The Pharmaceutical Applications of Nanotechnology

In last month's issue, we began a discussion of nanomedical applications for disease diagnosis, therapy, and prevention, and of why the new technologies that make these advances possible are likely to change the practice of medicine. Now, we'll look at more ways in which the use of nanomaterials in drugs and medical devices may affect the provision of health care and lead to new medical liability issues.

Nanomedical Devices

Currently, many medical devices, such as orthopedic implants and heart valves, are made of titanium and stainless steel alloys or special plastics, like polyethylene. These alloys and plastics are used because they are biocompatible and because, in the case of orthopedic implants, previous technology could not create synthesized hydroxyapatite of sufficient strength to be used in the body. For an implant to act like natural bone and provide needed structural strength, the surrounding tissue has to be able to grow onto and into the implants. But traditional implant materials are fairly dense and non-porous and, in many cases, natural tissue does not adhere well to the foreign material, causing implants to fail after a period of time. Plastic implants also tend to wear out quickly ' about 10 years is average life ' so their use requires invasive surgery and expensive implant replacements.

New nanostructured materials may solve these problems. For example, by controlling the formation of crystals of hydroxyapatite at the atomic scale, new synthetic bone material has been created with the strength of stainless steel. What's more, the nanocrystalline synthetic bone material mimicks the size and morphology of native bone crystals and is gradually replaced by living human bone. This is possible due to the nanoscale: The synthesized nanocrystals are small enough to allow the body's living cells to grow between and latch onto the nanocrystals. The cells engulf the crystals, break them down and remodel them into real bone. (One such material, NanOss', is the first nanotechnology medical “device” ever to receive FDA clearance. It was approved by the CDRH as a Class II medical device in 2005. See Baluch, Angstrom Medica: Securing FDA Approval and Commercializing a Nanomedical Device, 2 Nanotechnology L. & Bus. 168, 2005.) Over time, such implants should be incorporated seamlessly into the once-damaged tissue and become indistinguishable from normal, living bone ' a significant advantage over the current implantation of foreign substances. Other new biomaterials, such as nanostructured implant surface coatings, facilitate the integration of synthetic materials into body tissue. New nanoporous or nanocrystalline materials, when fused to a hip, knee, or dental prosthesis for example, allow the natural tissue to gradually infiltrate into and throughout the device, a much more biofidelic solution compared to current implant technology. See, e.g., Miller, Cho & McGehee, A Realistic Assessment of the Commercialization of Nanotechnology: A Primer for Lawyers and Investors, 1 Nanotechnology L. & Bus. 10, 2004.

Substantial research is also in progress for new nanomedical devices, such as active implantable devices. These include miniature devices that could be implanted to correct auditory, visual, and other sensory impairment. For example, researchers are working on retinal implants (neuroprostheses) for vision rehabilitation, which would absorb light and deliver electrical signals that are relayed to and interpreted by the brain. Vogel, Societal Impacts of Nanotechnology in Education and Medicine, in Societal Implications of Nanoscience and Nanotechnology, 143, 146 (M. Roco & W. Bainbridge eds., 2001). See also, Liu and Webster, Nanomedicine for Implants: A Review of Studies and Necessary Experimental Tools, 28 Biomaterials 354 (2007).

Nanomedicine and the FDA

The mission of the U.S. Food and Drug Administration is, in part, to ensure that the drugs, drug delivery systems, medical devices, vaccines, and other biologic products reaching the marketplace are safe and effective. The FDA is also responsible for advancing the public health by helping to speed innovations that make medicine more effective and more affordable. The oncoming “Age of Nanotechnology” brings into sharp focus the tension between assuring that regulated products are safe and effective while at the same time ensuring that new and potentially life-saving treatments are made available to the public as quickly as possible.

The role of the FDA as gatekeeper for the application of nanotechnologies to medicine is governed by a basic principle: The FDA regulates products, not technology. The FDA, for example, does not regulate materials or manufacturing processes, per se, but instead regulates the end products. This principle affects the stage at which the FDA becomes engaged in the regulation of nanotechnology and when, in the process, any regulation takes effect. Under the FDA's category-based system, 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). Recognizing that 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, the FDA established the Office of Combination Products (OCP) in 2002 to address these challenges.

The FDA regulates only to the “claims” made by the product sponsor. If the manufacturer makes no nanotechnology claims regarding the manufacture or performance of the product, the FDA may be unaware at the time the product is being review and approved that nanotechnology is being employed. See FDA, Regulation of Nanotechnology Products, at www.fda.gov/nano technology/regulation.html.

A handful of existing products regulated by the FDA contain nanomaterials ' including several drugs processed through the CDER and several medical devices processed through CDRH ' and each was approved by the FDA using existing pathways and without any special testing. (There is not yet any systematic way to identify nanotechnology products using the FDA's Web site, but several commentators have gleaned the information from a number of reliable sources. See Cindy Strickland, Nano-Based Drugs and Medical Devices: FDA's Track Record, 4 Nanotechnology L. & Bus. 179, June 2007 (identifying seven specific drugs and three medical devices that have been approved); Bawa, Melethil, Simmons and Harris, Nanopharmaceuticals: Patenting Issues and FDA Regulatory Challenges, 5 The SciTech Lawyer No. 2, Fall 2008; Bawa, Nanoparticle-based Therapeutics in Humans: A Survey, 5 Nanotechnology L. & Bus. 135, Summer 2008 (identifying seven nanopharmaceuticals currently on the market).

The FDA has recognized that existing regulatory processes and pathways should be assessed and, where necessary, modified to accommodate nanotechnology. In response to the rapid emergence of nanoscience-based medical applications and concerns about possible health and safety risks, the FDA formed an internal FDA Nanotechnology Task Force and a NanoTechnology Interest Group (NTIG) in 2006. (The NTIG has participation from all FDA Centers (e.g., CDER, CBER, CDRH) and all FDA Offices that report directly to the Office of the Commissioner (e.g., OCP). Each Center has established a multidisciplinary nanotechnology-focused working group. These working groups are charged with identifying and defining the regulatory challenges in each discipline and proposing solutions to overcome these challenges. See FDA, FDA and Nanotechnology Products, FAQs, ' 13, at www.fda.gov/nanotechnology/faqs.html.)

The Report

The Task Force published its Report in July 2007 (FDA, Nanotechnology Task Force Report, July 2007, at www.fda.gov/nanotechnology/nano_tf.html), and in 2008 held a Public Meeting intended “to gather information that will assist the Agency in implementing the recommendations of the Nanotechnology Task Force Report.” The Task Force Report did not suggest the need for any immediate nano-specific regulatory action, but did recognize that obvious knowledge gaps exist concerning new risks presented by nanomaterials. In light of the limits of current science, however, the Task Force specifically declined to recommend adoption of any new labeling rules requiring identification of the presence of nanoscale materials.

The Report's authors also noted that the nature of nanoscale materials permits the development of highly integrated combinations of drugs, biological products, and/or devices, having multiple types of uses, such as combined diagnostic and therapeutic intended uses.

As a consequence, the FDA recognized that many anticipated nanomedical products will be difficult to categorize as drugs, devices, or biologics, and many will be considered combination products. Because combination products involve components that are normally regulated under different types of regulatory authorities, and frequently by different FDA centers, they raise challenging regulatory and review issues. See, e.g., Sadrieh and Espandiari, Nanotechnology and the FDA: What Are the Scientific and Regulatory Considerations for Products Containing Nanomaterials?, 3 Nanotechnology L. & Bus. 339, Sept. 2006. Thus, the current paradigm for selecting regulatory pathways for such combination products may need to be assessed to ensure predictable determinations of the most appropriate pathway for highly integrated nanomedical combination products.

The FDA has thus far been relatively unconcerned about the safety issues of nanoscale products under its auspices, and believes that existing standards for safety and efficacy will be adequate for most nanotechnology medical products. See, e.g., FDA, Regulation of Nanotechnology Products, at www.fda.gov/nanotechnology/regulation.html; FDA and Nanotechnology Products, FAQs,
' 13, at www.fda.gov/nanotechnology/faqs.html; Lutter, FDA Nanotechnology Task Force Meeting, Oct. 10, 2006, at www.fda.gov/nanotechnology/meetings/transcript.pdf. Some commentators are critical of that position, urging the FDA both formally and informally to move more quickly to specifically address nanomaterial risks. For example, in May 2006, the International Center for Technology Assessment (ICTA) and a coalition of consumer, health, and environmental groups filed a formal legal petition with the FDA, calling on the agency to address the risks of nanomaterials through enactment of comprehensive nano-product regulations, including treating nanomaterials as new substances, using nanomaterial-specific toxicity testing paradigms, and requiring nano-product labeling. (Petition available at www.icta.org/doc/nano%20FDA%20petition%20final.pdf.) The FDA is still reviewing the ICTA petition, which “raises complex issues requiring extensive review and analysis by agency officials, and in relation to which the agency is seeking public input.” FDA, Nanotechnology Task Force Report, July 2007, at www.fda.gov/nanotechnology/nano_tf.html. Experts have also offered recommendations for more science-based FDA regulations to address the wide range of nanomedical products (nanopharmaceuticals, nanomedical devices, nanobiologics); such as by the creation of a multidisciplinary expert panel to identify unique safety issues associated with nanoscale products; development of a new paradigm for evaluating data pertaining to safety and efficacy of nanoscale products by a team of experienced regulators from the drug (CDER), biologic (CBER), and device (CDRH) areas of the FDA; and developing unique tools and techniques to better characterize nanoscale materials used in medical applications. See, e.g., Bawa, et al., Nanopharmaceuticals: Patenting Issues and FDA Regulatory Challenges.

While the FDA seems intent on handling the new generation of nanotechnology-based medical products with the traditional product-by-product regulatory model, some experts question the wisdom of that approach. For example, it is feared that attempts to classify nanobiotechnological products into the traditional categories of medical products ' drug, device, biological or combination product ' is clumsy and will result in inconsistent regulatory treatment. One reason is that nanotechnology applications can produce indistinct effects no longer easily classified as mechanical, chemical or biological, thereby creating problems in categorizing the nanomedical products into one of the available traditional classifications. The legal classification of nanomedical products is of basic importance because the widely divergent FDA market-approval processes and the applicable standards of safety and effectiveness depend on how they are regulated. See Miller, Beyond Biotechnolog: FDA Regulation of Nanomedicine, 4 Colum. Sci. & Tech. L. Rev. 5 (2002); Foote and Berlin, Can Regulation Be As Innovative As Science and Technology? The FDA's Regulation of Combination Products, 6 Minn. J.L., Sci. & Tech. 619 (2005).

Conclusion

It remains to be seen what additional internal processes or regulatory actions, if any, the FDA will pursue to address nanospecific product and safety issues. This is an evolving area of regulatory law and all pharmaceutical, medical device, and health care risk managers and their attorneys must stay closely attuned. In the meantime, with the many unknowns that nanotechnology and its application to medical purposes present, it appears highly likely that many of the questions posed by this new technology will be answered first in the courtroom. That's why medical care providers and their legal representatives need to start looking at the issues raised by nanomedicine; by doing so, they will put themselves in a better position to assess the values and reduce the risks of employing these new technologies for improving patient health outcomes.

Ronald C. Wernette is a partner with Bowman and Brooke LLP in the firm's Troy, MI, office, where he focuses his practice on toxic exposure, product liability, and other personal injury defense. He is a member of the Defense Research Institute Product Liability Committee and ABA Section of Science & Technology Law. He can be reached at [email protected].

In last month's issue, we began a discussion of nanomedical applications for disease diagnosis, therapy, and prevention, and of why the new technologies that make these advances possible are likely to change the practice of medicine. Now, we'll look at more ways in which the use of nanomaterials in drugs and medical devices may affect the provision of health care and lead to new medical liability issues.

Nanomedical Devices

Currently, many medical devices, such as orthopedic implants and heart valves, are made of titanium and stainless steel alloys or special plastics, like polyethylene. These alloys and plastics are used because they are biocompatible and because, in the case of orthopedic implants, previous technology could not create synthesized hydroxyapatite of sufficient strength to be used in the body. For an implant to act like natural bone and provide needed structural strength, the surrounding tissue has to be able to grow onto and into the implants. But traditional implant materials are fairly dense and non-porous and, in many cases, natural tissue does not adhere well to the foreign material, causing implants to fail after a period of time. Plastic implants also tend to wear out quickly ' about 10 years is average life ' so their use requires invasive surgery and expensive implant replacements.

New nanostructured materials may solve these problems. For example, by controlling the formation of crystals of hydroxyapatite at the atomic scale, new synthetic bone material has been created with the strength of stainless steel. What's more, the nanocrystalline synthetic bone material mimicks the size and morphology of native bone crystals and is gradually replaced by living human bone. This is possible due to the nanoscale: The synthesized nanocrystals are small enough to allow the body's living cells to grow between and latch onto the nanocrystals. The cells engulf the crystals, break them down and remodel them into real bone. (One such material, NanOss', is the first nanotechnology medical “device” ever to receive FDA clearance. It was approved by the CDRH as a Class II medical device in 2005. See Baluch, Angstrom Medica: Securing FDA Approval and Commercializing a Nanomedical Device, 2 Nanotechnology L. & Bus. 168, 2005.) Over time, such implants should be incorporated seamlessly into the once-damaged tissue and become indistinguishable from normal, living bone ' a significant advantage over the current implantation of foreign substances. Other new biomaterials, such as nanostructured implant surface coatings, facilitate the integration of synthetic materials into body tissue. New nanoporous or nanocrystalline materials, when fused to a hip, knee, or dental prosthesis for example, allow the natural tissue to gradually infiltrate into and throughout the device, a much more biofidelic solution compared to current implant technology. See, e.g., Miller, Cho & McGehee, A Realistic Assessment of the Commercialization of Nanotechnology: A Primer for Lawyers and Investors, 1 Nanotechnology L. & Bus. 10, 2004.

Substantial research is also in progress for new nanomedical devices, such as active implantable devices. These include miniature devices that could be implanted to correct auditory, visual, and other sensory impairment. For example, researchers are working on retinal implants (neuroprostheses) for vision rehabilitation, which would absorb light and deliver electrical signals that are relayed to and interpreted by the brain. Vogel, Societal Impacts of Nanotechnology in Education and Medicine, in Societal Implications of Nanoscience and Nanotechnology, 143, 146 (M. Roco & W. Bainbridge eds., 2001). See also, Liu and Webster, Nanomedicine for Implants: A Review of Studies and Necessary Experimental Tools, 28 Biomaterials 354 (2007).

Nanomedicine and the FDA

The mission of the U.S. Food and Drug Administration is, in part, to ensure that the drugs, drug delivery systems, medical devices, vaccines, and other biologic products reaching the marketplace are safe and effective. The FDA is also responsible for advancing the public health by helping to speed innovations that make medicine more effective and more affordable. The oncoming “Age of Nanotechnology” brings into sharp focus the tension between assuring that regulated products are safe and effective while at the same time ensuring that new and potentially life-saving treatments are made available to the public as quickly as possible.

The role of the FDA as gatekeeper for the application of nanotechnologies to medicine is governed by a basic principle: The FDA regulates products, not technology. The FDA, for example, does not regulate materials or manufacturing processes, per se, but instead regulates the end products. This principle affects the stage at which the FDA becomes engaged in the regulation of nanotechnology and when, in the process, any regulation takes effect. Under the FDA's category-based system, 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). Recognizing that 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, the FDA established the Office of Combination Products (OCP) in 2002 to address these challenges.

The FDA regulates only to the “claims” made by the product sponsor. If the manufacturer makes no nanotechnology claims regarding the manufacture or performance of the product, the FDA may be unaware at the time the product is being review and approved that nanotechnology is being employed. See FDA, Regulation of Nanotechnology Products, at www.fda.gov/nano technology/regulation.html.

A handful of existing products regulated by the FDA contain nanomaterials ' including several drugs processed through the CDER and several medical devices processed through CDRH ' and each was approved by the FDA using existing pathways and without any special testing. (There is not yet any systematic way to identify nanotechnology products using the FDA's Web site, but several commentators have gleaned the information from a number of reliable sources. See Cindy Strickland, Nano-Based Drugs and Medical Devices: FDA's Track Record, 4 Nanotechnology L. & Bus. 179, June 2007 (identifying seven specific drugs and three medical devices that have been approved); Bawa, Melethil, Simmons and Harris, Nanopharmaceuticals: Patenting Issues and FDA Regulatory Challenges, 5 The SciTech Lawyer No. 2, Fall 2008; Bawa, Nanoparticle-based Therapeutics in Humans: A Survey, 5 Nanotechnology L. & Bus. 135, Summer 2008 (identifying seven nanopharmaceuticals currently on the market).

The FDA has recognized that existing regulatory processes and pathways should be assessed and, where necessary, modified to accommodate nanotechnology. In response to the rapid emergence of nanoscience-based medical applications and concerns about possible health and safety risks, the FDA formed an internal FDA Nanotechnology Task Force and a NanoTechnology Interest Group (NTIG) in 2006. (The NTIG has participation from all FDA Centers (e.g., CDER, CBER, CDRH) and all FDA Offices that report directly to the Office of the Commissioner (e.g., OCP). Each Center has established a multidisciplinary nanotechnology-focused working group. These working groups are charged with identifying and defining the regulatory challenges in each discipline and proposing solutions to overcome these challenges. See FDA, FDA and Nanotechnology Products, FAQs, ' 13, at www.fda.gov/nanotechnology/faqs.html.)

The Report

The Task Force published its Report in July 2007 (FDA, Nanotechnology Task Force Report, July 2007, at www.fda.gov/nanotechnology/nano_tf.html), and in 2008 held a Public Meeting intended “to gather information that will assist the Agency in implementing the recommendations of the Nanotechnology Task Force Report.” The Task Force Report did not suggest the need for any immediate nano-specific regulatory action, but did recognize that obvious knowledge gaps exist concerning new risks presented by nanomaterials. In light of the limits of current science, however, the Task Force specifically declined to recommend adoption of any new labeling rules requiring identification of the presence of nanoscale materials.

The Report's authors also noted that the nature of nanoscale materials permits the development of highly integrated combinations of drugs, biological products, and/or devices, having multiple types of uses, such as combined diagnostic and therapeutic intended uses.

As a consequence, the FDA recognized that many anticipated nanomedical products will be difficult to categorize as drugs, devices, or biologics, and many will be considered combination products. Because combination products involve components that are normally regulated under different types of regulatory authorities, and frequently by different FDA centers, they raise challenging regulatory and review issues. See, e.g., Sadrieh and Espandiari, Nanotechnology and the FDA: What Are the Scientific and Regulatory Considerations for Products Containing Nanomaterials?, 3 Nanotechnology L. & Bus. 339, Sept. 2006. Thus, the current paradigm for selecting regulatory pathways for such combination products may need to be assessed to ensure predictable determinations of the most appropriate pathway for highly integrated nanomedical combination products.

The FDA has thus far been relatively unconcerned about the safety issues of nanoscale products under its auspices, and believes that existing standards for safety and efficacy will be adequate for most nanotechnology medical products. See, e.g., FDA, Regulation of Nanotechnology Products, at www.fda.gov/nanotechnology/regulation.html; FDA and Nanotechnology Products, FAQs,
' 13, at www.fda.gov/nanotechnology/faqs.html; Lutter, FDA Nanotechnology Task Force Meeting, Oct. 10, 2006, at www.fda.gov/nanotechnology/meetings/transcript.pdf. Some commentators are critical of that position, urging the FDA both formally and informally to move more quickly to specifically address nanomaterial risks. For example, in May 2006, the International Center for Technology Assessment (ICTA) and a coalition of consumer, health, and environmental groups filed a formal legal petition with the FDA, calling on the agency to address the risks of nanomaterials through enactment of comprehensive nano-product regulations, including treating nanomaterials as new substances, using nanomaterial-specific toxicity testing paradigms, and requiring nano-product labeling. (Petition available at www.icta.org/doc/nano%20FDA%20petition%20final.pdf.) The FDA is still reviewing the ICTA petition, which “raises complex issues requiring extensive review and analysis by agency officials, and in relation to which the agency is seeking public input.” FDA, Nanotechnology Task Force Report, July 2007, at www.fda.gov/nanotechnology/nano_tf.html. Experts have also offered recommendations for more science-based FDA regulations to address the wide range of nanomedical products (nanopharmaceuticals, nanomedical devices, nanobiologics); such as by the creation of a multidisciplinary expert panel to identify unique safety issues associated with nanoscale products; development of a new paradigm for evaluating data pertaining to safety and efficacy of nanoscale products by a team of experienced regulators from the drug (CDER), biologic (CBER), and device (CDRH) areas of the FDA; and developing unique tools and techniques to better characterize nanoscale materials used in medical applications. See, e.g., Bawa, et al., Nanopharmaceuticals: Patenting Issues and FDA Regulatory Challenges.

While the FDA seems intent on handling the new generation of nanotechnology-based medical products with the traditional product-by-product regulatory model, some experts question the wisdom of that approach. For example, it is feared that attempts to classify nanobiotechnological products into the traditional categories of medical products ' drug, device, biological or combination product ' is clumsy and will result in inconsistent regulatory treatment. One reason is that nanotechnology applications can produce indistinct effects no longer easily classified as mechanical, chemical or biological, thereby creating problems in categorizing the nanomedical products into one of the available traditional classifications. The legal classification of nanomedical products is of basic importance because the widely divergent FDA market-approval processes and the applicable standards of safety and effectiveness depend on how they are regulated. See Miller, Beyond Biotechnolog: FDA Regulation of Nanomedicine, 4 Colum. Sci. & Tech. L. Rev. 5 (2002); Foote and Berlin, Can Regulation Be As Innovative As Science and Technology? The FDA's Regulation of Combination Products, 6 Minn. J.L., Sci. & Tech. 619 (2005).

Conclusion

It remains to be seen what additional internal processes or regulatory actions, if any, the FDA will pursue to address nanospecific product and safety issues. This is an evolving area of regulatory law and all pharmaceutical, medical device, and health care risk managers and their attorneys must stay closely attuned. In the meantime, with the many unknowns that nanotechnology and its application to medical purposes present, it appears highly likely that many of the questions posed by this new technology will be answered first in the courtroom. That's why medical care providers and their legal representatives need to start looking at the issues raised by nanomedicine; by doing so, they will put themselves in a better position to assess the values and reduce the risks of employing these new technologies for improving patient health outcomes.

Ronald C. Wernette is a partner with Bowman and Brooke LLP in the firm's Troy, MI, office, where he focuses his practice on toxic exposure, product liability, and other personal injury defense. He is a member of the Defense Research Institute Product Liability Committee and ABA Section of Science & Technology Law. He can be reached at [email protected].