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5 Standards and Regulation Referencing a Congressional Research Service paper (Schierow, 2008), Dr. Kulinowski pointed out that there are numerous challenges involved in regulating nanotechnology because of a diversity of nanomaterials and their applications, a lack of characterization data, and a lack of standard- ization in nomenclature, metrics, and materials, and possibly inadequate statutory authority. In addition, the multidisciplinary nature of nanotech- nology endeavors makes them difficult to communicate, the information needed to adequately regulate nanotechnologies may be proprietary, and there are limited resources devoted to the task. NANOMATERIAL DEFINITIONS Defining nanomaterials for regulatory purposes is a significant hurdle that has yet to be overcome. Dr. Duncan noted that some groups have defined the upper limit of nanomaterials as being those that measure 1000 nanometers, which covers many nano-size products already on the market. In contrast, the NNI and the FDA define that upper limit as being 100 nm. The NCL has a cutoff of 220 nanometers based on the fact that biological filters in the body are that size. Some of the fenestrations in the liver and spleen are about 250 nanometers in size, according to Dr. McNeil. “We know we have some issues here with the terminology, and mak- ing the way we speak connect to something that a regulator or decision- maker in a company would be able to act on,” Dr. Kulinowski said. 53

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54 NANOTECHNOLOGY AND ONCOLOGY How nanomaterials are defined profoundly affect how they are regu- lated, she pointed out. For an example, Dr. Kulinowski showed how the EPA evolved in its regulation of nanomaterials. Initially the agency claimed that nanomaterials were not considered new chemicals, with more of an emphasis on the molecular identity of the material and not its size, shape, or surface. The agency regulated nanomaterials as falling under the domain of the Toxic Substances Control Act, and engaged in a voluntary data gathering approach initially. But now the EPA is starting to define nanoscale materials as new uses of existing chemicals, she said, which allows the agency to impose some additional reporting require- ments, toxicology testing, and specific mandates for worker protection, as well as mandatory data collection. “The EPA is shifting their emphasis from a very specific chemical defi- nition of how the atoms are connected, to how does it act, what does it do, is it biologically or environmentally different, and does it have different physical and chemical properties that could matter in an environmental or biological system,” Dr. Kulinowski said. Several speakers called for more standards in terminology and met- rics. Dr. Desai noted the importance of having an appropriate descriptive term in the label or package insert of a nanomedicine so that the clini- cian and patients fully understand what they are using and can make an informed decision. But Abraxane’s particle size is 130 nanometers (nm) so the FDA did not allow his company to call Abraxane a nanoparticle because it was bigger than their 100 nm cutoff for nanoproducts. He added that other regulatory agencies internationally accepted Abraxane being labeled as a nanoparticle. Dr. Sackner-Bernstein implied there might be flexibility in the FDA definition of nanotechnology. “It’s about size and properties, but basi- cally if you think it’s going to behave differently, come talk to us. The last thing anybody wants is for a product to get far along and then to discover a problem. Discussing this up front, even if you’re not sure, is a way to address this issue,” he said. Quoting from an FDA document (FDA, 2009). Dr. Duncan added “It is quite likely that new therapeutic benefits are being derived from products that are smaller than their traditional form, but fall above the 100 nm size-range limit of nanotechnology…. Particle size is not the issue. As new toxicological risks that derive from the new materials and/or new conformations of existing materials are identified, new tests will be required.” Dr. Duncan stressed the importance of accurate categorization of materials and products. “What if we suddenly decided today that every transport system is called a plane. If we try and control a boat or a bicycle or a train using the same regulation we use for a plane it is not helpful.” Dr. Gaspar agreed, “This is not irrelevant, because the problem is that

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55 STANDARDS AND REGULATION if we start calling different things the same name it will be a complete mess,” he said. NANOTECHNOLOGY STANDARDS Some progress in developing nanotechnology standards has been made. Dr. Zhao and his colleagues at the CAS have published 21 stan- dards for nanoscience and nanotechnology in China, three of which were adopted by the International Standards Organization. Dr. McNeil noted that standards development is one of the goals of the Nanotechnology Characterization Laboratory and that it has collaborated with the ISO and the ASTM to finalize three formal voluntary consensus standards for bio- compatibility testing of nanomaterials intended for medical applications. In collaboration with NIST, NCL also developed three gold nanoparticle reference materials so results can be compared between laboratories. The ISO has been creating standards and definitions for different nanotechnologies, according to Dr. Duncan, but these will not be broadly applicable to all the areas for which definitions and standards are needed. She stressed the need to limit definitions for nanotechnologies to the sec- tors in which they will be used. “If we have a particular class of materials or consumer products that needs a specific definition for regulation, they should come up with it in that sector and not try and impose it on all the other sectors,” she said. But Dr. Desai noted there is still a lack of standards for what types of tests are needed for nanomedicines. “There is no standard or general list of tests, so you have to put these tests that together build understanding of the product, and then convince the regulatory agencies that these are the tests that are needed,” he said. Dr. Libutti said that during his discus- sions with the FDA about his clinical trial of nanoparticles of TNF, the agency made it clear that they wanted to know the fate of the particles, how the particles would be tracked, and any additional toxicities that might occur based on the fact that they are a nanoparticle. Consequently Dr. Libutti built into the trial the ability to monitor for the presence of the particles in the urine, serum, and various tissues. One of the important components of this trial, Dr. Libutti said was the ability to perform tissue biopsies in real time after the patients received the experimental nanopar- ticles. Using these biopsies, the investigators could assess whether the nanoparticles hit their targets. One participant at the workshop noted that it is ironic that one has to define the trafficking of nanoparticles, when there is no such requirement for any of the small molecules that are administered clinically. “If you give systemic chemotherapy, you don’t have to demonstrate that it traffics any- where. You do a randomized controlled trial and you see what happens

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56 NANOTECHNOLOGY AND ONCOLOGY with survival basically. Are we creating a new more robust paradigm that will only be applied to nanotechnology?” the participant said. Dr. Libutti responded by noting the bar for nanomedicines does seem to be set differently or higher than for conventional small molecules, but he added “maybe that is not such a bad thing, because I think we are learning a lot doing that. I certainly wish more of that were done for the so-called targeted molecular therapies, because for many of them, we don’t even know that that they are actually hitting their target.” Dr. Josephson noted that for nanomedicines that are injected, the regulatory framework is well established “because there’s a long history that precedes the word nano. If there’s a problem, it comes up in promot- ing nano as new, when it’s not new as far as injectable parenterals go, nor is the history of how to handle these materials,” he said. WORKING WITH THE FDA Dr. Desai stressed that “You need to work with the FDA and any other regulatory agency to enable understanding of the technology, whether it is from the point of view of physical–chemical characterization or from the point of view of manufacturing, because the FDA is not necessarily the experts. It is your job to explain and educate the FDA as to the particulari- ties of your product.” He noted that most nanomedicines will likely require nonstandard type equipment for their manufacturing, with which the FDA will be unfamiliar. “Our experience with the FDA was very positive as they were keen to learn,” Dr. Desai said. “They came over to our manufacturing site for an education in nanotechnology manufacturing.” Dr. McNeil concurred the FDA’s willingness to be open to new infor- mation, citing how he has shown them the difficulty of addressing some of the questions they were asking of nanotechnology product sponsors. After almost three years of collaborative research with NIST that was unable to fully answer one of those questions, he approached the review- ers at the FDA and told them that the question is difficult to address, but that they were finding that it was not germane to biocompatibility. “As soon as that information was known, they realized that it may not be all that important for that specific application. My interactions with the FDA have been very positive,” Dr. McNeil said. Dr. Sackner-Bernstein noted that the FDA recently formed a council to focus on how to facilitate medical device innovation, which might include some nanotechnologies. “This council is going to focus on understanding the barriers to product development, and make sure those barriers are aligned with the clinical need. We’re not going to make it easy, but we’re going to make it appropriate, and that kind of appropriateness and pre-

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57 STANDARDS AND REGULATION dictability is what’s going to help innovators drive forward new devices to treat these needs,” Dr. Sackner-Bernstein said. He also pointed out that FDA is working to have more integration of scientific expertise outside the agency, and that the FDA’s internal scien- tists are working with NIST to learn more about the scientific and techni- cal aspects of nanomaterials. But he pointed out that the FDA is always going to be behind the scientific knowledge curve. “One of the criticisms is that the agency doesn’t have enough scientists to understand new sci- ence. Well, that’s never going to happen, because if it’s new, there’s going to be only 5 or 10 people in the world who are there because they want to break the new science and develop the new products, not because they want to work at the FDA,” he said. Dr. Grodzinski added, “We, in both government funding and regulatory agencies, are trying as hard as we can, so don’t get too disappointed with us.” Dr. Kulinoski suggested incentives to produce and communicate risk data in a “regulator-ready” form so it not only reaches the government officials who need to consume the information, but it is written such that they can understand it and can incorporate it into their decision making. Combination Products What makes regulation of nanomedicines particularly challenging is that they often cross FDA regulatory boundaries by combining mul- tiple therapeutics, therapeutics with diagnostics, or other devices with therapeutics. Dr. Desai noted that the multiple components of many nano- therapeutics may require consultation with more than one center at the FDA. For example, because Abraxane is comprised of both the biologic albumin and the small-molecule drug paclitaxel, it was regulated under FDA’s drugs division, but there was a consult with the biologics division because of the albumin. Dr. Duncan quoted from an FDA website (FDA, 2009), “FDA expects many nanotechnology products that we regulate to span the regulatory boundaries between pharmaceuticals, medical devices and biological. These will be regulated as ‘combination products’ for which the regula- tory pathway has been established by statute.” Dr. Gaspar applauded FDA’s combination product regulation pathway, but in regards to diag- nostics that can predict who will respond to specific therapeutics and should therefore undergo regulatory review simultaneously with the therapeutic, Dr. Gaspar added, “On both sides of the Atlantic we haven’t found a common regulatory path that can look at this in an integrated form.”

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58 NANOTECHNOLOGY AND ONCOLOGY Generics and Follow-On Products A major regulatory gap that needs to be addressed is how to regulate generic versions of nanomedicines, and what Dr. Gaspar termed “follow- on products” that are related to old products that were previously not classified as nanoparticles, but are considered nanoparticles today. “We are facing these problems as we speak now—they are already on the table as the generics are already here,” Dr. Gaspar said. For example, Doxil is a liposome encapsulated chemotherapeutic that is also PEGylated. “When we look at potential generic formulations of this, the differences on the surface properties related to the manufacturing process are theoretically so wide that we currently cannot conceive of having a generic formula- tion going through as a generic product,” he said. “We don’t have the possibility, based only on physical–chemical data, to translate equivalence between the innovative product and its generic version.” Dr. Gaspar noted that the classical regulatory approach for a generic product formulated as an intravenous aqueous solution, such as iron oxide colloids for iron replacement therapy, does not require pharmaco- kinetic assessments, even if the formulation contains nanoparticles. He also pointed out that not only can the surface characteristics of a generic nanomedicine differ from its original formulation, but that the manufac- turing process can be completely different. The so-called generic formula- tions of iron-oxide nanoparticles behave differently in animal and clinical studies, he said. Dr. Desai concurred that generic nanomedicines pose potential regu- latory problems. “The generics ultimately will have to show that they are equivalent to the nanotechnology product in question, so what tests would they use to show this?” he asked, and stressed that it is important to fully characterize nanomaterials, not only so they pass regulatory mus- ter today, but so there is a basis in which to compare generic versions that are created later. SETTING REGULATORY POLICY There was much discussion at the workshop of how much regula- tion is enough regulation, with some participants advocating for clos- ing current regulation gaps, but not overregulating nanotechnologies such that innovation is stifled. Dr. Duncan noted that overregulation of clinical research in the United Kingdom has reduced productivity without enhancing safety via excessive bureaucratic requirements and procedures. This resulted in the pharmaceutical industry now recruiting only one- third the number of patients to clinical trials in the UK compared with the period before the UK revamped its clinical research oversight so as to harmonize with European directives.

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59 STANDARDS AND REGULATION “I hope the standards and terminology that we’re using and putting into the regulatory setting will be appropriate to make things a safe and as low-risk as possible, but will not take us back to a position that’s stopping these sorts of technologies going forward,” Dr. Duncan said. Dr. Barker agreed saying “I hope we don’t overregulate this field to a point that we can’t do anything.” Dr. Gaspar stressed that a new regulatory framework for nanomedi- cines is not necessary. He noted that current regulation of nanotechnolo- gies continues to change as the science is updated. “So we don’t need a legally binding, completely different regulatory system in order to inte- grate science,” he said. But Dr. Gaspar added “We need to be very careful with the gaps between existing regulations, because those gaps are the traps where once we have an accident that is labeled nanotechnology in medicine, it will impact all of the overall products across the board in different technologies.” Dr. Zhao concurred with the need to be proactive in the risk evaluation of nanotechnologies so accidents do not occur that turn the public against the field. He suggested verifying the suitability of regulations already in place for nanoproducts, and creating new laws and regulations to cover any regulation gaps that might lead to nanotoxicities. Both Dr. Gaspar and Dr. Duncan called for regulating medical nan- otechnology products versus regulating nanotechnology. “Nanomedi- cine is not focused on the processes of nanomedicine technology, but is focused on the patients. And that completely changes the environment in which we are discussing the science and the regulation,” Dr. Gaspar said. Dr. Kulinowski noted recent attempts various states have made to close regulatory gaps they see in nanotechnology oversight. A recent report by the Wilson Center (Keiner, 2008) looked at the potential for state and local governments to take action in the absence of strong fed- eral action. This report found that in many cases, states have been given the authority to go even beyond what the federal government imposes. “States can begin to fill in the gaps where federal law is silent,” she said, “And we’re beginning to see that in the State of California.” The State of California has exercised its authority under a recent new law called the Health and Safety Code, which allows it to require manufacturers to produce information. Using this law, the state required all carbon nanotube manufacturers or importers to provide analytical test methods, transport information and other relevant health and safety data by January 2010. They were given a year to respond. “They’ve taken a very cooperative and deliberative model for engagement with indus- try. They’ve had lots of public seminars, invited stakeholder testimony and input, and been extremely collaborative. It’s really something to watch,” Dr. Kulinowski said. The State of California plans to impose

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60 NANOTECHNOLOGY AND ONCOLOGY similar requirements on the manufacturers and importers of other nano- materials, such as nanoscale metal particles. Dr. Kulinowski added that this illustrates that nanotechnology regu- lation can occur in a number of different ways from soft standards put out by scientific societies to more formal regulations by various state and federal agencies, including FDA, EPA, and OSHA. COLLABORATION WITH AND BETWEEN REGULATORY AGENCIES Several of the speakers spoke of the need for collaboration in the over- sight and regulation of nanotechnology and nanomedicines. Dr. Sackner- Bernstein noted a recent fruitful collaboration between DARPA and the FDA in the development of blood farming using stem cells, which he said could serve as a model for collaboration between government agencies. At the time there was no regulatory pathway for the type of product DARPA was trying to create, so the agency collaborated with the FDA early on in the development of their blood farming program. FDA helped them deter- mine the testing that needed to be done on their product so that eventually it would make it to the market. In a similar manner, a researcher funded through NIH who is trying to develop a nanoscale device could ask the NIH project officer to meet with the FDA and determine the information the agency will require of the device in order for it to be commercialized. “That would be something we certainly would be willing to explore, just as we did with DARPA,” Dr. Sackner-Bernstein said. Dr. Gaspar suggested looking at ways to integrate academia, industry, and regulators during the entire product life cycle, including pre- and post-market phases. “I think that is the way to move forward,” he said. He recently committed to being the coordinator of the EUFETS (a European contract manufacturer for cell and gene therapy) Regulation and Science Committee, which is integrating European regulatory organization and scientific societies. Dr. Sackner-Bernstein concurred that the FDA favors taking a life-cycle approach to regulating medical products. Dr. Gaspar, Dr. Duncan, and Dr. Zhao also called for global coopera- tion for nanosafety and regulation of nanotechnologies. Dr. Gaspar sug- gested the European Medicines Agency (EMEA) the FDA, the European Committee for Standardization (CEN), the International Organization for Standardization (ISO), the Organisation of Economic Co-operation and Development (OECD), and especially with the International Conference on Harmonisation of Technical Requirements for Registration of Pharma- ceuticals for Human Use (ICH) work together to forge consistent regula- tions and standards in nanomedicine. Dr. Gaspar pointed out that the Predictive Safety Testing Consortium

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61 STANDARDS AND REGULATION is a good example of global collaboration to improve the efficiency of pro- cedures. He suggested establishing institutional mechanisms for global cooperation based on specific goals and a specific timeline. “We need to act globally as soon as possible on the research and development phase,” he said. Despite differing national infrastructures, “We have a lot to gain in terms of communication across the Atlantic,” Dr. Gaspar said. Dr. Duncan added, “Every region wants to have its nanotechnology institute and do everything. But we should have the best in the world get together and solve the [regulation] problem.” Aiding that global cooperation was the first International Workshop on Nanomedicines, which was planned for September of 2010, and was sponsored by the European Medicines Agency. A report from that work- shop will identify issues and emerging science aspects, which may assist future developments in the field and be relevant to future regulatory con- siderations. Dr. Zhao noted the first Global Congress on Nanoengineering for Medicine and Biology, which was held in Houston in February 2010. He also said the first US–China symposium on Cancer Nanotechnology and Nanomedicine was held in Beijing in October 2008, and an interna- tional meeting on nanostandardization of biotechnology that was held in Shanghai in 2009 and had representatives from 26 countries.

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