Regulating Nanomedicine Can the FDA handle it?
Raj Bawa**1, MS, PhD **Patent Agent, Bawa Biotechnology Consulting LLC, Ashburn, Virginia, USA; Adjunct Associate Professor, Biology Department, Rensselaer Polytechnic Institute, Troy, New York, USA; and Founding Director, American Society for Nanomedicine, Ashburn, Virginia, USA. Abstract There is enormous excitement and expectation surrounding the multidisciplinary field of nanomedicine the application of nanotechnology to healthcare which is already influencing the pharmaceutical industry, especially in the design, formulation and delivery of therapeutics. Currently, nanomedicine is poised at a critical stage wherein regulatory guidance in this area assumes priority in providing for clarity and legal certainty to manufacturers, policymakers, healthcare providers and the public. There are hundreds, if not thousands, of nanoproducts on the market for human use but little is known of their health risks and toxicity. Less is known of nanoproducts that are released in the environment and that come in contact with humans. These nanoproducts, whether they are a drug, device, biologic or combination of any of the above, are creating challenges for the Food and Drug Administration (FDA), as regulators struggle to accumulate data and formulate testing criteria to ensure development of safe and efficacious nanoproducts. Evidence continues to mount that many nanoproducts inherently posses novel size based properties and toxicity profiles. Yet, there is no specific law or mechanism for oversight of nanomedicine and the FDA continues to treat nanoproducts as substantially equivalent ("bioequivalent") to their bulk counterparts. This poses unique regulatory challenges for the FDA. Such regulatory uncertainty could negatively impact venture funding, stifle nanomedicine research and development (R&D) as well as erode public confidence and acceptance of nanoproducts. The endresult of this could be a delay or loss of commercialized nanoproducts. Whether the FDA eventually creates new regulations, tweaks existing ones or establishes a new regulatory Center to handle nanoproducts, at the moment it should at least look at nanoproducts on a casebycase basis. The FDA should not attempt regulation of nanomedicine by applying existing statutes; incorporating it into the current regulatory scheme is a poor idea. Regulation of nanomedicine must balance innovation and R&D with the principle of ensuring high public health protection and safety. Keywords: nanomedicine, Food and Drug Administration, FDA, regulation, nanoparticles, nanotherapeutics, nanoproduct, combination products, patents, safety, efficacy, commercialization
Correspondence: Dr. Raj Bawa, Bawa Biotechnology Consulting LLC, 21005 Starflower Way, Ashburn, Virginia 20147, USA (Tel: 703-582-1745; 703-723-0034; Fax: 571-223-1844; Email: firstname.lastname@example.org). Copyright 2010 Raj Bawa. All rights reserved.
ADVENT OF NANOMEDICINE
Commercial nanomedicine, although at a nascent stage of development, is already a reality. Although many soughtafter innovations are decades away, there are hundreds, possibly thousands, of nanotechbased consumer products in the marketplace today. According to most experts the market potential for medicallyoriented new nanotechnologies, such as nanopharmaceuticals, will become increasingly significant in the future. Obviously, development is progressing more rapidly in certain sectors of nanomedicine, the most active areas of product development being drug delivery and in vivo imaging. However, it is impossible to gauge an accurate picture of the exact commercialization potential for nanomedicine. This is partly due to the extremely rapid development of healthcare products, a fragmented marketplace, the rapid rate of patent growth and the unpredictable nature of the research and development (R&D) process itself. Still harder to predict is the exact course nanomedicine will take. Will this relatively nascent area make small yet valuable contributions to medicine, or will it become a driving force that catalyzes a vast healthcare revolution? Many believe that "nano" is here to stay, and, in the future, it will generate both evolutionary as well as revolutionary products. As evidence, one can look beyond current challenges and point to governments around the world that continue to be impressed by nano's potential and are staking their claims and doling out billions of dollars, euros and yen for R&D. From a business pointofview, nanoproducts (or "nanoenabled products) offer the ability to extend the economic life of proprietary compounds and create additional revenue streams, thereby significantly affecting the commercialization landscape. For instance, nanopharmaceuticals offer potential solutions to fundamental problems in the drug industry ranging from poor water solubility of compounds to a
lack of target specificity [1, 2]. Eventually, nanotechnology should reduce the cost of drug discovery, design and development.
FDA AND NANOMEDICINE
There is growing evidence that various nanoproducts marketed for direct and indirect human consumption may be unsafe [3, 4]. These products may present unexpected human toxicity effects due to: (a) an increased reactivity compared to their "bulk" counterparts (discussed later); and (b) an increased potential to transverse biological barriers/membranes and reach/accumulate in tissues and cells due to their smaller size [5, 6]. Some have voiced concerns about the occupational and environmental risks associated with the manufacture and disposal of nanoproducts [7, 8]. This warrants some sort of oversight or regulation on the part of the Food and Drug Administration (FDA), which has so far chosen to regulate nanomedicine and nanoproducts via regulations already on the books. This decision is similar to that made a few decades ago with respect to biotechnology . But, regulating nanoproducts whether they be a drug, device, biologic or combination of any of the above are creating challenges for the FDA. Although these products may eventually integrate into modern medicine, currently, their path is paved with regulatory uncertainty as FDA regulators struggle to accumulate data and formulate testing criteria to ensure development of safe and efficacious nanoproducts . To facilitate the regulation of nanoproducts, the FDA has formed an internal NanoTechnology Interest Group ("NTIG") composed of representatives from all its regulatory Centers. In addition to the NTIG, the FDA has formed a Nanotechnology Task Force which in 2007 issued a FDA Task Force Report . However, to date, no clear guidelines or regulations have been proposed by the FDA
Task Force, whose mandate appears to be to simply encourage the continued development of innovative, safe and efficacious FDAregulated products incorporating/involving nanotechnology. In fact, via this Report , the FDA Task Force concluded that existing regulations are sufficient and comprehensive to ensure the safety of nanoproducts since these products would undergo premarket testing and approval either as new drugs under the New Drug Approval ("NDA") process, or in the case of medical devices, under the Class III premarket approval ("PMA") process [11, 12]: "FDA's authority over products subject to premarket authorization is comprehensive and provides FDA with the ability to obtain detailed scientific information needed to assess the safety and, as applicable, effectiveness of products, including relevant effects of nanoscale materials."
This conclusion by the FDA is based on the assumption that current regulatory requirements would detect any toxicity via the required clinical studies even if nanoproducts present sizerelated unique "nano" properties. Many experts have criticized this inaccurate extrapolation especially since most nanoproducts approved by the FDA have obtained approval based in whole or in part on studies of nonnanoversions (i.e., based on their bulk counterparts). In this regard, the approvals were granted based on safety data of equivalent nonnanoversions; the nanoproducts did not undergo the full PMA or NDA. Clearly, the current scope of FDA's regulatory authority is limited. The guiding principle here is that the FDA regulates endproducts, not any technology per se. The agency does not regulate nanomaterials or manufacturing processes, but the endproducts. In other words, the FDA only regulates products that incorporate nanotechnology .
This Report does, however, allude to the need for regulatory oversight of some nanoproducts but offers no regulatory remedy or framework : "In some cases, the presence of nanoscale materials may change the regulatory status/regulatory pathway of products. The Task Force believes it is important that manufacturers and sponsors be aware of the issues raised by nanoscale materials and the
possible change in the regulatory status/pathway when products contain nanoscale materials."
Experts continue to criticize the FDA rather lax and uncoordinated effort when it comes to regulating nanomedicine. All in all, governmental regulatory agencies are in disarray over the regulation of nanomedicine. The situation is not much different at other global regulatory agencies. As nanoproducts move out of the laboratory and into the clinic, federal agencies like the FDA [810, 1315] and the US Patent & Trademark Office (PTO)  continue to struggle to encourage the development of nanomedicine while imposing some sort of order. Numerous challenges confront regulatory agencies and important unanswered questions linger (Table 1). All this while a steady stream of nanoproducts continues to arrive in the marketplace. Given this backdrop, investors have been cautious and confused as to what route, if any, the FDA will take in regulating nanomedicine. FDA's delay in addressing nanoregulation could have a chilling effect on public confidence and commercialization efforts . So far, the process of converting basic research in nanomedicine into commercially viable products has been difficult. Securing valid, defensible patent protection from the PTO  along with clearer regulatory/safety guidelines from the FDA [810, 1315] is critical to any commercialization effort. In spite of all these bottlenecks, a large number of FDAapproved nanodrugs have been launched while many more are poised to receive regulatory approval [1, 2]. But, there are currently hundreds of unregulated and unlabeled nanoproducts on the market that incorporate engineered nanoparticles and nanomaterials. Similarly, tons of these engineered nanoparticles and nanomaterials continue to be produced annually. Table 1 Critical Questions for the FDA Regarding Nanomedicine Why has nanomedicine not gained prominence on the FDA's regulatory agenda? Are nanomaterials inherently toxic?
Is the science and technology moving too fast for proper review to take place to formulate appropriate laws? Can regulations truly tame the vastness encompassed by nanomedicine? Can nanomedicine be regulated under existing regulations and authorities? Are new regulations needed for all nanomedical products or only a subset of products containing nanomaterials? Has the FDA kept pace with emerging advances in nanomedicine? Who in addition to the FDA should be given the responsibility to regulate nanomedicine?
FDA REGULATION OF NANOPRODUCTS CURRENT POSITION
As stated previously, under the current regulatory regime, it continues to be the FDA's position that particle size is immaterial and that the safety of the large particle version (i.e., bulk counterparts) of an active ingredient can be used to predict the safety of the nanoscale version of the same ingredient. Put differently, according to the FDA if large particle versions of a product are considered to be safe, then it can be presumed that the nanoversions are safe as well. Furthermore, nanoingredients (e.g., nanoparticles) are presumed by the FDA to be bioequivalent to their bulk counterparts. Thus, currently, manufacturers of nanoproducts are neither required to obtain premarket approval from the FDA nor required to list nanoingredients on product labels. According to the FDA, the existing health and safety tests that it uses to assess the safety of normal size materials are considered adequate to assess the health effects of nanoproducts .
However, various scientific studies contradict this hypothesis. These studies establish that FDA's presumption of bioequivalence is scientifically flawed. Although nanoparticle toxicity is complex, it is well established that nanoscale products and particles, such as nanomedicines, often have fundamentally different properties as compared to their larger counterparts [1, 2]. Put
differently, "nanoscale" does not just mean that a product is smaller, it often means that the particle is fundamentally different. Specifically, as a particles size decreases, a greater proportion of its atoms are located on the surface relative to its core, often rendering the particle more reactive (over their conventional "bulk" counterparts). This reduction in particle size often renders it more reactive, increases its dissolution rate and saturation solubility and, if the particle is a drug, it frequently correlates to improved in vivo performance. In addition, as the particle size decreases, its total surface area increases exponentially, again often making it more water soluble and imparting to it an enhanced bioavailability. Nanoparticles also have a greater potential for biological interaction, and the intrinsic toxicity of any given mass of nanoparticles is greater than the same mass of larger particles.
Given this, there are public health concerns and risks with the FDA's dated position on bioequivalence. In addition to this, preexisting FDA regulations, marketing without any form of risk/benefit analysis and, in some instances, lack of a labeling requirement (for example, for cosmetics) are all creating confusion and concern. As a result, nanotech products are being regulated in the same manner as their bulk counterparts. This position of the FDA is rather surprising given that the US Environmental Protection Agency (EPA) and other scientific authorities [19, 20] concur that nanoparticles can have toxicological properties that differ from their bulk counterparts. The FDAs position on bioequivalency implies that the safety of bulk counterparts is predictive of the safety of the nano scale versions and that these are not more hazardous than their bulk counterparts.
FDA's Task Force Report of 2007  and a Public Meeting held in 2008  to gather information that will assist the Agency in implementing the recommendations of the Nanotechnology Task Force Report" have resulted in no nanospecific regulatory action. The FDA's Report concluded: "The available information does not suggest that all materials with nanoscale dimensions will be hazardous. Furthermore, if all nanoscale materials are compared to all non nanoscale materials, whether larger or smaller, it is not apparent that the nanoscale materials as a group would have more inherent hazard. However, consideration of the basic science of how materials interact with biological systems does indicate that a material's properties can change when size is increased or decreased into, or varied within, the nanoscale range. (Emphasis added)" So far the FDA has failed to follow through on its promise  that it would later on "issue additional guidance to provide greater predictability of the pathways to market and for ensuring the protection of public health." Hopefully, this issue will soon be addressed by the Obama administration. The new FDA commissioner, Dr. Margaret Hamburg, stressed regulatory science as a discipline in a speech delivered last fall in Philadelphia : "Just as biomedical research has evolved in the past decades, regulatory science the science and tools we use to assess and evaluate product safety, efficacy, potency, quality and performance must also evolve...Our efforts will be seriously compromised if we dont significantly increase the sophistication of our regulatory science soon...A strong and robust field of regulatory science is essential to the work of FDA, and I believe it represents an important driver of our nations health...The goal is to place the emerging, very promising areas in science and technology, such as genomics and personalized medicine, the development of stem cell therapies and therapies that harness the power of nanotechnology fully at the service of public health... We cannot afford to have a muscular investment in fundamental research and discovery with only a scrawny counterpart in regulatory capacity." Basically, from the FDA's perspective it is currently unresolved whether nanoproducts present unique risks (as compared to their bulk counterparts) that warrant regulatory oversight, and what
specific toxicity testing is needed to demonstrate their safety. However, stakeholders, government, industry, academia and the public at large have offered various proposals to regulate nanomedicine, including creating new laws and regulations, revising/modifying existing laws and regulations, interpreting existing laws and regulations to cover nanomedicine, designing new nonregulatory governance approaches such as voluntary industry standards and revising/modifying existing nonregulatory approaches . NANOPRODUCTS AS COMBINATION PRODUCTS According to the US Code of Federal Regulation, 21 CFR Section 310.3 (g): "New drug substance means any substance that when used in the manufacture, processing, or packing of a drug, causes that drug to be a new drug, but does not include intermediates used in the synthesis of such substance." Therefore, nanoformulations (e.g., "nanopharmaceuticals ") of existing therapeutics are considered new formulations but not necessarily new molecular entities (NMEs). All nanopharmaceuticals currently on the market have been approved by the FDA according to preexisting laws and without any special testing (e.g., with respect to pharmacokinetic profiles). However, approval of new "nanoformulations" has challenged the FDA's regulatory framework. Products, including some that may contain nanomaterials or involve nanomedicine, submitted to the FDA for market approval are evaluated on a categorybased system in one of the nine Centers that focus on a specific area of regulation. For example, a drug, biologic, or device would be assigned for evaluation respectively to the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), or the Center for Devices and Radiological Health
(CDRH). Obviously, categorizing nanoproducts according to this legal FDA classification is critical due to the widely divergent regulatory approval standards employed by the FDA [9, 23]. However, certain therapeutics are "combination products," which consist of two or more regulated components (drug, biologic, or device) that are physically, chemically or otherwise combined or mixed to produce a single entity. Here, the FDA's categorybased approval process has resulted in inconsistency . It is difficult to predict how nanoproducts will be regulated. Size changes within the nanoscale and the potential unpredictability therefrom are likely to add complexity to the FDA review process. The traditional productbyproduct regulatory model that the FDA currently employs may not be effective for all nanoproducts as it may be difficult to classify them into one of the available traditional classifications (i.e., drug, device, biological or combination product). However, in many cases, the FDA may view nanoproducts as technologically overlapping (miniaturization will blur distinctions between different categories) from a review perspective, and therefore, consider them as complex combination products. These are likely to pose challenging and complex regulatory review issues for the FDA .
RECOMMENDATIONS FOR THE FDA
There are numerous challenges confronting regulatory agencies like the FDA regarding reform
of regulatory guidance for nonotoxicological evaluation. Among these are limited availability of information correlating physicochemical properties of nanomaterials to risks, and a lack of validated preclinical screens and animal models for the assessment of nanomaterials . The toxicity of many nanoscale materials will not be fully apparent until they are widely distributed and their exposure is
felt by a diverse population. Therefore, a sort of postmarket tracking or surveillance system must be adopted along with any new proposed legislation to assist in product recalls. Although toxicological testing for health risks of nanoparticles is not currently a complete science , it is crucial to monitor their unique properties (if any) that may lead to serious adverse effects and toxicity. Since it is well established that premarket testing of drugs will not detect all adverse reactions , it is essential that the longterm testing of nanoscale materials should be in place for safety testing. Although the FDA has downplayed nanoproduct safety issues  and the need for modification of the current regulatory regime, it is starting to recognize that there are knowledge gaps and a lack of scientific expertise in these areas . The FDA is also encountering problems in applying its current regulations to nanoproducts as well as placing them into its present classification scheme. These issues are compounded by the fact that this agency is confronted with serious deficiencies in general (Table 2). Table 2 Critical Challenges Confronting the FDA chronic under funding the complexity of new products and claims submitted globalization of the industries regulated inability to attract and retain experts, insufficient capacity in modeling risk assessment and analysis inefficient regulatory structure lack of expertise in some technology areas and growing reviewer case loads However, proper planning and efforts by the FDA now to mitigate foreseeable problems will insure that scientific, ethical, commercialization and legal obstacles are overcome in future. In any case, regulating these products will require greater cooperation between drug companies, policymakers and the FDA. In light of these challenges, a multidisciplinary team of experienced
regulators from the drug, biologic and device areas of the FDA (working with a scientific panel of experts) should be formed to assist across the board (Table 3). Table 3 Recommendations for the FDA Regarding Nanomedicine Regulation SAFETY AND RISK Identify unique safety issues associated with nanomedical products. Correlate physiochemical property with in vivo biological behavior and therapeutic outcome. Develop research strategy that involves adsorption, distribution, metabolism and excretion (ADME) studies. Develop toxicology tests and conduct physicochemical characterization (PCC) studies for nanomaterials Understand mass transport across membranes and body compartments. Determine accurate biodistribution profiles following systemic administration via any route. Develop standards that correlate biodistribution of various nanoparticles to safety/efficacy by using parameters like size, surface charge, stability, surface characteristics, solubility, crystallinity, density etc. Create a databank relating to the interactions between nanomaterials and biological systems. DATA Adapt existing methodologies as well as develop new paradigms for evaluating data pertaining to safety and efficacy of nanomedical products. Develop guidance that provides specifics as to what kind of data is needed. Share data in an internationally harmonized environment. STANDARDIZATION Create reference classes for nanomaterials that are synthesized and characterized. Develop consensus testing protocols to provide benchmarks for the creation of classes of nanoscale materials. Create uniform standards and/or working definitions of nanomaterials. Define nanotechnology and nanomedicine for the purpose of nanoproduct regulation. Explore international harmonization efforts and formal treaties. Involve standardsetting organizations such as the International Standards Organization ("ISO") and ASTM International. TOOLS Assist in developing unique tools and techniques to characterize nanoscale materials. Develop imaging modalities for visualizing biodistribution. Develop mathematical and computer models for risk/benefit analysis. Monitor quality, safety, product liability and effectiveness. CLASSIFICATION SCHEME Reevaluate the current FDA classification scheme. Develop a classification based on (a) function or (b) risk of potential harm.
As nano begins to appear in a wide variety of products, its safety and effectiveness will
warrant careful review. To date, no formal regulations for nanotechnology have been drafted. Whether the FDA eventually creates new regulations or establishes a new center to handle its regulation, at the moment it should at least look at nanoproducts on a casebycase basis. The FDA should not attempt regulation of nanomedicine by applying existing statutes; incorporating them into the current regulatory scheme is a poor idea. It would be best if the FDA acknowledge that some nanomaterialcontaining formulations (or "nanoformulations") are NMEs. When warranted, nano versions of active ingredients should be treated by the FDA as NMEs. This will ensure that drugs, biologicals, etc. that have been previously approved by the FDA, but later modified as nanoverisons will undergo a new and complete round of safety testing in order to obtain premarket approval. It should seriously contemplate nanoingredient labeling. If the nanoproduct is for human consumption product labeling should be required to identify these nanocomponents, given their inherent potential toxicity profiles. Many consider that current laws for regulating nanomedical products may not be adequate to regulate their manufacturing and distribution. Clearly, the FDA needs to "update" its regulatory regime to accommodate nanotech products intended for human consumption. It should soon be determined whether nanoproducts should be regulated under the preexisting rules of established regulatory authority for combination products or whether it is necessary to pass new legislation to address certain unique sizerelated issues. Obviously, the goal here should be to protect human health while supporting innovation. If the FDA does not adequately address nanomedicine safety
issues, it could stifle research and commercialization efforts by blocking market access to innovative products. Eventually this could erode public confidence and acceptance of nanomedical products all negatively impacting public health. Public acceptance may be even more important than regulatory acceptance for certain sectors of nanomedicine, public acceptance often being in effect a "hidden regulator" . This is evident from certain biotechnology products like Calgene's Flavr Savr Tomato which was approved by the FDA but withdrawn from the US market because of public response . Underregulation could result in inappropriate approvals, some of which could be harmful to public health, while an overregulation could limit innovation or promote "black market" research activities. Therefore, it is hoped that the FDA will strike an appropriate balance and, where appropriate, promulgate nanomedicinespecific regulations undertakings that should expand the burgeoning field of nanomedicine. Regulatory oversight must evolve in concert with newer generations of nanomedical products.
STATEMENT OF DISCLOSURE/CONFLICTS OF INTEREST The author declares that he has no conflict of interest and has no affiliation or financial involvement with any organization or entity discussed in the manuscript. This includes employment, consultancies, honoraria, grants, stock ownership or options, expert testimony, patents (received or pending) or royalties. No writing assistance was utilized in the production of this manuscript and the author has received no payment for preparation of this manuscript. This paper reflects the current views of the author. They should not be attributed, in whole or in part, to the organizations with which he is affiliated, nor should they be considered as expressing
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