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While many definitions for nanotechnology exist, the National Nanotechnology Initiative (NNI) (a federal R&D program established to coordinate the multi-agency efforts in nanoscale science, engineering, and technology, in which FDA and 22 other federal agencies participate) calls it "nanotechnology" only if it involves all of the following:
For more information, see http://www.nano.gov/html/facts/whatIsNano.html.
The FDA has not established its own formal definition, though the agency participated in the development of the NNI definition of "nanotechnology." Using that definition, nanotechnology relevant to the FDA might include research and technology development that both satisfies the NNI definition and relates to a product regulated by FDA.
Specific references to the types of products FDA regulates, the FDA "Centers" responsible for their regulation, and guidance on the regulatory processes are found on the FDA Internet Web Site (http://www.fda.gov/). The following list is provided only for illustrative purposes:
FDA has a Grants Program in support of Orphan Products Research and Development. FDA does not otherwise conduct research in support of particular product applications. FDA does not have a grants program to support other research in non-FDA laboratories. FDA conducts research in several of its Centers to understand the characteristics of nano-materials and nanotechnology processes. Research interests include any areas related to the use of nanoproducts that FDA needs to consider in the regulation of these products. As an example of current research, FDA is collaborating with the National Institutes of Health, National Institute of Environmental Health Sciences (NIH/NIEHS) on studies, as part of the National Toxicology Program, examining the skin absorption and phototoxicity of nano-sized titanium dioxide and zinc oxide preparations used in sunscreens.
Issues that FDA anticipates include:
As noted above, FDA only regulates certain categories of products. Existing requirements may be adequate for most nanotechnology products that we will regulate. These products are in the same size-range as the cells and molecules with which FDA reviewers and scientists associate every day. In particular, every degradable medical device or injectable pharmaceutical generates particulates that pass through this size range during the processes of their absorption and elimination by the body. To date, FDA has no knowledge of reports of adverse reactions related to the "nano" size of resorbable drug or medical device products. If new risks are identified, arising from new materials or manufacturing techniques for example, new tests or other requirements may be needed.
FDA is aware of several FDA regulated products that employ nanotechnology. However, to date, few manufacturers of regulated products have claimed the use of nanotechnology in the manufacture of their products or made any nanotechnology claims for the finished product. FDA is aware that a few cosmetic products claim to contain nanoparticles to increase the stability or modify release of ingredients. Similarly FDA is aware of nanotechnology-related claims made for certain sunscreens. We are currently not aware of any safety concerns but FDA is planning additional studies to examine the effects of select nanoparticles on skin penetration.
Coordination of activities and policy of the US Government regulatory agencies is facilitated by FDA’s participation in the National Science and Technology Council, Subcommittee on Nanoscale Science, Engineering and Technology (NSET) and its Nanotechnology Environmental and Health Implications (NEHI) working group.
Current policy regarding combination products helps prevent duplication of effort and a protracted approval process. If the product meets the definition of a combination product (i.e., drug-device, drug-biologic, or device-biologic products), it will be assigned to an Agency center that will have primary jurisdiction for its regulation. The assignment of a “lead center” is based upon a determination of the “primary mode of action” (PMOA) of the combination product. For example, if the PMOA of a combination product is that of a biological product, then the combination product would be assigned to the Agency component responsible for premarket review of that biological product.
FDA published a proposed rule defining the primary mode of action of a combination product in the May 7, 2004, Federal Register. The proposed rule defines primary mode of action as “the single mode of action of a combination product that provides the most important therapeutic action of the combination product.” In some cases, neither FDA nor the sponsor can determine the most important therapeutic action at the time a request is submitted. A combination product may also have two independent modes of action, neither of which is subordinate to the other. To resolve these types of questions, the proposed rule describes an algorithm FDA would follow to determine the center assignment. The algorithm would direct a center assignment based on consistency with other combination products raising similar types of safety and effectiveness questions, or to the center with the most expertise to evaluate the most significant safety and effectiveness questions raised by the combination product.
Depending upon the type of combination product, approval, clearance or licensure may be obtained through submission of a single marketing application, or through separate marketing applications for the individual constituent parts of the combination product. For most combination products, a single marketing application is sufficient for the product’s approval, clearance or licensure.
The Office of Combination Products is responsible for developing policies and processes to help clarify the regulation of combination products, and is available as a resource to combination product manufacturers throughout the development of a combination product. Its website at www.fda.gov/oc/combination includes regulations, guidance documents, jurisdictional information, answers to frequently asked questions, and a variety of other information related to combination product development and regulation.
Some of these products are regulated as drugs, some as cosmetics, and some as devices, depending on medical claims made for the product and the product's mode of action. Cosmetics must be safe and truthfully labeled. The manufacturer of a cosmetic product is responsible for the safety of the product and its ingredients. Applications for new drugs must demonstrate the product's safety and efficacy or the product's bioequivalence to a previously approved drug product. Device applications must show a reasonable assurance of safety and effectiveness or substantial equivalence to a legally marketed device. Although proprietary product data may not be available, published research may include both analysis and summaries of these data
Watch for federal register announcements, and posting on FDA's website, of new guidance.
There is no international regulation of nanoproducts or the underlying nanotechnology. FDA participates in multinational organizations, such as the Organization for Economic Cooperation and Development, ASTM International, and the International Organization for Standardization, where cooperative work on nanotechnology has been suggested. FDA will also work with its foreign regulatory colleagues to share perspectives and information on regulation of nanotechnology."
The Office of the Commissioner FDA has established a NanoTechnology Interest Group (NTIG) on which all FDA’s Centers and all FDA Offices that report directly to the Office of the Commissioner participate. Within the Centers of FDA, staffs have established multidisciplinary working groups. The goal of these FDA working groups is to share information about nanotechnology and to provide a level of coordination of review for the various product types. The working groups are charged with identifying and defining the regulatory challenges in the various review disciplines and to propose a path forward. The mission of the groups is then to propose solutions to overcome these challenges.
The current regulations and Good Manufacturing Practice guidance documents of all FDA Centers describe the requirements with regards to product sterility.
“Nanosizing” is a term developed in the pharmaceutical industry to describe how some previously approved products with particle sizes greater than 100 nm are being produced with smaller particle sizes, in order to change certain physical and performance characteristics, such as pharmacokinetic profile (i.e. the rate and extent of absorption and clearance from the body).
The National Institute for Occupational Safety and Health (NIOSH) (http://www.cdc.gov/niosh/homepage.html) and the Occupational Health and Safety Administration (OSHA) (http://www.osha.gov) provide guidance for the protection of workers.
The Environmental Protection Agency (EPA) (http://epa.gov) provides guidance on the disposal of unused or expired nanoproducts.
The National Environmental Policy Act (NEPA) requires federal agencies to consider the environmental effects of any "major federal action" they propose to take, by preparing an environmental assessment (EA) or environmental impact statement (EIS) as appropriate. Agencies can establish categorical exclusions for categories of actions that do not individually or cumulatively have a significant effect on the human environment. However, agency procedures must provide for extraordinary circumstances in which a normally excluded action may have a significant environmental effect. Extraordinary circumstances identified in FDA's regulations under which its categorical exclusions would not apply include potential for serious harm to the environment and actions that adversely affect an endangered, threatened or otherwise specially protected species.
Many regulatory actions by FDA constitute major federal actions, including: actions on and withdrawal of applications to market new drugs and biological products; actions to prohibit or otherwise restrict the use of a substance in food, food packaging or cosmetics; and actions on pre-market notifications and pre-market applications for devices. Such regulatory activities may not require preparation of an EA or EIS, however, because FDA has established categorical exclusions for these and other categories of regulatory action.
For example, environmental considerations relating to drug approvals can include toxicity to organisms because of the introduction into the environment or increased levels in the environment of the active moiety due to use and disposal of the drug product. These considerations can warrant analysis of factors including the expected environmental fate of the product (involving identification and characterization of the substances of interest, environmental depletion mechanisms and environmental concentration). Under FDA's regulations, drug approvals generally can qualify for a categorical exclusion however if either: the approval does not increase the use of the active moiety; the estimated concentration at the point of entry to the aquatic environment will be below 1 part per billion; or the application is for a substance that occurs naturally in the environment and the approval will not alter significantly the concentration or distribution of the substance, its metabolites or degradation products in the environment.
The development of drugs, including oncology drugs, is addressed in published FDA guidance. In addition, a publication written in 1998 by DeGeorge et al. offers some additional thoughts about preclinical studies for evaluation of safety of oncology drugs. [ref: DeGeorge et al. (1998) Regulatory considerations for preclinical development of anticancer drugs. Cancer Chemother Pharmacol 41: 173-185]
FDA has not taken a position on this issue. FDA has experience with many “classes” of materials, nominally for the same indication or use, in which members of the class behaved very differently from one another, e.g. statins for lipid therapy. FDA has experience with implant materials such as polyurethane that are safe in one part of the body and not in others. FDA also has experience with materials for which the relationship between the physical or chemical characteristics and the biological response has been established. It may be possible to establish this relationship for nanomaterials.
Most sponsors would like to know their regulatory pathway as early in the product development process as possible, and FDA strives to do just that. In fact, most combination products are assigned very early in their development. FDA/OCP generally does not need preliminary animal toxicity data to make an assignment, because toxicity data per se usually would not be reflective of a product's mode of action. OCP needs to have enough information to determine with reasonable certainty a product's modes of action and its primary mode of action. Animal data aimed at studying the mechanism of action or proof of concept usually would be very helpful though not always necessary. In determining the jurisdiction of any product, nanotechnology related or not, FDA/OCP follows the basic reasoning below: