s widespread scarcity ofresources for activities that are not financedthrough the user fee programs recentlyenacted to support the new drug and med-ical device pre-market review programs.49

FDA’s resources are not only increasinglyscarce and shrinking in relation to need, butthey are also already spoken for. The tasksbeing performed by FDA staff are deter-mined by congressional mandate or earmark—such as the operation of pre-marketapproval programs, mandatory GMP inspec-tions or new initiatives such as bioterrorismprevention, pandemic preparedness anddrug safety; by activities reflected in FDA’sown public health priorities, such as bloodsafety or preventing food-borne illness; orby the demands of industry and other exter-nal constituencies. When a new challengesuch as nanotechnology comes along, FDA’smanagers find their resources alreadydeployed elsewhere, and they are deployedfor real reasons.

No one would argue that FDA’s currentresource allocation is in any sense perfect, butanyone who wants FDA to step up its effortson nanotechnology has to recognize that thatmeans taking resources away from someother activity. There simply is no reserve orpool of discretionary funds available to man-agers to respond to new problems.

Shifting resources in response to newproblems is what managers do in anyorganization, but FDA is in such a strainedfinancial situation that absent a nanotech-nology safety crisis, I believe significantshifts are unlikely to occur. The problemwith this scenario is that for lack ofresources, FDA may miss the opportunity toprepare in ways that could help prevent acrisis and all of the adverse consequencessuch a crisis would have for the future ofnanotechnology.


48. Of these, about 30 “full time equivalents” (“FTEs”) are available to the Office of Cosmetics and Colors, thegreat majority of whom work on the statutorily mandated color certification program, leaving only a handfulof employees at CFSAN to oversee the multi-billion dollar cosmetic industry.

49. Institute of Medicine. The Future of Drug Safety – Promoting and Protecting the Health of the Public. Washington,DC:The National Academies Press, September 2006.

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What FDA Is Doing

To its credit, in traditional FDA fashion,despite the lack of any new resources or for-mal reallocation of resources, FDA is not justsitting back. The Office of Science in theOffice of the Commissioner has been desig-nated as the focal point for nanotechnologyat FDA, and, along with program staff inFDA’s operating centers, has been makingpresentations to stakeholders about how nan-otechnology products fit into the agency’sexisting regulatory program.The agency hasa nanotechnology page on its website thatcontains information of this kind.50

The Office of Science has also been coor-dinating several efforts among FDA scientists,working internally and with other agencies,to learn more about nanotechnology, devel-op research agendas and priorities and con-sider regulatory approaches.

For example, FDA is an active member ofthe inter-agency Nanoscale Science,Engineering, and Technology (NSET) Sub-committee of the Committee on Technology,under the National Science and TechnologyCouncil (NSTC). This administration-ledgroup coordinates among agencies involvedin the development of nanotechnology prod-ucts. It includes a Nanotechnology Envir-onment and Health Implications (NEHI)Working Group, which the FDA representa-tive chairs.

Internally, FDA has established the FDANanotechnology Interest Group (NTIG),whose members are review-level scientistsfrom all the FDA centers.The NTIG consid-ers the development and approval of nan-otechnology products through discussionsand sharing of issues that the centers are

experiencing in their discussions with prod-uct sponsors and review of submissions.TheNTIG meets quarterly and has an invitedoutside speaker at each meeting to present tothe group his or her perspective on issues andapproaches to the use of nanotechnology indevelopment of FDA regulated products.

The FDA Acting Commissioner, Dr.Andrew C. von Eschenbach, also announcedin August 2006 the creation of the FDANanotechnology Task Force, which is aninternal task force charged with determiningregulatory approaches for nanotechnologythat address innovation, safety and effective-ness concerns. On October 10, 2006, FDA isholding a public meeting to seek informa-tion about the kinds of new nanomaterial-based products under development in theproduct categories FDA regulates andwhether there are emerging scientific issuesthat should be brought to FDA’s attention,including issues related to the safety of engi-neered nanomaterials.

FDA is also collaborating with outsidebodies on specific issues, including theNational Cancer Institute (NCI) andNational Institute of Standards andTechnology (NIST) on the application ofnanotechnology to cancer diagnosis andtreatment, and with international standard-setting bodies on the development of termi-nology, nomenclature, metrology and charac-terization of nanomaterials.

In addition to these coordination anddialogue activities, FDA’s centers are con-ducting a limited program of research relat-ed to nanotechnology product safety andeffectiveness. FDA is devoting about 16 staffyears and $1 million to this research, muchof which involves the potential for dermal

50. See http://www.fda.gov/nanotechnology/, accessed September 27, 2006.

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penetration by nanoparticles and develop-ment of methods for assessing the toxicity ofengineered nanomaterials. While seeminglywell targeted and useful, this research isspread over five FDA centers and is at best afirst step by these centers to build the scien-tific knowledge needed to regulate engi-neered nanomaterials.

Unfortunately, the only source of newresearch funding for nanotechnology amongfederal agencies is the National Nano-technology Initiative (NNI). The President’s2007 budget request for the NNI’s researchprogram is $1.278 billion, of which $44 mil-lion is allocated to seven agencies for researchon environmental, health and safetyissues.51None of that money is allocated toFDA, even though a growing number ofnanotechnology-based products fall directlyunder FDA’s oversight.

The Consequences of Scarce Resources

The internal discussion and coordination, thepublic meeting and the research FDA isundertaking to prepare for nanotechnologyare worthy efforts, but they are limited.Theyare the things FDA can do to address a newchallenge when it has no new resources andno reserve or contingency on which to draw.

These activities involve busy programmanagers and staff adding nanotechnology tothe long list of issues for which they arealready responsible. The October 10 publicmeeting will help give visibility to nanotech-nology as an important issue for FDA, but it

is a fairly passive way to build FDA’s knowl-edge base and will generate only the infor-mation parties choose and are willing to givein a public setting, which may or may not bethe information FDA needs.

Finally, FDA deserves credit for reallocat-ing some of its limited research capacity toaddress very immediate safety-related ques-tions, such as the dermal-absorption proper-ties of nanotechnology cosmetic ingredients,but the scale of the effort seems small.

I see two possible, broad consequences ofFDA proceeding at this pace.

1. In product areas where FDA lacks astrong pre-market review handle,such as cosmetics, dietary supple-ments and GRAS food ingredients,the commercial reality of productsin the marketplace will get too farahead of FDA’s knowledge aboutwhat is out there and of its ability toassure the public that the productsare safe. There is always the possibilitythis could result in an actual safety prob-lem, but there is an equal or greater riskof undercutting public confidence andwillingness to accept nanotechnology.Just one visible safety incident with amarketed product—whether the risk isreal or perceived—is often enough toprompt the press and public to ask:Where is FDA? What has it done toassure the safety of this product?Unsatisfying answers to those questionswill be a blow to public confidence innanotechnology and in FDA.


51. See National Science and Technology Council.“The National Nanotechnology Initiative – Research andDevelopment Leading to a Revolution in Technology and Industry, Supplement to the President’s FY 2007Budget.”Washington, DC: Office of Science and Technology Policy, July 2006.The analysis by Maynard (n. 13,supra) of federal research highly relevant to addressing the health risk of engineered nanomaterials identifies just$11 million allocated across five agencies in 2005—none of which is associated with FDA.

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2. Products coming through the pre-market approval systems, such asfood additives, medical devices andnew drugs, will be delayed. To play itsmarket gatekeeper role in a way that pro-tects consumers from harm and facilitatesbeneficial innovation, FDA needs to knowas much or more about the safety- andeffectiveness-related aspects of nanotech-nology as do the engineers and other sci-entists developing it.Without such knowl-edge, FDA might miss a safety issue, and itcertainly runs the risk of long delays in thereview process. When the regulatory sys-tem places the burden to prove safety onproduct sponsors, ignorance about safetyor how to assess it is almost as much of aconstraint on innovation as actual safetyconcerns. If FDA does not have a scientif-ically sound basis for concluding a productis safe, the regulatory response will beeither “no”or extended delay until the sci-entific understanding matures.

In the end, it all comes back to publicexpectations for FDA’s role in overseeing theintroduction of nanotechnology products. Ifthe public expects FDA to have an expertunderstanding of the technology and a cred-ible basis for assuring the safety of nanotech-nology products before they enter the mar-ket, this requires resources. If the publicexpects a post-market ability to learn active-ly from actual in-use experience, includingadverse events, and be prepared to act whenproblems occur, this, too, requires effort andresources that FDA would today have trou-ble mustering.

I think these are the expectations of alarge segment of the American people.Withthese expectations in mind, I outline in theConclusion and Recommendations sectionssome actions FDA could take within itscurrent authority to help meet them, as wellas some ways in which society, throughCongress, can better equip FDA to do thejob people expect it to do.

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As noted in the Introduction of this report,nanotechnology could possibly be seen asjust another new technology and anothernew challenge for FDA. FDA has managedits way through such challenges in the pastand, one might argue, will find a way to doit again. Thus, one could conclude that nospecial effort or enhancement of FDA’scapacities is needed to deal with the emer-gence of nanotechnology as a commerciallysignificant technology.

I disagree. Nanotechnology is emergingrapidly as a potentially transforming technol-ogy across virtually every product categoryFDA regulates. Its enormous potential tobenefit consumers and patients will be real-ized, however, only if its safety is understoodand reasonably assured and if people haveconfidence in its safety. The public expectsFDA to play an active role on both counts.

For these reasons, I think FDA’s capacityto regulate nanotechnology needs specialattention and action.While FDA has most ofthe legal tools it needs to regulate most of theproducts of nanotechnology, significant gapsin authority remain, especially in these areas:

• Pre-Market Oversight of Cosmetics.Cosmetics, obviously, comprise the productcategory for which FDA’s legal arsenal ismost lacking if the agency is to play a mean-ingful pre-market oversight role rather thansimply react to products and, possibly, prob-lems after they appear in the marketplace.While there is currently little, if any, affirma-tive evidence that the cosmetic productsmaking nanotechnology-related claims inthe marketplace today are unsafe, there isalso very little information in the publicdomain, or available to FDA, about the exact

composition, including material size andproperties, of these claimed nanotechnologyproducts or about the testing that has beendone to assess their safety.

• Acquiring Information about NewNanotechnology Products. The abilityto simply acquire information about nano-materials and nanotechnology products thatare in development or newly in the marketis another gap in FDA’s legal tool kit, butone that cuts widely across the agency’s pro-grams. The Federal Trade Commission(FTC) has authority to request and evensubpoena information to support its unfaircompetition investigations, and theEnvironmental Protection Agency (EPA)can “call in” data from companies to sup-port its safety evaluations of pesticides, butFDA has no legal tools to acquire informa-tion to help it anticipate safety concernsabout products it will be expected to regu-late efficiently and effectively.

• Adverse Event Reporting. Likewise,FDA lacks authority to require adverseevent reporting on marketed products bymanufacturers, except with respect tomedical devices and new drugs.This ham-pers FDA’s ability to detect patterns andinvestigate safety problems that arise post-market, ideally in time to take the correc-tive and preventive actions needed to pro-tect public health and maintain publicconfidence.The broad question that needsconsideration with regard to adverse eventreporting and information gathering ingeneral is how FDA can come to knowwhat it needs to know in time to do whatit needs to do.


Conclusion: Gaps in the Tool Kit

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While Congress should consider legislationto address these and other possible gaps inauthority, FDA’s resource crisis is at least asgreat, if not greater, a constraint on the agency’sability to meet public expectations as its lack oflegal tools. Whether for research and otherinformation gathering, providing science-

based guidance to industry or using the legaltools it has, FDA’s resources are seriously defi-cient and need sustained attention andimprovement in the coming years to dealeffectively not only with nanotechnology butalso with a host of other public health, innova-tion and public-confidence challenges.

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The recommendations presented belowinclude ideas for addressing the gaps inFDA’s legal authority and resources out-lined above, thus better equipping FDA tooversee nanotechnology and other newtechnologies over the longer term. I alsosee a pressing need for FDA to considersome near-term actions that it could take,within its current authority and resources,to address some of the nanotechnologyproducts now entering the market and todemonstrate the agency’s ability to stayahead of the product-introduction curve. Iwill first recommend some of these short-er-term actions and then address longer-term legislative and resource needs.

Each of the recommendations that fol-low deserves much more analysis andthought than I have been able to give themin this overview report, and this list is by nomeans exhaustive. My hope with these rec-ommendations is, first, to illustrate that thereare actions FDA can take, and ways societycan better equip FDA, to meet society’sexpectations, and, second, to stimulatethinking and debate on these issues.

Near-Term Actions

My near-term recommendations relate pri-marily to cosmetics and food-related prod-uct categories: dietary supplements, GRASsubstances, food additives and food packag-ing. The central goals are to provide guid-ance to the industry on some critical ques-tions that affect the regulatory status andpathway of many nanotechnology productsand to help FDA obtain the information itneeds to stay abreast of this market and beprepared for its regulatory job.

Establish Criteria for “New for Legal andRegulatory Purposes” and “New for SafetyEvaluation Purposes” In the end, safety evaluations of engineerednanomaterials and products involve case-by-case assessment and judgment. For nanotech-nology products that do not require individualproduct review and approval by FDA,however,manufacturers often have to make a thresholddetermination of whether the product poses anew safety question or otherwise should beconsidered a new or different material, com-pared with the conventional form.The conven-tional form may, for example, have been mar-keted as a dietary supplement or listed in FDAregulations as a GRAS substance or as anapproved food additive or food contact materi-al. If the manufacturer judges the nanotechnol-ogy version to be the same as the listed one,there is no legal requirement to seek FDA pre-market review and FDA may not becomeaware of the product until after it enters themarket.The burden would then rest on FDA todetermine after the fact whether there is a safe-ty or regulatory concern warranting action.

FDA should thus promptly provide com-panies guidance for making what amount tomarket-entry decisions.The primary need isto establish criteria for judging when a nano-material is “new” for legal and regulatorypurposes, i.e., for purposes of distinguishingit from versions that are already listed inFDA’s GRAS, food additive and food pack-aging regulations or that have been reviewedthrough the Cosmetic Ingredient Review(CIR).The criteria might be based solely onmaterial size, surface-volume ratios or otherphysical characteristics, or they could includeother properties that FDA might judge rele-vant.This is for FDA to determine.The point

Recommendations


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is to have a basis for companies knowingwhen they need to come to FDA prior tomarketing versus when they can rely for legaland regulatory purposes on the existingapproval, GRAS affirmation or CIR reviewof the conventional form of the material.

A necessary extension of clarifying what is“new” for legal and regulatory purposeswould be to establish criteria for determiningwhen a nanomaterial should be considered“new for safety evaluation purposes.” Thesecriteria presumably would include function-al properties that relate to the likelihood thatthe safety profile of the nanotechnology ver-sion would be different from the convention-al one. Such criteria would be helpful for allcategories of FDA-regulated products as aguide to decisions about the need for toxici-ty testing beyond what already exists on theconventional form. Another application ofsuch criteria might be to narrow the “new”category so that FDA review of nanotechnol-ogy versions of already-approved conven-tional forms would be required when there isa scientific basis for judging that such reviewis needed to ensure safety.

Currently, the science needed to set thesecriteria may be lacking, especially to definewhen a nanomaterial is “new for safety eval-uation purposes.” Nevertheless, addressingthese threshold questions, which are at theheart of determining the regulatory status ofmany engineered nanomaterials and thetesting needed to ensure their safety, is fun-damental to FDA’s job. Moreover, simplyembarking on the process of setting the cri-teria, which should involve the external sci-entific community and the industry, wouldstimulate necessary discussion and better

definition of the scientific issues that requirefurther research. Leaving these issues unad-dressed will foster uncertainty, leave compa-nies to make their own decisions based oncriteria of their choosing and make orderlyoversight of the rapidly developing marketfor nanotechnology products difficult, if notimpossible.

Resolve the Meaning of “Micronized” inthe OTC Sunscreen MonographRelated to the definition of “new” is the spe-cific question of what forms of titaniumdioxide are allowed under the OTC drugmonograph for sunscreens. The preamble tothe monograph states that “micronized”forms of titanium dioxide had been consid-ered in establishing the monograph and thusare covered, but the term “micronized” wasnot defined.52 By defining this term and clar-ifying the extent to which the monographembraces the full range of nanomaterials,FDA would help resolve the status of one ofthe more visible early products of nanotech-nology to enter the market, thereby buildingconfidence that FDA is on top of itsregulatory task.

Request Cosmetic Companies to SubmitSafety Substantiation DataFDA’s safety substantiation program for cos-metics53 requires companies either to “ade-quately” substantiate the safety of their ingre-dients or to provide a label statement warn-ing that the safety of the product has notbeen determined. An increasing number ofcosmetic products are on the market bearingnanotechnology claims or reporting formu-lations using nanoscale ingredients, and with

52. See “Sunscreen Drug Products for Over-The-Counter Human Use; Final Monograph.” Rockville, MD: UnitedStates Food and Drug Administration, 64 Fed. Reg. 27666, May 21, 1999.

53. See 21 CFR 740.10.


labels that do not bear the warning state-ment. Presumably, this means that the com-panies have in hand or can cite “adequate”safety substantiation data.The regulation doesnot provide for FDA access to the substanti-ation data, and FDA’s general inspectionauthority does not authorize access to cos-metic company records.

In order to better inform FDA about thenanotechnology cosmetic products on themarket today and the basis for their safety,FDA should request the voluntary submis-sion of substantiation data on all productsmaking nanotechnology claims or containingnanomaterials. The agency should provideappropriate confidentiality protection for theinformation. FDA should take care in formu-lating the scope of the request, includingwhether it covers all products bearing anynanotechnology-related claim or just claimsfor products whose nanomaterials satisfysome FDA criteria, such as the criteria for“new.” By establishing this flow of informa-tion from the cosmetic industry, FDA willnot only be better informed but also have amuch more secure basis on which to assurethe public of the products’ safety and/orjudge whether additional regulatory tools orinitiatives are needed to inform the agencyand protect consumers.

Provide the Cosmetic Industry Guidance onWhat Constitutes “Adequate” SubstantiationCosmetic companies marketing products thatcontain engineered nanomaterials do sotoday without the benefit of FDA guidanceon what it takes to adequately substantiatetheir safety.The scientific basis for substanti-ating the safety of some cosmetic ingredientsis no doubt unclear and still evolving, butbecause nanotechnology products are a pres-ent reality, FDA should provide some guid-ance on the nature of the data that should be

generated and criteria for evaluating the data.For example, product-specific dermal pene-tration and potential hazard tests would seeman appropriate core data element of a sub-stantiation package, with products found toachieve penetration requiring further studyand evaluation.

While FDA does not currently have legalauthority to access a company’s substantia-tion data, the provision of such guidancewould at least provide the industry with acommon starting point and could contributeto the establishment of a de facto standard ofcare for the industry. As recommendedbelow, the credibility of FDA’s oversight ofnanotechnology cosmetics longer term mayrequire giving FDA authority to review acompany’s substantiation data.

Provide Guidance on When the Use of Engineered Nanomaterials and Their Associated Claims Turn Cosmeticsinto DrugsProducts that are ostensibly cosmetics butcontain ingredients that are intended to“affect the structure or function of the body”are drugs and must satisfy the FDC Act’sstandards for drug safety and efficacy. Somenanotechnology cosmetics bear such claims,for example, by stating that a product is“bioactive” and “facilitates the increasedgrowth of collagen.” By providing guidanceon when the use of engineered nanomateri-als and their associated claims make the prod-uct a drug, FDA will be asserting its tradi-tional regulatory authority and responsibilityfor drugs and providing assurance that cos-metic ingredients having biological impactreceive appropriate review.

Call for Data on Food UsesAs with cosmetics, FDA does not ordinarilyhave access to food company records and

56

safety-related data. Nevertheless, manycompanies are investing in nanotechnologyresearch and development and presumablydeveloping considerable knowledge aboutthe safety and other properties of engi-neered nanomaterials that would be relevantto FDA’s regulatory and public confidenceroles. FDA should attempt to access at leastsome of this information by collaboratingwith industry, perhaps through a trade asso-ciation, on a voluntary call for data on fooduses of nanotechnology. Again, FDA wouldhave to determine a reasonable scope for theinformation requested, including the prod-ucts covered and the nature of the informa-tion FDA seeks, and provide appropriateconfidentiality.

By taking on these issues and reaching outfor industry information on nanotechnologyproducts, FDA would be playing a properleadership role and establishing the credibili-ty of its regulatory oversight role.While theseactions do not require new legal authority,they do require resources that FDA currentlylacks.Thus, in recommending these actions, Ispeak as much to those who control FDA’sbudget as I do to those with regulatoryresponsibilities: if gathering information andproviding guidance of the kind outlined hereare appropriate means for meeting publicexpectations for oversight of nanotechnologyproducts, FDA should be provided theresources to do the work.

Long-Term Legal and Policy Actions

Beyond immediate actions it can take undercurrent law, FDA’s ability over the longer termto meet public expectations in its oversight ofnanotechnology products probably requiressome statutory change. I will outline a fewideas in this section aimed at enhancing FDA’s

authority to be informed and provide appro-priate pre-market and post-market oversight.The issues that may justify legislative changeare not, however, unique to nanotechnology.Thus, ideally, legislative change that might beprompted by nanotechnology would be craft-ed to enhance FDA’s ability to deal with anyemerging technology.

Importantly, however, I do not proposechanging the basic structure and approach ofthe FDC Act, with its various regulatoryframeworks for different product categoriesreflecting the varying degrees of oversightjudged by Congress to be appropriate forproducts ranging from hand cream to cancerdrugs. In particular, though the cosmetic cat-egory is the least intensively regulated, I donot see a pressing need for sweeping changeto, for example, require mandatory pre-mar-ket approval of all cosmetic ingredients. FDAcertainly needs access to cosmetic industrysafety data and some flexible new tools to dealwith new cosmetic technology, but, for mostcosmetic ingredients, the current systemappears to work reasonably well in most cases.

A final prefatory note: parties concernedabout FDA’s effectiveness should not beafraid to seek legislation.A common reserva-tion about the legislative route is that whengoing into the process, one never knows forsure what the outcome will be. While thatmay be true enough, in our system Congressis the sole source of FDA’s authority andother tools for doing its job. If partiesbecome afraid to legislate, FDA is left withtools that may be outdated and simply insuf-ficient to do what the public expects, whichleaves FDA unprepared to do its job. On asubject such as nanotechnology, the legisla-tive system works best if parties with a com-mon interest can come together on a com-mon agenda. In any event, if the public wantsFDA to do its job well in a changing world,


parties should not shy away from askingCongress to provide the necessary tools.

As a starting point, I recommend consid-eration of five new or expanded tools toenhance FDA’s oversight, both pre-marketand post-market.

Call for Data AuthorityOne of FDA’s greatest limitations in prepar-ing to regulate products of nanotechnologyor any rapidly emerging technology is its lackof early, detailed, product-specific knowledgeabout how the technology is being applied.That knowledge is essential in order to pre-pare scientifically to make decisions that aresound from the perspective of protectingpublic health and timely from the perspectiveof facilitating innovation. And, without theability to be knowledgeable about emergingtechnologies, FDA has difficulty establishingthe credibility of its oversight.

To address its need to be informed, FDAshould have administrative authority to call forthe submission of specified information onemerging technologies and products under itsjurisdiction, including products in the develop-ment pipeline. The legislation granting suchauthority should carefully define the purposesfor which FDA may call for data and establishcriteria and a process so that the requests arefocused and targeted. Confidentiality of tradesecrets and other proprietary information mustbe carefully protected.54

Discretionary Pre-Market Notification AuthorityWhile I believe the basic structure of currentlaw works well in most cases, the effective-ness and credibility of FDA’s oversight ofnovel technologies is reduced when the sys-

tem allows for market entry without anyprior safety review by FDA. FDA lacks sucha review opportunity for cosmetics, mostdietary supplements, GRAS food ingredientsand OTC products or reformulations mar-keted for the first time by a company.

To address this issue,FDA should be provid-ed rule-making authority to establish interimpre-market notification mechanisms to addressemerging and novel technologies. FDA wouldhave the discretion to identify product cate-gories for which pre-market notificationwould be required, the circumstances that trig-ger notification and the data that would haveto be submitted. The goal would be to giveFDA the basis for assessing whether the prod-uct satisfies the applicable statutory safety stan-dard; still, such a mechanism would be a noti-fication process, not a full pre-market approval.If FDA believes the product does not satisfy thesafety standard, it could block marketing byobjecting to the notification.

Such mechanisms should be authorized asinterim measures, such as for a period of fiveor ten years, so that FDA can effectively over-see the introduction of the novel technologywithout establishing a permanent new regula-tory regime. During this period, FDA andother parties could assess whether any addi-tional oversight is needed on an ongoing basis.

Records AccessFor cosmetics, most dietary supplements andGRAS ingredients, FDA has no generalauthority to examine company records relat-ed to the safety of the product.This includesthe data underlying cosmetic safety substanti-ations, unless based on the voluntaryCosmetic Ingredient Review. Without suchaccess, FDA is constrained in its ability to

54. Precedents for FDA use of the call-for-data tool, albeit without explicit statutory authority, lie in its implemen-tation of the OTC monograph program and the Drug Efficacy Study Implementation (DESI) program follow-ing enactment of the 1962 drug efficacy amendments to the FDC Act.

58

detect and assess possible safety issues and haslittle basis for assuring the public that partic-ular products meet applicable safety standards.

The proposed call for data and pre-marketnotification tools would go a long way toremedy this problem by giving FDA access tothe safety information on which the compa-ny relies for marketing its products. Absentthese tools, FDA’s general inspection author-ity for cosmetics and foods should beexpanded to allow access to safety substanti-ation data for cosmetics and other informa-tion in company records related to the safetyof cosmetics, foods, GRAS ingredients, foodadditives and food packaging.

Post-Market Monitoring AuthorityFDA’s lack of general authority to requirepost-market monitoring has been high-lighted recently by the GAO in the contextof FDA’s oversight of drug safety.The issuehas broader application, however, to therange of circumstances involving FDA-reg-ulated products where novel and beneficialtechnologies are entering the market,notwithstanding the inherent inability ofpre-market testing to fully assess possiblelong-term effects across large populationsof consumers or patients. In these cases,FDA should have authority to require post-market monitoring and surveillance ifneeded to assure the long-term safety of theproduct. Implantable medical devicesincorporating innovative nanomaterialsprovide one possible example of wheresuch monitoring might be justified.

The authority should be built into FDA’spre-market approval systems across theboard. However, the burden should be onFDA to justify invoking it in particularcases, and it should be invoked only forwell-defined purposes and where it will be

feasible to produce information that canhelp assure the safety of the product.

Adverse Event Reporting Currently, FDA can mandate adverse eventreporting only for prescription drugs and med-ical devices. Across the board, however, FDA’sinability to know what the sponsor knowsabout adverse events is an unnecessary obstacleto FDA being able to provide effective post-market oversight.There are many issues abouthow to manage adverse event reports, andmaking good use of them requires a seriousinvestment in staff time and information man-agement systems. But, information about whatmay have gone wrong with a product or its useis basic to FDA’s ability to protect health andvouch for the safety of products.

FDA should be given broad authority todevise mandatory adverse event reportingsystems that are appropriate for each productcategory and least burdensome to achieve thelegitimate oversight purpose.

Resource Needs

In general, for reasons discussed elsewhere inthis paper,Congress needs to reverse the declinein FDA’s resource base and to rebuild FDA’scapacity to meet the public’s expectations. Indoing so,Congress should make some provisionfor FDA’s ability to respond to the challengesposed by emerging new technologies.

Fund “Early Warning” InformationCollection There have been calls for many years to investmore in maintaining and building FDA’s sci-ence base, which includes the staff and facili-ties to keep up with rapid scientific advancesin all quarters of FDA’s jurisdiction.Doing thisis certainly a large part of being prepared to


regulate novel technologies. In addition, how-ever, Congress should consider funding with-in the Office of the Commissioner, and ineach of the operating centers, focal points forthe gathering of “scientific intelligence” tokeep FDA abreast of technological develop-ments and to keep the agency involved in dis-cussions occurring within the greater scientif-ic community.While there are offices that aretasked with this responsibility, their operatingbudgets, and thus resilience to respond to newdevelopments, are terribly thin. Congressshould increase this funding.

Fund Regulatory ResearchThe burden should be on product sponsors totest the safety of their products. FDA’s researchresponsibility is to ensure that proper toxicity-testing protocols are available and that theagency has the scientific knowledge and tech-nical tools, including analytical methodologies,to play its product review and post-marketmonitoring roles. FDA’s $1 million investmentin such research is noteworthy and admirable,but it is not sufficient in light of the array ofapplications of nanotechnology the agency canexpect to confront in coming years.

Build the Scientific and Regulatory StaffEffective, science-based oversight of nanotech-nology products—oversight that understandsthe safety issues well enough to prevent prob-lems while not unduly slowing innovation—will require specialized scientific expertise andfocused effort by regulatory policy makers inall of FDA’s programs. Congress should pro-vide FDA the resources to acquire the neededscientific expertise, so that being prepared tooversee nanotechnology does not requiredepriving other FDA programs of the scientif-ic resources they need.

FDA also needs to add regulatory capacityacross all its programs, at both the policy-

making and field-oversight levels. Providingscientifically sound regulatory guidance toindustry is one of the most important thingsFDA can do to stay in front of any potentialsafety issues posed by nanotechnology prod-ucts. FDA needs a field force that can conductinspections, respond to problems and do theother “bread-and-butter” things that are need-ed for an effective and credible regulatory pro-gram. In the end, FDA’s capacity to providetimely guidance and to do these other things isimpaired by the scarcity of its resources.

Concluding Observation

Americans expect a lot of the Food and DrugAdministration. Food and cosmetics are to besafe. Medical products are to be safe and effec-tive. And FDA is to achieve this withoutimpeding technological innovation or theprompt introduction of new products. FDAhas a long history of rising to this challenge,never perfectly but almost always with anearnest effort and creative use of the tools at itsdisposal.This, of course, is FDA’s responsibility.

But society has a responsibility, too. Society– citizens, businesses, and organized interestgroups – created FDA and the expectationssurrounding it. And only society, actingthrough the political process, can give FDA thetools it needs to do its job. Nanotechnology isyet another important challenge for FDA thatbrings into question whether the agency isequipped to do what is expected.

At present, FDA is not fully equipped, ineither its legal authority or resources, whichmeans society has a responsibility to act – tobe clear about its expectations and to giveFDA the tools it needs to meet them. FDAshould continue its resourceful use of thetools it has and help lead the discussion ofwhat more it needs to be successful, but therest is up to others.

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i.This category includes all cosmetic ingredients exceptcolor additives, which are regulated under separateauthority in a manner similar to food additives.

ii.For simplicity’s sake, this table omits FDA’s authoritiesfor animal drugs and therapeutic biologics, which areregulated under separate but similar, and in some respectsoverlapping, statutory provisions.

iii.This includes only cases in which, by statute or regula-tion, FDA has established a specific requirement that aproduct’s sponsor independently substantiate safety priorto marketing but without a requirement that that sub-stantiation be submitted to FDA.

iv. By regulation, FDA provides that cosmetic ingredientsand products “shall be adequately substantiated for safetyprior to marketing,” but provides the option, in theabsence of safety substantiation, of stating on the label:“Warning – The safety of this product has not beendetermined.”

v. Intentionally added food substances that are “generallyrecognized as safe” are exempt from the definition offood additive and from the requirement of pre-marketapproval. If FDA has not formally recognized the GRASstatus of a substance, companies commonly assembleinformation to demonstrate GRAS status, but there is nolegal requirement that they do so, and, in the event of asafety concern, the burden of proof is on FDA todemonstrate that the substance is not GRAS and thus afood additive.

vi. FDA has established a voluntary pre-market notifica-tion procedure for “novel foods” that has been used rou-tinely by developers of genetically modified whole foodsto inform FDA in advance of marketing that the devel-oper has reviewed the safety of the food and considers itsubstantially equivalent to the traditional food for safetypurposes.This procedure does not involve a full FDAsafety review or result in an FDA conclusion on the safe-ty of the product.

vii.This requirement applies only to dietary supplementscontaining “new dietary ingredients,” which are definedas those that were not marketed in the United Statesprior to October 15, 1994, and only if the new dietaryingredient has not been present in the food supply in achemically unaltered form. 21 USC 350b.

viii.Components of food packaging materials and otherfood contact substances are “food additives” if there is areasonable expectation they will migrate to food, unlessthey are GRAS. Rather than submitting full foodadditive petitions, however, sponsors of food contactsubstances have the option of submitting a pre-market

notification substantiating safety, which, if FDA doesnot object, provides the legal basis for marketing thesubstance.

ix. Pre-market notification is the vehicle for market entryof medical devices that are “substantially equivalent” to apreviously marketed “predicate device” or are subject toan FDA-promulgated performance standard.

x.This applies if FDA decides the pre-market notificationdoes not adequately demonstrate safety or if the sponsorotherwise chooses to submit a food additive petition.

xi. Most OTC drugs are regulated by FDA under amonograph system that includes FDA review of the safe-ty and effectiveness of their active ingredients and theissuance of regulations listing, by category of intendedOTC uses, the ingredients that can lawfully be usedbased on FDA’s conclusion that they are generally recog-nized as safe and effective for their intended uses.Products formulated using these active ingredients and“safe and suitable” inactive ingredients are not considered“new drugs” and are thus not subject to the requirementfor a new drug application and the issuance of a product-specific license as a prerequisite for marketing. 21 CFRPart 330.

xii. New medical devices that are not substantially equiv-alent to predicate ones and not subject to a performancestandard, or that are otherwise deemed a “Class III”device, can be marketed only after full FDA review andapproval of that specific device product.

xiii. FDA has issued GMP regulations for foods (21 CFRPart 110), but these are not backed up by any statutoryprovision making compliance with GMPs a prerequisitefor marketing.This means that the burden remains onFDA to prove that a product is unlawfully contaminatedor otherwise “adulterated,” not merely that it has violatedthe GMP regulation.

xiv. FDA was authorized in 1994 to issue regulationsmandating GMPs for dietary supplements but has yet todo so.

xv. For all the product categories FDA regulates, the FDCAct authorizes FDA to go to federal court to obtain anorder seizing particular lots of product that FDA is pre-pared to prove are in violation of the FDC Act for safetyor any other reason. FDA can also seek an injunctionbarring future shipments of violative products and canpursue criminal prosecution for violations of the FDCAct. In criminal investigations, FDA can gain access tosafety-related records and other company-held informa-tion if there is probable cause that the records are evi-dence of a crime.

Table1Endnotes


xvi.The FDC Act contains no express authority torequire post-market monitoring or testing of anapproved food additive, but FDA has on occasion elicit-ed a sponsor’s agreement to conduct monitoring foradverse events as a condition of approval. FDA has alsoby regulation established a seldom-used procedure forrequiring additional studies on a marketed additivewhen a safety question has arisen, as a condition ofcontinued marketing of what FDA calls an “interim”food additive. 21 CFR Part 180.

xvii. Id.

xviii. For certain high-risk devices, FDA can, on a case-by-case basis, require product manufacturers to conduct“post-market surveillance” for the purpose of collectingdata that can reveal unforeseen adverse events or “otherinformation necessary to protect public health.”

xix. FDA can require post-market testing as a prerequi-site for marketing in two limited situations.The first isunder the accelerated approval program, which pro-vides for the approval of drugs for serious or life-threatening illnesses based on surrogate end points ofeffectiveness provided the sponsor conducts post-mar-ket studies to verify safety and effectiveness. 21 CFRPart 314, Subpart H.The second, and even moreunusual, case is when human-efficacy studies on a drugare not ethical or feasible. 21 CFR Part 314, Subpart I.FDA can also require post-approval testing of marketeddrugs if needed to assess the safety and effectiveness of

those drugs for use by children. 21 USC 355c(b).

xx. Sponsors of new drugs are required to report toFDA within 15 days any adverse event coming to theirattention that is both serious and unexpected, and toreport all other adverse events on a quarterly basis. 21USC 355(k) and 21 CFR 310.305.

xxi. FDA may inspect safety records only if it first has a“reasonable belief ” that the food “presents a threat ofserious adverse health consequences or death.” 21 USC350c(a).

xxii. FDA may inspect safety records only if it first hasa “reasonable belief ” that the supplement, which is bylaw deemed a food,“presents a threat of serious adversehealth consequences or death.” 21 USC 350c(a).

xxiii. See note 11.

xxiv. Id.

xxv. Id.

xxvi.As a general matter, FDA inspectors can accesssafety-related data on any medical device that is“restricted” to use only on the prescription of healthpractitioners or that is otherwise subject to use condi-tions to assure its safety. 21 USC 704(a). In addition,FDA has broad authority to require device manufactur-ers to collect and report safety-related data, and itsinspectors have access to those data as well. 21 USC704(e).

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THE PEW CHARITABLE TRUSTS serves the public interest by providing information, advancingpolicy solutions and supporting civic life. Based in Philadelphia, with an office inWashington, D.C., the Trusts will invest $204 million in fiscal year 2006 to provide organi-zations and citizens with fact-based research and practical solutions for challenging issues.

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