Fda and nanotech: baby steps lead to regulatory uncertainty

41 FDA and Nanotech: Baby Steps
Lead to Regulatory Uncertainty
Bawa Biotech LLC, Ashburn, VA, USA and Rensselaer Polytechnic Institute, Troy, NY, USA 41.1 Introduction
of the FDA is to ensure that drugs, medical devices, vaccines, veterinary products, and tobacco prod- Emerging technologies bring with them concerns ucts reaching the consumer are both safe and effec- and uncertainties about how they should be regu- tive. It is also responsible for the safety of foods lated [1] . Clearly, when these technologies relate to (including dietary supplements and food addi- human healthcare, regulation in some form is war- tives), dyes and cosmetics. Obviously, many of ranted. But what if the regulatory agencies lack the these products utilize nanotechnologies or contain expertise or will to fully understand these technolo- nanomaterials. Should these products be regu- gies? This is one of the critical issues facing regula- lated? If so, how and to what degree? These are tory agencies globally. For over a decade, this some of the questions the FDA is grappling with challenge has continued to haunt the US Food and in relation to “ nanogovernance ” (Box 41.1 ). Drug Administration (FDA) as it struggles to Internationally, regulatory guidance for nano- handle the issue of nanogovernance. The “ baby technology is generally lacking. In fact, regulatory steps ” this federal agency has taken over the past agencies around the world continue to struggle in decade are generally inadequate and have contrib- their efforts to develop new, meaningful regula- tory defi nitions and balance them with policies The FDA is a critically important regulatory that are already in place (Section 41.3 ). However, agency of the US government. The breadth of prod- guidance is critically needed to provide clarity ucts that it regulates represent about 20% of US and legal certainty to manufacturers, policymak- consumer products worth billions of dollars. ers, healthcare providers, and the consumer. Employing various laws and regulatory mecha- Common sense warrants that some sort of guid- nisms (and depending on the particular product ance, oversight, or regulation by the FDA is in class (Section 41.3 )), the FDA conducts specifi c pre - order, but so far it has chosen to regulate nano- market and/or post - market oversight. The mission medicines and nanoproducts solely via what is Bio-Nanotechnology: A Revolution in Food, Biomedical and Health Sciences, First Edition. Edited by Debasis Bagchi, Manashi Bagchi, Hiroyoshi Moriyama, and Fereidoon Shahidi.
2013 John Wiley & Sons, Ltd. Published 2013 by John Wiley & Sons, Ltd.
FDA and Nanotech: Baby Steps Lead to Regulatory Uncertainty 721 Box 41.1 Questions for the FDA to c onsider r egarding n anogovernance as it fulfi lls its mission of
safeguarding public health.
● When will nanotech take prominence on the FDA ’ s ● Should there be a wider coordinated effort on the part of federal agencies to review, amend, or create nano - ● It is likely that various marketed nanoproducts (e.g., regulations where appropriate and warranted? Who in sunscreens containing zinc oxide and titanium dioxide) addition to the FDA should be given the key responsi- warrant some sort of safety labeling to alert the unsus- bility to regulate nanomedical products for human pecting consumer. Are most nanomaterials used in ● Can nanotech, as applied to public health, be solely ● Are nanoscience and nanotechnology moving too fast regulated under existing regulations and authorities? for meaningful FDA review to take place? Can regula- tions truly tame the vastness encompassed by “ nano ” ? products containing nanomaterials or involving nano- ● As a general rule, should industry input drive the for- technology or should they be limited to only a subset mulation of appropriate rules and regulations by ● It appears to this author that there is a general lack of ● It is clear that the FDA is pushing industry to provide strategic planning, effective collaboration and cohesion the agency with product - specifi c data for areas like among federal agencies with respect to a nanogover- cosmetics, where the FDA lacks statutory pre - market nance framework. In fact, in 2012, the President review authority. Are such voluntary industry mea- Council of Advisors on Science and Technology (PCAST) concluded that “ individual agency contribu- ● Is the “ broadly inclusive approach ” of considering tions” to the NNI strategic plan “ lack the cohesion of whether FDA - regulated products containing nanoma- terials or involving nanotechnolgy appropriate or uncoordinated effort hurt venture and commercializa- ● It does not appear that the present nanotech - specifi c To date, the FDA has not offi cially embraced the review process/regulatory framework at the FDA is narrow defi nition of nanotechnology proposed by the appropriately based on current science. Has the FDA NNI (Section 41.2 ). What is the “ offi cial ” position of the kept pace with emerging advances in nanotech R & D FDA regarding the defi nition of nanotechnology, with respect to predicting, defi ning, measuring and nanoscale, nanomaterials, and nanomedicine? monitoring potential “ nanotoxicities ” ? already on the books. There are hundreds, if not mulate data and formulate testing criteria to thousands, of nanoproducts in the market for ensure the development of safe and effi cacious human use, but little is known of their health risks, safety data, or toxicity profi les. Even less In 2011, the FDA reopened a dialog on nanotech is known of nanoproducts that are released into regulation when it published proposed guidelines the environment that can potentially contact on how the agency will identify whether nanoma- humans. Then, there are products such as cosmet- terials have been used in FDA - regulated products. ics that are fl ooding the market but are not even However, since these guidelines were published, there has been no concrete movement on this issue. Under the current regulatory regime, it continues Meanwhile, evidence continues to mount that many (if not most) nanoproducts inherently (e.g., nanoparticles) are presumed to be “ bioequiv- possess novel size - based properties and toxicity profi les. This scientifi c fact has been largely ignored Thus, manufacturers of nanoproducts are neither by the FDA, and the agency continues to adopt a required to obtain premarket approval from the precautionary approach to the issue in hopes of countering negative publicity. The FDA has simply product labels at this time. These nanoproducts, maintained the status quo with regard to its regula- whether they are a drug, device, biologic, or com- tory policies pertaining to nanotech. As a result, it bination of any of these, are creating challenges for the FDA regulators as they struggle to accu- 41.2 Defi ning nanotechnology in the
permeability and retention (EPR) effect, that makes context of medicine – Does size matter?
nanoparticle anticancer drug delivery an attractive option, typically operates in a range of 100 – 400 nm. One of the major problems that regulators, policy- Liposomes in a size range of 150 – 200 nm have been makers, researchers, and lawyers continue to face shown to have a greater blood residence time than regarding nanotechnology is the confusion about its defi nition [2, 3] . Although the term is widely nanoparticles via macrophage can also be accom- used, there is no internationally acceptable defi ni- plished in ranges beyond the arbitrary cut - off of tion or nomenclature for it. In fact, nanotechnology nm. Moreover, the NNI defi nition excludes is a misnomer, since it is not one technology but encompasses many technical and scientifi c fi elds like medicine, materials science, chemistry, physics, 1 nm), a scale that is included within the defi nition engineering, and biology. One can view it as an of nanotechnology by many nanoscientists. umbrella term used to defi ne products, processes, Add to this confusion the fact that nanotechnol- and properties at the nano/microscale. In this ogy is nothing new. For example, nanoscale carbon chapter, conforming to convention, the applica- particles ( “ high - tech soot nanoparticles ” ) have tions and products of nanotechnology as they been used as a reinforcing additive in tires for over relate to medicine or pharma will be referred to as a century. Another example is that of protein vac- nanomedicines. Alternate analogous terminology cines – they squarely fall within the defi nition of used in the scientifi c literature or in patents includes nanotechnology. In fact, many biomolecules are in nanobiotechnology and medical nanotechnology. the nanoscale range. For example, various peptides Nanomedicines include drugs, therapeutics, vac- are similar in size to quantum dots and some cines, and biologicals that are intended to remedy viruses are in the size range of engineered nanoparticles. Hence, most of molecular medicine Numerous defi nitions of nanotechnology have and biotechnology can be classifi ed as nanotech- sprung up over the years. One often cited, yet nology. Technically speaking, biologists were clearly incorrect, defi nition is that proposed in the studying all these nanoscale biomolecules long 1990s by the US National Nanotechnology Initia- before the term “ nanotechnology ” became fashion- tive (NNI), a federal R & D program established by able. The tendency of numerous nanomaterials the US government to coordinate the efforts of gov- to aggregate may also blur the line as to what is ernment agencies involved in nanotechnology. It truly nanoscale. What if the the size of these aggre- simply limits nanotechnology to “ about 1 to 100 gated nanomaterials lies outside of the NNI defi ni- nanometers” [4] . Various US government agencies tion but their characteristics and properties are and offi ces, including the FDA and the US Patent identical to their nanoscale counterparts from and Trademark Offi ce (PTO), continue to use this defi nition based on a sub - 100 nm size. This overly Although the FDA is part of the NNI and partici- rigid NNI defi nition presents numerous diffi cul- pated in the development of the narrow defi nition of nanotechnology, it has not adopted the NNI ’ s range may be important for nanomaterials where defi nition for its own regulatory purposes. Neither quantum effects are critical, this size limitation is has it established a formal regulatory defi nition not critical to a drug company from a formulation, delivery, or effi cacy perspective because the desired nanomedicine. Instead, as of 2012, the agency is or novel physiochemical properties (e.g., improved taking a broadly inclusive approach by determin- bioavailability, reduced toxicities, lower dose, or ing whether FDA - regulated products contain nano- enhanced solubility) may be achieved in a size materials or whether they involve nanotechnology range greater than 100 nm. For example, the plas- (Section 41.3 ). We will have to wait and see if this resonance in gold nanoshells that imparts their unique property as anticancer thermal agents While the 1 – 100 nm real - estate is where much of is due to the fact that their size is around 150 nm nanomedicine operates, having an arbitrary cut - off and not less than 100 nm. Similarly, the enhanced of 100 nm excludes much of the fi eld. In this context, FDA and Nanotech: Baby Steps Lead to Regulatory Uncertainty 723 a size range is irrelevant and has no signifi cance above – is creating challenges for FDA regulators to nanomedicine. In light of this confusing back- as they struggle to accumulate data and formulate ground, the following practical defi nition of nano- testing criteria to ensure the development of safe technology, unconstrained by an arbitrary size limitation, has been developed by the author [2, 3] : tate the regulation of nanoproducts, the FDA has formed a Nanotechnology Task Force, which The design, characterization, production, and issued an FDA Task Force Report in 2007 [14] . It application of structures, devices, and systems concluded that existing regulations were suffi - by controlled manipulation of size and shape ciently comprehensive to ensure the safety of nano- at the nanometer scale (atomic, molecular, and products because these products would undergo macromolecular scale) that produces structures, premarket testing and approval either as new devices, and systems with at least one novel/ drugs under the New Drug Application ( “ NDA ” ) process or, in the case of medical devices, under the Class III Premarket Approval ( “ PMA ” ) process [14, 15] : 41.3 FDA confronts nanotech
FDA ’ s authority over products subject to premar- Professor Gregory N. Mandel, a noted scholar on ket authorization is comprehensive and provides intellectual property law, has highlighted the FDA with the ability to obtain detailed scientifi c inherent limitations of and opportunities for regu- information needed to assess the safety and, as applicable, effectiveness of products, including relevant effects of nanoscale materials. Regulatory systems are designed to handle the technology in place when the regulatory system This conclusion by the FDA in 2007 was errone- is adopted. New technologies place stress on and ously based on the assumption that regulatory disrupt these systems. It is not surprising that an requirements in place would detect any and all advance as transformative as nanotechnology toxicity via the required clinical studies, even raises substantial problems for the existing, mature (some would say “ ossifi ed ” ) regulatory “ nano ” properties. Many experts criticized this regime. This disruption, however, can provide inaccurate extrapolation, especially since most an opportunity to illuminate problems with the existing system and to rethink how emergent technologies are governed. For the fi rst time in nanoversions ” (i.e., approval was based on their history, there is the opportunity to develop a bulk counterparts). In other words, the approvals governance system simultaneously with an were granted based on safety data for equivalent non - nanoversions and the nanoproducts did not There is growing evidence that various nano- undergo the full PMA process or NDA process. products marketed for direct and indirect human It has been the view of the FDA that existing consumption may be unsafe [6, 7] . These products health and safety tests that it uses to assess the could present unexpected human toxicity effects safety of normal - size materials (i.e., non - nanover- due to (i) increased reactivity compared with their sions or bulk counterparts) are generally consid- “ bulk ” counterparts, and (ii) an increased potential ered adequate to assess the health effects of to traverse biological barriers or membranes and nanoproducts [12 – 15] . However, studies have reach or accumulate in tissues and cells owing to established that not all nanoscale materials are their smaller size [8, 9] . In addition, there are con- created equal. Some nanomaterials or products cerns about the occupational and environmental that incorporate nanotechnology may be toxic and risks associated with the manufacture and disposal their toxicities depend upon various factors that are material - specifi c (charge, polarity, chemical Regulating nanoproducts – whether they are a drug, device, biologic, or combination of any of the nanoscale features). Although nanoparticle toxicity is important that manufacturers and sponsors be products and particles often have fundamentally aware of the issues raised by nanoscale materials different properties as compared to their larger and the possible change in the regulatory status/ bulk counterparts [16, 17] . Put differently, “ na - smaller; it often means that it is fundamentally dif- In 2011, the FDA reopened the dialog on nano- ferent, and one cannot presume that it will be safe tech regulation by publishing proposed guidelines or “ bioequivalent ” to its larger bulk counterpart. on how the agency will identify whether nanoma- Let us elaborate this point scientifi cally. It is a terials have been used in FDA - regulated products. fact that materials with a large surface The guidelines were published in the Federal Reg- volume ratio are more reactive than “ monolithic ” ister in 2011 [19] . Their purpose was to help indus- materials. Given this, as the size of a drug particle try and developers identify when to consider the decreases (e.g., from “ micro ” to “ nano ” ), a greater possible regulatory status, safety, effectiveness, or proportion of the atoms of the smaller drug particle health issues that could arise from the use of nano- are located on the surface relative to its core, often materials or nanotech in FDA - regulated products. rendering the smaller drug particle more reactive Specifi cally, this document asks industry to con- than its conventional “ bulk ” or monolithic coun- sider (i) whether an engineered material or end - terpart. In a clinical - setting, this could correspond product has at least one dimension in the nanoscale to a reduction in required dose, thereby improving range (about 1 – 100 nm), or (ii) whether an engi- toxicity profi les and patient compliance. Not only neered material or end - product exhibits properties can this render the drug particle more reactive, but or phenomena (including physical/chemical prop- its dissolution rate, water solubility and saturation erties or biological effects) that are attrib utable to solubility may also increase. This frequently cor- its dimensions, even outside of the nanoscale range relates with enhanced in vivo bioperformance. Fur- (up to 1 μ m). Also in 2011, the FDA commissioner, thermore, as we granulate a drug particle into Dr. Margaret Hamburg, emphasized science - based smaller particles, the total surface area of the smaller particles becomes much greater, again, often making it more water - soluble and increasing Our goal is to regulate these products using the its bioavailability. Finally, nanoparticles have a greater potential for interaction with biological technology remains a top priority within the tissues, and the intrinsic toxicity of any given mass of nanoparticles is greater than that of the same doing so, we will be prepared to usher science, public health, and FDA into a new, more innova- Clearly, the current scope of FDA ’ s regulatory authority is limited. The guiding principle here is Recently in 2012, the FDA commissioner summa- that the FDA regulates end products, not any tech- rized in general terms a “ broadly inclusive initial nology per se. The agency does not regulate nano- approach ” with respect to nanogovernance in a materials or manufacturing processes, but the end two- page policy paper published in Science [21] : products. In other words, the FDA only regulates nanoproducts (i.e., products that incorporate nano- [The] FDA does not categorically judge all prod- technology) and not nanotechnology per se [18] . ucts containing nanomaterials or otherwise Given this, there are serious public health concerns involving the application of nanotechnology as and toxicological risks with the FDA ’ s position. intrinsically benign or harmful. As with other The FDA Task Force Report of 2007 does, however, emerg ing technologies, advances in both basic allude to the need for more oversight of some and applied nanotechnology science may be nanoproducts, but it offers no regulatory remedy unpredictable, rapid, and unevenly distributed across product applications and risk manage-ment tools. Therefore, the optimal regulatory In some cases, the presence of nanoscale materi- approach is iterative, adaptive, and fl exible . . . It is als may change the regulatory status/regulatory iterative by developing and delivering incre- pathway of products. The Task Force believes it mental components of a regulatory system, such FDA and Nanotech: Baby Steps Lead to Regulatory Uncertainty 725 as guidances specifi c to product areas, each as warranted and when ready. It is adaptive by pro- viding a mechanism, within statutory con- straints, to change the rules, presumptions, or pathways for these regulatory components, in light of new information gained from research or from experience in regulating earlier products. And it is fl exible by using all available means, 41.4 Nanoproducts as
ranging from workshops to consultations to combination products?
guidances to rules, in order to match the burden of regulation to its need. (citations removed, Products submitted to the FDA for market approval, including some that may contain nanomaterials or involve nanomedicine, are evaluated according to In spite of these “ baby steps ” by the FDA regard- a category - based system in one of the nine centers ing nanoregulation, most experts continue to criti- that focus on a specifi c area of regulation. For cize its rather lax and uncoordinated effort. As of example, a drug, biologic, or device would be November 2012, no clear guidelines or regulations assigned for evaluation to the Center for Drug have been proposed by the FDA. The “ broadly Evaluation and Research (CDER), the Center for inclusive initial approach ” needs to be expanded Biologics Evaluation and Research (CBER), or the into real - world regulatory guidelines that can be Center for Devices and Radiological Health depended upon by industry and consumers alike. (CDRH), respectively. Obviously, categorizing All in all, US regulatory agencies are in disarray nanoproducts according to this legal FDA classifi - cation is critical owing to the widely divergent much different at regulatory agencies in other regulatory approval standards employed by the countries either [22 – 27] . As numerous nanoprod- FDA [29, 30] . According to the Federal Food, Drug ucts move out of the laboratory and into the clinic, and Cosmetic Act of 1938, the scope of the FDA ’ s US federal agencies such as the FDA [11 – 14, 18 – 19, authority varies from category to category, with the 27, 28] and the PTO [1, 2, 20] continue to struggle strongest authority being over new drugs and to encourage the development of nanoproducts devices and the weakest authority being over cos- while imposing some sort of order. Numerous chal- metics and whole foods [12] . As a result of these lenges confront the FDA as important unanswered variations, the FDA ’ s ability to regulate nanoprod- questions linger (Box 41.1 ). All the while, a steady ucts effectively will depend largely on the category stream of nanoproducts, particularly nanomedi- into which the product seeking approval falls. cines (Table 41.1 ), continue to be approved by the However, certain therapeutics are “ combination FDA under preexisting regulations. A large number products, ” which consist of two or more regulated of these approved nanomedicines have already components (drug, biologic, or device) that are physically, chemically, or otherwise combined or Given this backdrop, investors have been cau- mixed to produce a single entity [31, 32] . In such tious and confused as to what route, if any, the FDA cases, the FDA determines the “ primary mode of will take in regulating nanotechnologies, and to single mode of action of a combination product addressing nano - regulation could have a chilling that provides the most important therapeutic effect on public confi dence and commercialization action. ” This process is frequently imprecise as it is efforts [13, 17, 27] . Meanwhile, various stakehold- not always possible to clearly elucidate a combina- government, industry, academia, and the tion product ’ s PMOA. This is because, at the time public at large – have offered various proposals to of an investigational application, it is not clear regulate nanomedicine. These include [29] : which mode of action provides the most important therapeutic action or because the product has two different equally critical modes of action. ● revising/modifying existing laws and regula- Determining which framework will apply to any combination product is the task of the Offi ce of Table 41.1 Selected FDA-approved nanomedicines. *
Johnson & Johnson Metastatic ovarian patients with chronic kidney disease on dialysis Nanocrystalline fenofi brate Oral tablets reduces elevated plasmaconcentrations of triglycerides, LDL, and total cholesterol and raises abnormally low levels of HDL symptoms, such as hot fl ushes and night sweats in menopausal women Table 41.1 (Continued)
patients who are refractory to or intolerant of conventionalAmphotericin B therapy replacement therapy for patients with severe combined immunodefi ciency disease; adenosine deaminasedefi ciency conjugate of recombinant methionyl human G -CSF(Filgrastim) and monomethoxypolyethyleneglycol) acid, l-alanine, l-tyrosine,and l-lysine) Table 41.1 (Continued)
patients who are refractory to or intolerant of conventionalAmphotericin B *To highlight the nanomedicine landscape, this table only lists FDA -approved nanomedicines. Nanomaterials are not included here unless they serve as nanomedicines per se. FDA -approved imaging or diagnostic agents are omitted from the table. The table also excludes nanomedicines that are (i) in various phases of clinical trials; or (ii) in pre -clinical research, including basic research, bench -science, early animal testing, etc.; or (iii) futuristic nanomedicines that offer revolutionary benefi ts that are impossible to confi rm. A vast majority of these excluded nanomedicines will never be approved by the FDA, let alone commercialized. Note that therapeutic approval by FDA does not necessarily indicate that the nanomedicine is commercially available to consumers. Various factors, in addition to FDA approval, impact the commercialization of nanomedicines. Abbreviations used in table: AIDS, acquired immunodefi ciency syndrome; HDL, high -density lipoprotein; IV, intravenous; LDL, low -density lipoprotein; PEG, polyethylene glycol; PEG -G-CSF, pegylated granulocyte colony -stimulating factor; PEG-hGH, pegylated human growth hormone; SQ, subcutaneous injection; VEGF, vascular endothelial growth factor. Combination Products (OCP). Obviously, the OCP 41.5 Recommendations, conclusions,
will be the fi rst offi ce within the FDA to review and future prospects
many nanoproducts. The OCP makes its assign-ments on a case - by - case basis depending on the Advances in medical or health - related nanotech PMOA. But this process is again, frequently impre- and the FDA system for governing it are inevitably cise as it is not always possible to clearly elucidate intertwined. However, the “ baby steps ” the agency a combination product ’ s PMOA, often because at has undertaken over the past decade have led to the time of an investigational application it is not regulatory uncertainty. There are some excellent clear which mode of action provides the most recent reports highlighting this issue [34 – 39] . important therapeutic action, or the product has It appears that the Environmental Protection two different equally critical modes of action. It is Agency (EPA) is leading the way in nanomaterial very possible that nanoproducts will blur the regulation [27, 39] . However, numerous challenges distinction between mechanical and chemical confront federal agencies such as the FDA regard- action at the nanoscale or that they may be both ing reform of regulatory guidance for nano therapeutic and diagnostic in operation. In fact, toxicological evaluation. Among these are the this spanning of regulatory boundaries between limited availability of information correlating the the various categories has often resulted in incon- physicochemical properties of nanomaterials with risks, and a lack of validated preclinical screens FDA and Nanotech: Baby Steps Lead to Regulatory Uncertainty 729 and animal models for the assessment of nanoma- nomenclature and the defi nition of nanotech terials [40] . The toxicity of many nanoscale materi- als will not be fully apparent until they are widely So far, the process of converting basic research in distributed and their exposure is felt by a diverse nanomedicine into commercially viable products population. Therefore, postmarket tracking or a has been diffi cult. Securing valid, defensible patent surveillance system must be adopted (along with protection from the PTO [2, 3, 44] along with clear any proposed legislation) to assist in product regulatory/safety guidelines from the FDA [5, 11 – recalls. Although toxicological testing for health 13, 18, 21, 27, 28, 34 – 38] is critical to any commercial- risks of nanoparticles is not currently a complete science [41] , it is crucial to monitor their unique properties (if any) that may lead to serious adverse nanomedicines (Table 41.1 ) have been launched, effects and toxicity. Because it is well established and many more are poised to receive regulatory that premarket testing of drugs will not detect approval [16, 17] . Furthermore, there are currently all adverse reac tions [42] , it is essential that long - hundreds of unregulated and unlabeled nanoprod- term testing of nanoscale materials be in place to ucts on the market that incorporate engineered allow safety testing. In this regard, toxicity data nanoparticles and nanomaterials. Tons of these specifi c to nanomaterials needs to be collected continue to be produced and recycled annually. It and an effective risk research strategy devised. would be best if the FDA were to acknowledge that However, none of this will be possible if suffi cient funding is not allocated to federal agencies such as “ nanoformulations ” ) are indeed new chemical entities (NCEs). When warranted, nanoversions of Although in the past the FDA has downplayed active ingredients should be treated by the FDA as nanoproduct safety issues [43] and the need for NCEs. This will ensure that drugs, biologics, etc. modifi cation of the current regulatory regime, it is that have been previously approved by the FDA beginning to recognize that there are knowledge but later modifi ed as nanoversions will undergo a gaps and a lack of scientifi c expertise in these areas new and rigorous round of safety testing in order [13, 14, 21, 27, 28] . The FDA is also encountering problems in applying its current regulations to all It is diffi cult to foresee how nanoproducts will nanoproducts, as well as in placing these products be regulated. Size changes within the nanoscale into its present classifi cation scheme. However, if range and the potential unpredictability arising the FDA plans properly now to mitigate foreseeable therefrom are likely to add complexity to the FDA problems in the future, it will go a long way toward review process. The traditional product - by - prod- overcoming scientifi c, ethical, commercialization, uct regulatory model that the FDA currently and legal obstacles. In any case, regulating these employs may not be effective for all nanoproducts products will require greater cooperation between because it may be diffi cult to put them into drug companies, policymakers, and the FDA. In one of the available traditional classifi cations light of these challenges, a multidisciplinary team (i.e., drug, device, biologic, or combination prod- of experienced regulators from the drug, biologic, uct). However, in many cases, the FDA may and device areas of the FDA (working with a scien- view nanoproducts as technologically overlapping tifi c panel of experts) should be formed to assist (miniaturization will blur distinctions between dif- across the board. Box 41.2 lists recommendations ferent categories) from a review perspective, and for the FDA to consider as it tackles the regulatory therefore consider them as highly integrated nano- medical combination products. These complexities Because the FDA regulates only the claims are likely to pose additional challenges and review made by the manufacturer ( “ product sponsor ” ), issues for the FDA [13, 27, 28, 32, 33] . if no nanoclaims regarding the manufacture or Currently, there are few reliable means to iden- performance of the product are specifi ed, the tify marketed “ nano - containing ” products, and agency may be left in the dark during the prod- consumers are unable to judge for themselves uct review and approval process. Related to this which ones may be toxic. Given this, the FDA and as discussed previously is the critical issue of Box 41.2 Recommendations for the FDA r egarding n anomedicine r egulation.
᭺ Develop guidance that provides specifi cs as to ᭺ On a case - by - case basis and in conjunction with industry, identify unique safety issues associated ᭺ Share data in an internationally harmonized ᭺ Actively seek product safety data from industry where FDA statutory authority exists for pre ᭺ Create reference classes for nanomaterials that are ᭺ Incentivise and encourage voluntary industry ᭺ Develop consensus testing protocols to provide submissions of safety data on nanomaterials or benchmarks for the creation of classes of nanoscale products that incorporate nanotechnology prior to market launch, especially in cases (e.g., cosmetics) ᭺ Create uniform standards for and/or working defi - where the FDA lacks statutory authority for pre - ᭺ Refi ne the current defi nitions of nanomaterial, ᭺ Correlate physiochemical properties with in vivo nanotechnology, nanoscale and nanomedicine for biological behavior and therapeutic outcome. ᭺ Develop a research strategy that involves adsorp- ᭺ Explore international harmonization efforts and tion, distribution, metabolism, and excretion ᭺ Involve standard - setting organizations such as the ᭺ Develop toxicology tests and conduct physico- International Organization for Standardization chemical characterization (PCC) studies for ᭺ Consult and collaborate with other federal agencies ᭺ Understand mass transport across membranes and ᭺ Determine accurate biodistribution profi les follow- ᭺ Assist in developing unique tools and techniques ing systemic administration via a specifi c route. ᭺ Develop standards that correlate the biodistribu- tion of various nanomaterials with safety/effi cacy by using parameters such as size, surface charge, ᭺ Develop mathematical and computer models for stability, surface characteristics, solubility, crystal- ᭺ Monitor quality, safety, product liability, and ᭺ With industry input, create a databank relating to the interactions between nanomaterials and bio- ᭺ Reevaluate the current FDA classifi cation scheme. ᭺ Develop a classifi cation based on (a) function or (b) ᭺ Adapt existing methodologies, as well as develop new paradigms for evaluating data pertaining to safety and effi cacy of nanomedical products. labeling on a case - by - case basis, balancing the pub- ucts. Whether the FDA eventually creates new lic ’ s desire for such labeling with the likelihood regulations, tweaks existing ones, or establishes a that the public may shy away from some benefi cial new regulatory center to handle nanoproducts, for products given the negative image of certain the time being it should at least look at nanoprod- ucts on a case - by - case basis. The FDA should not attempt regulation of nanomedicine by applying review will continue to be subjected to an uncer- existing statutes alone, especially where scientifi c tain regulatory pathway. This could negatively evidence suggests otherwise. Incorporating nano- impact venture funding, stifl e research and devel- medicine regulation into the current regulatory opment in nanomedicine, and erode public accep- scheme is unwise. Regulation of nanotech must tance of nanoproducts. The end - result of this could balance innovation and R & D with the principle be a delay in or loss of commercialized nanoprod- of ensuring maximum public health protection FDA and Nanotech: Baby Steps Lead to Regulatory Uncertainty 731 and safety. Regulatory oversight must evolve in (editor), Bionanotechnology: Global Prospects . CRC Press , Boca Raton, FL , 2009 , pp. 309 – 337 . concert with newer generations of nanomedical 4. National Nanotechnology Initiative . Available at: http://www.nano.gov/ [last visited Oct. 15, 2012 ]. It is hoped that the “ baby steps ” that the FDA 5. Mandel , G. Nanotechnology governance . Alabama has taken in the past decade regarding nanogover- Law Review 59 ( 5 ), 1323 – 1384 ( 2008 ).
nance will translate into more meaningful, fl exible 6. De Jong , W.H. ; Borm , P.J.A. Drug delivery and and science - based guidance in the near future. In nanoparticles: applications and hazards . International the end, the long - term prognosis of nanomedicine Journal of Nanomedicine 3 , 133 – 149 ( 2008 ).
will hinge on effective, valid nanogovernance 7. Sanvicens , N. ; Marco , M.P. Multifunctional nanopar- requiring the full commitment of various regula- properties and prospects for their use in tory agencies such as the FDA, as well as the regu- human medicine . Trends in Biotechnology 26 , 425 – 433
lated community such as the manufacturing sector. 8. Bawarski , W.E. ; Chidlowsky , E. ; Bharali , D.J. ; Mousa , S.A. Emerging nanopharmaceuticals . Nanomedicine:
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41.6 Statement of disclosure/
confl icts of interest
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