How to build (and regulate) a body part: regulating tissue engineered products in Canada.
Subject: Federal jurisdiction (Laws, regulations and rules)
Gene therapy (Laws, regulations and rules)
Genetic engineering (Laws, regulations and rules)
Tissue engineering (Laws, regulations and rules)
Author: von Tigerstrom, Barbara
Pub Date: 01/01/2011
Publication: Name: Health Law Journal Publisher: Health Law Institute Audience: Professional Format: Magazine/Journal Subject: Health; Law; Sports and fitness Copyright: COPYRIGHT 2011 Health Law Institute ISSN: 1192-8336
Issue: Date: Annual, 2011 Source Volume: 19
Topic: Event Code: 930 Government regulation; 940 Government regulation (cont); 980 Legal issues & crime Advertising Code: 94 Legal/Government Regulation Computer Subject: Government regulation
Product: Product Code: 8521212 Genetic Engineering NAICS Code: 54171 Research and Development in the Physical, Engineering, and Life Sciences
Legal: Jurisdiction: Canada; European Union; United States Statute: Canada. Assisted Human Reproduction Act 2004
Accession Number: 291893055
Full Text: Efforts to replace or repair human tissues go back hundreds of years, (2) but recent developments in biomedical and engineering sciences have made possible a new generation of technologies, creating the multidisciplinary field of "tissue engineering." Tissue engineered products for skin and cartilage are already on the market, and recent breakthroughs include the successful implantation of engineered bladders and tracheas, as well as progress toward engineering more complex organs like lungs and intestines. Most tissue engineering applications still require years of development and testing before they can be clinically useful, but these recent advances have generated a great deal of excitement. This technology promises great benefits for patients, but also raises some novel ethical, legal, and policy issues.

In particular, tissue engineering presents significant challenges for regulatory agencies responsible for overseeing the safety, efficacy, and quality of medical products. Tissue engineered products involve the convergence of several novel technologies, all complex in themselves and interacting in significant and perhaps unpredictable ways with each other and with the human body into which the product will be implanted. The complexity and novelty of these products will make them difficult to classify and will stretch the limits of our existing knowledge about how to assess the safety and efficacy of medical products. It will therefore be important to consider the extent to which our current regulatory framework is adequate to deal with these new types of products, and examine recent developments elsewhere that might provide models for reform. The way that regulatory requirements will be applied under this framework is just as important, however, so we also need to consider the challenges involved in assessing the novel technologies used in tissue engineering and their interactions. Concerns that have been raised about the resources and expertise available to agencies like Health Canada and the U.S. Food and Drug Administration (FDA) are highly relevant in this context, since tissue engineered products will place significant demands on the regulatory agencies charged with reviewing them. After introducing the field of tissue engineering, this article will discuss these challenges, and assess the extent to which Canada's regulatory framework is prepared to meet them.

I. What is tissue engineering?

According to an often-cited early definition, "tissue engineering" is "an interdisciplinary field that applies the principles of engineering and the life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function." (3) A recent standards document defines it as the "use of a combination of cells, engineering, materials and methods to manufacture ex vivo living tissues and organs that can be implanted to improve or replace biological function." (4) Tissue engineering is part of a larger field known as "regenerative medicine," which "replaces or regenerates human cells, tissues or organs, to restore or establish normal function." (5) Regenerative medicine "uses a combination of several technological approaches that moves it beyond traditional transplantation and replacement therapies. These approaches may include, but are not limited to, the use of soluble molecules, gene therapy, stem cell transplantation, tissue engineering and the reprogramming of cell and tissue types." (6) What makes tissue engineering distinctive within the broader field of regenerative medicine, which can include other cell and tissue therapies, is that tissue engineering involves the use of cells and scaffolds, usually along with biomolecules (such as growth factors), to manufacture tissues and organs ex vivo (outside the body). (7) This also distinguishes tissue engineered products from "artificial" organs or tissues that are composed only of medical devices with no cellular component. (8)

Efforts to use biomaterials to replace human body parts date back at least to Roman times, with ivory, bone, wood, and metal used to replace parts such as teeth or limbs. (9) Skin grafts and transplantation of teeth were pioneered as early as the 1700s. (10) This was followed by organ and tissue transplants including the first kidney and heart transplants in the 1950s and 1960s. (11) The modern era of tissue engineering was made possible by developments in cell culture (growing cells outside the human body) and microsurgery, and began in the 1980s with experiments in generating cartilage and skin using cells and scaffolds. (12) By the time of a famous review of the field in the early 1990s, researchers were reportedly working on tissue engineering applications for virtually every part of the body: the nervous system, skin, cornea, liver, pancreas, trachea, esophagus, intestine, kidney, bladder, urethra, cartilage, bone, muscle (including heart muscle), and blood vessels. (13)

The first commercially marketed products in tissue engineering were engineered cartilage and skin, approved by regulatory agencies in both Europe and the United States. (14) After a period of rapid development and excitement, the field stalled somewhat in the early 2000s, as researchers and companies struggled with the many challenges of developing these novel products and bringing them to market. (15) In recent years, however, a number of important successes have been reported. (16) A U.S. team has successfully implanted engineered bladders made by growing cells obtained from a biopsy and seeding them onto a biodegradable scaffold made of collagen or a collagen-polyglycolic acid composite. (17) A similar approach was used to reconstruct urethras in five patients. (18) In both cases, the implanted tissues appeared to be functioning after several years of follow-up. Another important milestone was the successful implantation of a tissue engineered trachea into a woman whose airway had been severely damaged as a complication from tuberculosis and in whom previous attempts at treatment had failed. A multinational team used a donor trachea which had been stripped of its cells ("decellularized") and then seeded with cells derived and cultured from the patient's own mesenchymal stem cells and epithelial cells. (19) This procedure was hailed as the first whole tissue engineered organ transplant (20) and the first stem cell-based tissue engineered organ replacement. (21) Researchers including some members of this team have been working to further develop this technology. (22) A second tissue engineered trachea was successfully implanted in 2010; (23) this procedure also used a decellularized donor trachea and the patient's own stem cells, but in this case the trachea was grown inside the boy's own body rather than in a lab. (24) Most recently, a fully "synthetic" engineered trachea, using autologous stem cells and a nanocomposite polymer scaffold, was success25 fully transplanted into a patient with tracheal cancer. (25)

Recent reports show that researchers are also getting closer to being able to engineer other tissues and organs, including the liver, (26) larynx, (27) lung, (28) intestine, (29) blood vessels, (30) and component tissues of teeth. (31) Although it will still be some time before engineered tissues are in common use and begin to fulfill their great clinical promise, these developments have generated renewed excitement. (32)

One of the challenges with understanding and regulating tissue engineering is that there is considerable variation within the field. Different medical conditions and different organs and tissues raise distinct challenges for researchers, so there is no one-size-fits-all approach to tissue engineering. In each of the three main components (cells, scaffolds, and signals) there are many different options, each of which may raise significant issues, and which can be combined in different ways.

The source of cells used in tissue engineering can be autologous (from the patient him- or herself) or allogeneic (from a donor). The autologous approach has the advantage of avoiding the risk of immune rejection by the patient, but each tissue engineered product must be custom-made for the individual patient, which allows for tailored therapies but can cause delays and technical challenges. (33) It may be necessary to use donor cells if it is not possible to get sufficient numbers of healthy cells from the patient. (34) Allogeneic cells can be used in "off-the-shelf" tissue engineered products which could be available much more quickly and allow for greater standardization, but carry the risks of immune rejection and the transmission of disease from donor to recipient. Xenogenic cells (from non-human animal species) could also be used, but would present additional risks, such as the transmission of zoonotic diseases.

Many different cell types have been used in tissue engineering research; stem cells are especially promising because of their capacity to form different kinds of cells. (35) Human embryonic stem cells (hESCs) are pluripotent, meaning they can differentiate into any cell type in the human body, while adult stem cells such as mesenchymal stem cells (also known as mesenchymal stromal cells) and hematopoietic stem cells are multipotent cells that can differentiate into a limited range of cell types. In recent years, the discovery that adult cells can be reprogrammed to be pluripotent ("induced pluripotent stem cells" or iPSCs) has opened up new possibilities. (36) It is hoped that iPSCs can provide a less ethically problematic source of pluripotent stem cells than hESCs, and that they can be used to create personalized regenerative medicine products, but there remain many challenges with using iPSCs for clinical applications. (37)

Cells used in tissue engineering are grown in culture and in the case of stem cells, differentiated into the desired cell type. The biomolecule components of tissue engineered products provide signals to the cells to promote and direct their development. These molecular signals are usually growth factors. It is also possible to insert a gene into the cells to affect their functioning. (38) In addition to using genetic modification to enhance the functioning of the cells, tissue engineered products can also be designed to act as vehicles for gene therapy, potentially offering a novel means of correcting metabolic disorders. (39)

A scaffold is a "support or delivery vehicle or matrix for facilitating the migration, binding, or transport of cells of bioactive agents." (40) It provides a three-dimensional "microenvironment" in which the cells will grow. (41) Scaffolds are especially important for structural tissue, (42) but their function is not simply structural. They also interact with the cells and influence their development,43 providing mechanical signals to the cells in addition to the molecular signals. (44) New techniques of cell self-assembly may eventually eliminate the need for separate scaffolds, (45) but most current tissue engineering approaches involve the use of some kind of a scaffold.

Scaffolds can be natural or synthetic. Decellularized organs and tissues as a form of natural scaffold have been used successfully in several recent applications. (46) Starting with an organ or tissue from a human donor (allogeneic source) or, in some cases, from a non-human animal (xenogeneic source), the cellular components are removed by chemical or biological agents or physical processes, leaving the extracellular matrix intact. (47) As well as providing a three-dimensional structure, this extracellular matrix provides cues to the cells that "affect cell migration, proliferation, and differentiation." (48) Synthetic scaffolds may be composed of various materials such as ceramics, glass, or polymers, in the form of a solid porous material, gel, or foam. (49) They may be made of biodegradable or resorbable materials, in which case careful attention to the degradation or resorption mechanism and its byproducts is required. (50) "Gene-activated matrices" are scaffolds combined with DNA so that as the scaffold degrades, it releases DNA that affects cells in the surrounding environment, which can enhance wound healing and bone regeneration. (51)

Advances in nanotechnology have contributed significantly to the development of scaffolds for tissue engineering. In fact, a whole new subfield of "regenerative nanomedicine" has emerged. (52) Nanomaterials (materials with dimensions in the nanoscale, i.e. one to 100 nanometres (53)) have distinct properties that "can be exploited to influence cell attachment, proliferation and differentiation." (54) In the human body, cells grow within an "extracellular matrix." Recent research has discovered that the extracellular matrix is composed of nanoscale fibres and proteins; therefore, researchers have been trying "to design advanced nanocomposite scaffolds that can better mimic the [extracellular matrix] and eventually assemble more complex and larger functional tissues" (55)--essentially, to "engineer an [extracellular matrix] substitute capable of influencing cellular behaviour." (56)

Three main techniques are being used. Nanoscale surface patterning uses lithography and printing techniques to create nanoscale patterns on various surfaces, which will influence cellular responses. (57) Surface patterning can also be used to create channels in a three-dimensional structure, allowing for a flow of oxygen, nutrients, and waste. (58) Electrospinning is another technique, in which nanoscale fibres are made using polymer solutions forced through a small nozzle and exposed to magnetic fields. (59) The fibres can be formed into mats of aligned fibres ora porous mesh. The alignment of the fibres influences the differentiation and alignment of cells: for example, scaffolds made with this technology have been shown to promote the directional alignment of muscle cells, so that they mimic normal skeletal muscle architecture, and also to direct the differentiation of stem cells into specific cell types. (60) In addition, mesh scaffolds of electrospun fibres "can be manipulated into three-dimensional structures to re-create native architecture." (61) The third technique, self-assembly, uses nanoscale particles which form themselves into fibrous structures. (62) These particles can include biologically active ones such as peptides, which then guide cell behaviour. (63) This technique has also been used to create structures that encourage blood vessel growth, a significant step toward engineering a vascularized tissue. (64) Scaffolds made of electrospun fibres or self-assembled nanoparticles can also be acted on or "remodelled" by the cells, so they can be designed to break down or degrade in a specific way. (65)

As can be seen from this overview, there is tremendous variation within the realm of tissue engineering, and different models raise different issues. For example, does the tissue develop only ex vivo or also in vivo? Is it custom-made from autologous cells or an allogeneic "off-the-shelf" product? Does it involve the use of hESCs, iPSCs, or xenogeneic material? Is the scaffold made from decellularized donor tissue, conventional synthetic materials, or nanomaterials? Each of these variations will present specific scientific, ethical, and legal challenges. By definition tissue engineered products will have several components, each of which is complex and may involve the use of novel technologies; for example, a single engineered tissue or organ could use stem cells, genetic modification, and nanotechnology. This convergence of emerging technologies significantly increases the complexity of the tissue engineered products and multiplies the challenges of regulating them.

II. Regulation of Tissue Engineered Products

Tissue engineering raises many legal and ethical issues, which have received relatively little attention to date, (66) although some of the relevant issues have been explored in the broader context of regenerative medicine and other areas of biotechnology. The range of issues is broad, including ethical and legal questions about the source materials used in tissue engineering (e.g. hESCs), informed consent for donors of biological materials and for clinical trial participants, the potential uses of tissue engineering technology, and intellectual property. (67) This article focuses on one area of law that will have a significant and direct impact on the development and use of tissue engineering in Canada, which is the legal framework for therapeutic product regulation. This is the area of law that focuses on the products--traditionally drugs and medical devices--used in medical treatment, and aims to ensure that they are safe, effective, and of acceptable quality. Product regulation has been identified as an important policy issue in regenerative medicine, (68) and is the one area in which there is already some literature on tissue engineering from a legal perspective. Some progress has been made since the framework was described as a "regulatory fog" a decade ago. (69) As will be seen below, new regulations and guidance documents that deal specifically with tissue engineered products and their component technologies have been developed in several jurisdictions. However, there are still several reasons to believe that the regulation of tissue engineered products will present significant challenges to regulatory agencies in Canada and elsewhere.

A. Overview of the Canadian Legal Framework

In Canada, regulation of therapeutic products is undertaken by Health Canada under the authority of the federal Food and Drugs Ad (70) and its regulations. There are two main categories of therapeutic products: drugs and medical devices. A drug is defined as "any substance or mixture of substances" for use in "diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormal physical state, or its symptoms" or "restoring, correcting or modifying organic functions." (71) When the "substance or mixture of substances" is made from biological starting material, it is referred to as a biological drug or biologic, (72) in Canada also referred to as a "Schedule D drug" after the schedule in which they are listed in the Food and Drugs Act. (73) Although cells and tissues are not specifically listed in Schedule D, Health Canada's practice has been to treat these as biologics. (74) Biologics and other drugs are governed by the Food and Drug Regulations. (75) A device is defined as "any article, instrument, apparatus or contrivance, including any component, part of accessory thereof" for use in "diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormal physical state, or its symptoms" or "restoring, correcting or modifying a body function or the body structure." (76) Medical devices are also regulated under the umbrella of the Food and Drugs Act, but are subject to a separate Medical Devices Regulation. (77)

A specific regulation governing cells, tissues, and organs for transplantation (CTO Regulations) was adopted in 2007. (78) However, this regulation only applies to cells and tissues that are no more than "minimally manipulated" and that will perform the same function in the recipient as in the donor ("homologous use"). (79) It is unlikely that tissue engineered products, which would involve a significant degree of manipulation, would fall within the scope of this regulation. Any medical device that includes cells or tissues and is the subject of investigational testing is also specifically excluded from the regulation. (80) Therefore, it is the Food and Drug Regulations and Medical Device Regulations that would likely apply to tissue engineered products. The Food and Drug Regulations require authorization from Health Canada before a new drug (including a biologic) is used in a clinical trial, (81) and approval before it is placed on the market. (82) These approvals require submission of evidence supporting the safety, efficacy, and quality of the product. (83) Manufacturers must also comply with "Good Manufacturing Practices" (GMP) requirements. (84) In order to provide appropriate oversight for the wide range of products falling under the definition of a device, (85) the Medical Device

Regulations divide them into four classes, according to the level of risk. (86) The manufacturers of all medical devices have an obligation to ensure that they meet, and have evidence of, safety and effectiveness requirements set out in the Regulations. (87) The other requirements that apply differ according to the class of device. Class I devices are not required to be licensed but establishments that make or sell them must be licensed (establishment licensing). (88) Class II, III, and IV devices must be licensed before they can be imported or sold, (89) and this requires submission of an application to the Minister, accompanied by prescribed information; the information required increases with the device classification. (90) Tissue engineered products, if they are considered medical devices, would be Class IV devices, because the Regulations stipulate that any "medical device that is manufactured from or that incorporates human or animal cells or tissues or their derivatives" is classified as Class IV. (91) A licensing application for a Class IV device must include "detailed information on all studies on which the manufacturer relies to ensure that the device meets the safety and effectiveness requirements," (92) and in the case of a device "manufactured from or incorporating animal or human tissue or their derivative, objective evidence of the biological safety of the device." (93)

B. Product Classification

An initial threshold issue is whether tissue engineering necessarily creates a "product" that can be regulated within this framework. Some tissue engineered products are designed to be mass-produced and sold "off-the-shelf," similar to more traditional drugs, biologics, or devices. However, some will be custom-made for individual patients who have a particular need, like the engineered tracheas described above (94)--each made one at a time, using experimental techniques and the patient's own cells. Thus, some have suggested that tissue engineered products, at least in some cases, are "not really products per se." (95) Tissue engineering has been described as "essentially a customized process that, although involving some commercial components, is directed towards individual patients." (96) In some respects, it may resemble transplant surgery more than the manufacture of a product. This individualized approach involves a different business model, in which the main value is in the clinical and technical services needed to develop, assemble, and implant the engineered tissue. This affects commercial development and reimbursement, but it also has implications for regulation.

The existing regulatory framework is directed toward products, with clinical practice and technical services provided by laboratories or other entities being regulated separately under distinct legislation. Over a decade ago, it was recognized that some cell therapies, given "the patient-specific nature of these therapies, and the need to minimize costs incurred," might be widely used in hospitals, and it was suggested that a process might be established by which this could be done without "requiring the IND [investigational new drug application] process, provided they are performed according to Canadian Health Protection Branch (HPB) approved guidelines in medical centers accredited according to HPB guidelines." (97) To date, no such process has come into being, but it may be time to revisit this proposal or some variation of it.

Any proposals to regulate the services or medical practices involved in tissue engineering would, however, have to take account of the division of powers and its impact on our legal framework. In Canada, the distinction between products and practices has a constitutional dimension, since the regulation of therapeutic products pursuant to the Food and Drugs Act falls under federal jurisdiction, while the regulation of medical practice and other aspects of health services is within the jurisdiction of the provinces. The question of the extent of Health Canada's authority has already arisen in the CTO Regulations, for example, where the federal government had to delineate the limits of its responsibilities for the safety of tissues and organs vis-a-vis provincial jurisdiction over transplant medicine. (98) The boundary between federal regulation of medical products and state regulation of medical practice is also being debated in the context of regulation of stem cell therapies in the United States. (99) The Supreme Court of Canada recently addressed the issue of federal jurisdiction over health-related matters in the reference regarding the Assisted Human Reproduction Act. (100) A majority of the Court held that some provisions of that legislation were not valid exercises of the federal criminal law power but attempts to regulate medical practice, which falls within provincial jurisdiction. (101) Of particular relevance to the regulation of tissue engineering and regenerative medicine more generally, among the provisions said to be beyond federal jurisdiction were those that required certain activities and premises to be licensed. (102) The federal structure is thus an important factor that will need to be taken into consideration and is likely to present some challenges for the effective regulation of tissue engineering.

It remains very likely, however, that at least some tissue engineered products will indeed fall within the existing therapeutic products regulatory framework. The next question is how those would be classified. Drugs, biologics, and medical devices can have similar therapeutic purposes, so their classification depends on their characterization (whether as a "substance or mixture of substances" or an "article, instrument, apparatus or contrivance") and the way in which they achieve those purposes. The regulation of each type has traditionally been quite distinct, with separate regulations, a discrete administrative unit responsible for each product type, (103) and separate application and guidance documents, application lees, and administrative processes. The divide between drugs and devices, in particular, has historically been quite significant. For example, there are separate international organizations dealing with the harmonization of drug regulation (the International Conference on Harmonisation), on one hand, and device regulation (Global Harmonization Task Force and the new International Medical Device Regulators' Forum), on the other. (104) The evidence required to support an application for approval of a drug is typically more extensive than for devices, although this depends very much on the class of device, with Class I requiring no application at all, whereas Class IV devices would require submission of safety, efficacy, and quality evidence similar to that required for a drug.

Since the regulatory "pathways" are different for drugs, biologics, and devices, it is important for a sponsor developing a product to know how it will be classified. For tissue engineering, this can be problematic in two related respects: first, there can be uncertainty as to what classification will be applied to a product, especially as between biologics and devices, and second, there are issues as to how a product will be regulated where it combines elements of two or more product types. In the early history of tissue engineering and regenerative medicine, there have been several examples where the same product or similar products have been classified as a biologic or as a device, either by different regulatory agencies or at different points in time by the same agency. (105) For example, the FDA approved a cartilage repair product called Carticel[TM] as a device, but later required a biologics licence application for the same product. (106) Furthermore, given the complex nature of tissue engineered products, they contain elements of biologics (cells), devices (scaffolds), and often drugs as well (molecular signals). How should such a product be classified?

Modern regulatory regimes have evolved to account for the possibility that some products might contain components of different product categories. These are referred to as "combination products." In the United States regulations, the definition of a combination product includes: "A product comprised of two of more regulated components (i.e. drug/device, biologic/device, drug/biologic, or drug/device/biologic) that are physically, chemically, or otherwise combined or mixed and produced as a single entity." (107) The definition also covers two or more separate drug, device, or biological products that are packaged together as a single unit, and drug, device, or biological products that are packaged separately but intended only for use with a specific other drug, device, or biological product. (108) These would include things like a drug of biological packaged with of intended for use with a delivery device. Tissue engineered products would fall under the first type, in which different product categories (at least biologics and devices, and possibly all three categories) are combined into a single entity. Other examples of single-entity combination products would include a device coated with a drug or a transdermal patch used to deliver a drug. (109) The FDA has approved, as combination products, a bone graft product containing genetically engineered human protein and an absorbable collagen sponge (110) and a syringe filled with bovine collagen and bovine thrombin for use in controlling bleeding during surgery. (111)

The assessment of a combination product is assigned to one of three centers (for drugs, devices, or biologics) within the FDA according to its "primary mode of action" (PMOA). (112) For example, if the PMOA is from the drug component of the product, the review will be assigned to the Center for Drug Evaluation and Research. The PMOA has been defined as "the single mode of action of a combination product that provides the most important therapeutic action." (113) In cases where it is not possible to determine which mode of action is primary "with reasonable certainty," an "algorithm" is used to determine the center to which the product should be assigned. This will be the center that "regulates other combination products that present similar questions of safety and effectiveness," or of there are no such products, to the center "with the most expertise related to the most significant safety and effectiveness questions presented by the combination product." (114) The FDA has an Office of Combination Products which makes the determination of PMOA and assigns the product to a centre for assessment, and then coordinates the review. The regulations specify that although one center will have primary jurisdiction, "this does not preclude consultations by that component or, in appropriate cases, the requirement by FDA of separate applications." (115)

Presently, Canada's legislation does not recognize combination products; there are no provisions relating to combination products in the current Food and Drugs Actor any of the regulations. A bill introduced in federal Parliament in 2008 would have amended the Food and Drugs Act to recognize combination products for the first time in our legislation.116 Amended provisions would have created a new general definition of "therapeutic product" which would have included: (a) a drug; (b) a device; (c) cells, tissues or organs "distributed or represented" for a therapeutic purpose; and (d) a "combination of two or more of the things referred to in paragraphs (a) to (c)." (117) This amendment would have provided a more solid foundation for the regulation of combination products, and therefore would have been a useful first step, but the Bill does not provide any details as to how these products would be regulated. Health Canada is continuing to pursue a program of legislative and regulatory "modernization," (118) but it is not yet clear whether this will include a new approach to combination products and as of the date of writing, no new bill or proposed new regulations have been made public.

In the absence of specific legislative provisions, Health Canada's approach to combination products is outlined in a Policy, the current version of which dates from 2006. (119) This Policy is described as an "interim mechanism to address the gap in the current regulatory schemes" pending legislative amendments. (120) The Policy essentially follows the U.S. approach of basing classification decisions on the PMOA (though using the slightly different phrase "principal mechanism of action"). It states that a combination product "will be subject either to the Medical Devices Regulations or the Food and Drug Regulations according to the principal mechanism of action by which the claimed effect or purpose is achieved." (121) If the PMOA is "pharmacological, immunological, or metabolic" then the product will be subject to the Food and Drug Regulations (unless this action occurs only in vitro); otherwise, it will be subject to the Medical Devices Regulations. (122) Unlike the U.S. regulations, the Canadian Policy has no provision to address the situation in which it cannot be determined which mode or mechanism of action is primary. The sponsor of a combination product can apply for a classification decision before applying for approval for investigational testing (clinical trials) or marketing. (123) A number of commentators have raised questions about the prevailing approach to regulating combination products, and in particular the PMOA approach. As one critic explains: "The ambiguity [of PMOA] is intrinsic to the phrase itself. It assumes that every combination product has a primary mode of action. Unfortunately, a combination product can have two or more 'therapeutic actions' equally contributing to a product's 'overall therapeutic effects.' This can result in similar products being assigned to different centers." (124) The FDA's approach has been criticized as "'yielding a lack of consistency, predictability and transparency." (125) The PMOA concept is especially problematic for tissue engineered products, which integrate chemical and physical functions. (126) The new generation of products involves not just the combination of discrete components, but the convergence of technologies which interact with each other and with the body to produce a therapeutic effect. Consider, for example, a tissue engineered product for wound healing that uses engineered skin made of stem cells and a scaffold to cover the wound, and includes genetically modified cells or a gene-activated matrix to promote regeneration in surrounding tissue. (127) Could we predict with any certainty what would be considered the PMOA of such a product? Where nanomaterials are incorporated into a product, this makes matters even more difficult: at "the nanoscale, ... chemical and mechanical action are not easily distinguishable." (128) Thus, for novel complex products, determining which mode of action is the primary one is difficult, if not impossible, making the PMOA criterion inappropriate or unsuitable. (129) The FDA's algorithm to assign products to the center with the most experience with similar products or similar safety and effectiveness issues may help in some cases, but has also been criticized; (130) in any event it has not yet been adopted in Canadian law or policy.

How serious are these concerns? At the end of the day, what is most important is that each product receives a full and fair assessment based on evidence that addresses the critical safety, efficacy, and quality issues that could affect a determination as to whether it should be used in human patients. Do the difficulties in classifying combination products interfere with this fundamental objective? Certainly some of what follows from a product's classification involves matters that, while not insignificant, do not touch the core purposes of the regulatory scheme; for example, the application lees to be paid by sponsors differ according to whether the product is classified as a drug or device under the combination products Policy. (131) Although the Policy states that either the Medical Devices Regulations or the Food and Drug Regulations will apply, it also provides that regardless of a combination product's classification, "both the primary and ancillary components shall meet acceptable standards of safety, efficacy and quality." (132) This should ensure that all relevant issues are addressed, whichever classification is applied.

However, under the Policy, a sponsor applying for approval of licensing "is required to attest ... that the ancillary component of the combination product meets acceptable standards of safety, efficacy and quality." (133) The application would have to include evidence supporting claims of safety, efficacy and quality for the primary component, but for the component that is considered "ancillary," only attestation is required. This is particularly problematic where, as in the case of tissue engineered products, the designation of primary and ancillary components is difficult and therefore may be rather arbitrary. This limitation is ameliorated somewhat by another provision in the Policy stating that "[a]dditional information to support the safety, efficacy or quality of either component of the combination product may be requested during the review period." (134) One would expect that supporting evidence would be requested for any components that are novel, complex, or involve significant risks. From a sponsor's perspective, however, this is less than ideal, since it will not know at the time of applying what evidence the regulatory agency will demand. To some extent this can be mitigated by informal discussions with agency staff, but this approach still creates uncertainty for a product sponsor. As to the review of applications, the Policy states that it "will be undertaken according to the expertise required to assess the risk/benefit profile of the product," which can include review by "a team of reviewers" from more than one administrative unit (e.g. drugs, biologics, or devices). It does not, however, provide for any equivalent to the FDA's Office of Combination Products that would coordinate this review. In summary, it is possible for tissue engineered products to receive a fair and adequate review under Health Canada's current combination products Policy, but changes could be made to make the process more consistent, transparent, and predictable.

Ultimately, what is most important is that each application receives a review by the regulatory agency that is appropriate in the sense that it will consider the most significant safety, efficacy, and quality issues, and be conducted by those who have sufficient expertise to assess the evidence on those questions. There is no single legislative of administrative model that will ensure this, though some will work better than others. The substantive requirements that apply to a combination product must take account of all of the relevant components and the interaction between them. In order to have comprehensive review without undue delays and cumbersome processes, internal coordination and a clear and accessible single point of contact for applicants are critical.

C. Alternative Approaches to Regulating Complex Products

If the PMOA approach to combination products is rejected, what alternatives might work better? A few authors have suggested, in the U.S. context, that there should be a distinct center for combination products within the FDA, (135) rather than the current Office of Combination Products which mostly plays a coordinating role while the centers carry out substantive review. It is not clear that this would necessarily be an optimal arrangement, though, because it might result in an inefficient duplication of resources and expertise. Administrative reorganization also would not resolve issues about the regulatory requirements that would apply, including the format of applications and the supporting evidence that would be required. Another, more radical, suggestion is to eliminate the jurisdictional divides within the FDA, moving to a more flexible approach rather than assigning products to specific centers to review. (136) This approach also has some disadvantages, however. A flexible approach is appealing in some respects but relies more on agency discretion, which can be problematic. (137) Generally, "[i]nnovators and the manufacturers of innovations want regulatory predictability and certainty," even at the cost of flexibility. (138)

An important development in the European regulatory framework provides an example of an alternative approach. In 2007, the Advanced Therapy Medicinal Products Regulation (ATMP Regulation) was adopted, (139) and created a specific new regulatory classification of "tissue engineered product." The definition of ATMP includes three product types: somatic cell therapy and gene therapy products, categories that had already been defined in earlier regulations, and tissue engineered products. (140) "Tissue engineered product" is defined as:

... a product that:

--contains or consists of engineered cells or tissues, and

--is presented as having properties for, or is used in or administered to human beings with a view to regenerating, repairing or replacing a human tissue.

Although this category and definition were introduced for the first time in the 2007 ATMP Regulation, it is debatable whether a regulatory gap previously existed in Europe with respect to tissue engineered products, or whether they would have been (and in fact had been) simply dealt with under previously existing categories. (142) Nevertheless, the ATMP Regulation represents a significant advance for several reasons. One is that it sets out a clear procedure for centralized approval of ATMPs, providing a clear pathway for sponsors to get a single approval to market an ATMP in any EU country. This aspect is very important for anyone wanting to market a tissue engineered product in Europe, but it is not particularly relevant as a model for Canada. Of greater interest for our purposes are the definitions of new regulatory classifications and the relationships between them, and institutional innovations that accompanied these substantive changes.

Given the challenges of fitting an innovative technology like tissue engineering into existing regulatory classifications, the idea of creating a new, specialized category has some appeal. However, the creation of a new category of tissue engineered products did not entirely displace the preexisting categories of drugs (or "medicinal products" in the European terminology) and devices. The Directives that govern medicinal products and medical devices continue to apply to ATMPs, as modified by the ATMP Regulation. (143) The European regime also uses the concept of PMOA (in Europe referred to as "principal mode of action") to determine which of these Directives should apply to combination products. (144) Under the Regulation, marketing authorizations for ATMPs are given by the European Medicines Agency (EMA) based on the opinion of the Committee for Medicinal Products for Human Use (CHMP), just like other medicinal products. (145) However, a key difference is that for ATMPs, the CHMP is advised by a new Committee for Advanced Therapies (CAT); (146) the CHMP is expected to follow the opinion of the CAT and it not, must explain the reasons for giving a divergent opinion. (147) This ensures that the primary review body is the CAT, which has specialized expertise in advanced therapies.

The Regulation also defines and has specific provisions for a "combined advanced therapy medicinal product": a product that incorporates "as an integral part of the product, one or more medical devices ... or one or more active implantable medical devices" as well as a cell and tissue component that contains "viable cells or tissues." (148) Tissue engineered products that incorporate a scaffold component as well as cells would likely fall within this definition. (149) The device component of a combined ATMP must meet the requirements for devices set out in other relevant EU directives, (150) and evidence of this must be included in the application for marketing authorization. (151) The EMA conducts a final evaluation of the "whole product" based on this information and the assessment or opinion of the body responsible for devices. (152) The evaluation of combined ATMPs was among the "most discussed issues" in debates on the new Regulation, (153) and the provisions on combined ATMPs certainly do not eliminate all of the challenges with review of these products. (154) However, the ATMP Regulation does contain important provisions that should help to provide greater clarity. Although the PMOA criterion still applies, the Regulation provides that for any product that "contains viable cells or tissues, the pharmacological, immunological or metabolic action of those cells or tissues shall be considered as the principal mode of action of the product." (155) This significantly reduces the uncertainty as to the PMOA for tissue engineered products, and confirms that they are to be regulated under the ATMP. The Regulation also sets out priority rules for classification where

a product would fall within more than one type of ATMP: if a product falls within the definition of a somatic cell therapy medicinal product and a tissue engineered product, it will be considered as a tissue engineered product; if it falls within the definition of a somatic cell therapy medicinal product or tissue engineered product and a gene therapy medicinal product, it will be considered as a gene therapy medicinal product. (156) This type of rule "is beneficial because it reduces uncertainty about which regulatory requirements should apply." (157)

Furthermore, the ATMP Regulation contains a novel exemption that could go some way to addressing the issue, mentioned above, of whether a full approval process is needed for individualized tissue engineering innovations that do not fit the standard "product" or clinical trial model. Although the Regulation mandates centralized approval of all ATMPs before they are placed on the market, the "hospital exemption" excludes from this requirement products that are "prepared on a non-routine basis according to specific quality standards, and used within the same Member State in a hospital under the exclusive professional responsibility of a medical practitioner, in order to comply with an individual medical prescription for a custom-made product for an individual patient." (158) The regulation of these products is left to member states, but the Regulation imposes minimum requirements for national regulation, including traceability, pharmacovigilance, and quality standards equivalent to those imposed on other ATMPs. (159) It is worth considering whether this exemption could be a model for Canada, although its implementation would likely raise jurisdictional issues in our context.

Just as important as the substantive provisions in the ATMP Regulation--or perhaps even more so--are the institutional innovations that have been put in place by the Regulation. The creation of the CAT is important because it brings together specialized expertise relevant to advanced therapies such as cell therapy and tissue engineering. (160) An expert committee to provide advice to the CHMP should improve the quality of review for these products. The Regulation also provides for the formulation of guidelines for good clinical practice (GCP) and good manufacturing practice (GMP) that are specific to ATMPs. (161) Although, as will be seen below, the EMA is not alone in making progress with providing guidance on issues relating to cell and tissue therapies and other advanced biomedical technologies, provision for specialized GCP and GMP guidelines is useful. Finally, experts in the field have observed that "the EU authorities have already made headway with the procedural issues" involved in the review of tissue engineered products, including the drafting of terms of engagement between the relevant bodies. (162) Therefore, the ATMP Regulation and its implementation provides one model to which Canada can look in seeking to improve its regulatory framework for tissue engineering.

D. Regulatory challenges with tissue engineered products

Regardless of how they are defined or classified, tissue engineered products will present significant challenges for regulatory agencies. Tissue engineering uses several novel technologies, each of which raises issues with respect to the application of regulatory requirements for safety, efficacy, and quality. The most important of these will be reviewed in this section. Furthermore, these issues are multiplied and unique challenges are presented by the integration of diverse technological innovations into a single product. In tissue engineering, perhaps more than any other area of biomedical technology, "what is technically possible risks outstripping the ability of regulatory frameworks to cope with the resulting products." (163)

All tissue engineering involves the use of cells, often stem cells. There has been a great deal of discussion in recent years about the need to adapt regulatory requirements to the unique characteristics of cell and tissue products, and especially stem cell-based therapies. Traditional concepts that have been used to assess drugs and even biologics do not always translate well in this context. For example, basic principles of pharmacokinetics (e.g. absorption and excretion of pharmaceuticals), which play an important role in assessing pharmaceutical products, do not apply to stem cell-based products. (164) Concepts of purity and potency that are commonly used in quality testing have to be adapted for products composed of living cells. (165) Animal models, which are normally used in preclinical studies to assess safety and efficacy, are more difficult to design and evaluate, and their value may be more limited, where the product is composed of human cells and tissues. (166) Stem cell-based products also have specific risks in addition to those, like infection or immune rejection, that are present with other cell and tissue therapies. (167) It is important to ensure that stem cells differentiate into the desired cell types, (168) for reasons of both safety and efficacy. Some stem cells, especially hESCs, have a propensity to form tumours or teratomas, (169) there fore any undifferentiated stem cells remaining in the product when it is implanted may present a risk to the recipient. Regulatory agencies have already made some progress in identifying and addressing these issues. For example, the FDA has issued guidance documents on several cell therapy topics, (170) and the EMA has adopted a Guideline on Human Cell-Based Medicinal Products (171) and a "reflection paper" on stem cell-based products. (172)

Tissue engineering may use xenogeneic source material (material from other animal species) for either scaffolds or cells. It is also possible that xenogeneic materials might be used in processing, such as in cell culturing. Where a human patient is exposed to any xenogeneic materials, a risk of zoonotic infection exists. Zoonoses, or infectious diseases transmitted across species, raise specific safety concerns and therefore regulatory agencies have developed guidance documents on xenotransplantation and the use of non-human animal materials in therapeutic products. For example, as mentioned earlier, Health Canada has issued guidance on medical devices that incorporate animal tissue. (173) The FDA and EMA have also released guidance documents on xenotransplantation and xenogeneic cell-based products, respectively. (174)

Gene therapy and genetic modification have been the subject of considerable public attention and debate, and present significant safety issues for regulatory agencies. In tissue engineering, genetic modification can be used as a way of influencing cell function, or the engineered tissue can be a vehicle for gene transfer that is intended to have either local or systemic effects. (175) Within Health Canada, genetic therapies fall under the responsibility of the Biologics and Genetic Therapies Directorate. The FDA has produced guidance documents on gene therapy, (176) as has the EMA, (177) where gene therapy products are now regulated under the new ATMP Regulation. (178)

As explained above, nanotechnology has been very important to the development of tissue engineering, and it is reasonable to expect that many future products will incorporate some type of nanomaterials. Though this promises a "major breakthrough" in tissue engineering, (179) it raises additional safety issues because of the special properties of nanoscale materials and uncertainty about how to test the safety of nanomaterials. (180) Nanomaterials are useful precisely because they have unique properties, but these present significant challenges for regulatory agencies. Of particular interest for therapeutic product regulation, nanomaterials interact differently with biological systems, and "can be more biologically active" than other materials. (181) Nanotechnology is growing very quickly and although some nanotechnology products have already been approved, we have no long-term experience with them of established methods of assessing their safety. (182) There are still "gaping holes" in our knowledge about how nanomaterials will interact with the human body. (183) Furthermore, nanotechnology is in fact "not one technology, but many": (184) the term "incorporates a broad, diverse range of materials, technologies, and products, with an even greater spectrum of potential risks and benefits." (185) Even within the limited realm of tissue engineering, different technologies may create distinct risks. For example, self-assembly of nanoparticles may present particular challenges because the self-assembling processes must be controlled. (186)

Regulatory agencies, including Health Canada, have been working to address these challenges, but their efforts are still at a fairly early stage. For example, Health Canada and the FDA have both recently released documents that aim to define nanomaterials for regulatory purposes. (187) Canada can benefit from the ongoing work of larger agencies such as the FDA and the EMA to develop further guidance and testing methods for nanotechnology products. (188) However, a recent assessment of the European therapeutic products regime concluded that "appropriate regulatory responses [to nanomedicines] have not yet been developed." (189) As to the FDA in the United States, "it is unclear whether ... existing structures and the institutional structure of the FDA itself are suited to effectively oversee nanotechnology products. Questions exist as to whether there is adequate capacity to extend into this rapidly progressing area." (190) There is no reason to believe that Canada is any further ahead.

The regulation of tissue engineered products can draw on what has been learned so far in regulating other types of products that use some of these emerging technologies, such as stem cell-based therapies or nanomedicines. However, once several technologies are combined into a single tissue engineered product, unique issues arise. A tissue engineered product is more than the sum of its parts: its components and the technologies used in their production will interact, and in part it is this interaction that creates the functionality of the engineered tissue. For example, the nanomaterial scaffolds described above influence cell behaviour and development, and in some cases, the cells act on the scaffolds as well. Tissue engineered products "are not defined solely by components alone because product assembly and cell-scaffold interactions also influence the characteristics of the final product." (191) This means that it will be necessary not only to test each component for safety and quality, but also the combined construct. (192)

Furthermore, many of these interactions will occur after the engineered tissue has been implanted in the patient's body, and may change over time as the scaffold degrades and cells develop. Tissue engineered products "may not be in their final form when administered to patients, as in vivo remodeling can occur. This unusual situation may preclude complete functionality testing." (193) In other words, we will not know exactly how the product functions until after it has been implanted: "the final product specifications determined through in vitro testing may not provide predictive information about clinical safety and efficacy of the product because of remodeling of the cell-scaffold construct in vivo." (194) Even preclinical animal studies are likely to be of limited value. It is generally recommended that preclinical animal studies use "the clinical product in its final formulation ... whenever possible," (195) but this will often be difficult or impossible for products that are designed for the human body and contain human cells, and even if the same final product is used, it may interact differently with the body of a different species.

Bearing in mind all of these issues, consider the challenges facing a regulatory agency charged with reviewing an application for approval of a tissue-engineered product that uses a combination of two, three, or more of these novel technologies, e.g. stem cells, nanotechnology, and genetic modification. The review is expected to protect the public from any undue safety risks and ensure that the product will work as intended. For a regulatory agency to have any real hope of carrying out its mandate in a satisfactory manner and within a reasonable time, it must have adequate resources and expertise at its disposal. "The main barrier to regulatory flexibility is probably expertise." (196)

Unfortunately, Health Canada is already facing considerable pressures with respect to its regulatory capacity, and it is not alone. The Auditor General of Canada has criticized Health Canada with respect to the resources allocated to core functions in regulatory programs including drug products and medical devices. A 2006 report found that funding for core activities had declined or remained constant while demands on the programs continued to grow. (197) Furthermore, Health Canada had not defined the level of activity or resources required to meet its regulatory responsibilities, and therefore "does not know if it is fully meeting its responsibilities as the regulator of drug products, medical devices, and product safety." (198) The Auditor General's report recommended that "Health Canada should review the core funding allocated to regulatory programs to ensure that all programs receive sufficient funding to meet regulatory responsibilities and to adequately protect the health and safety of Canadians." (199) Five years later, another report focusing on the regulation of medical devices found that funding had increased and steps had been taken to address funding shortfalls. (200) However, it also found that Health Canada was not meeting its obligations for "timely review of medical devices applications" and still did not know whether it was meeting other obligations. (201) The failure to meet services standards for timely review was said to be due to funding shortfalls. (202) New regulations regarding fees for drug and medical device applications are intended to address funding shortfalls and their impact on Health Canada's ability to carry out its responsibilities in a timely manner, partly in response to the Auditor General's recommendations. (203) This should help to some extent, but the move to a cost-recovery model also brings with it other challenges. (204)

Although the U.S. FDA is one of the largest and most sophisticated therapeutic products regulatory agencies in the world, it has also faced a lack of sufficient funds and staff. (205) The FDA has been described as "chronically underfunded," (206) and a survey of experts found that the FDA's capacity (including expertise, personnel, and financial resources) was inadequate for both drugs and medical devices. (207) A recent external review has recommended major changes to the FDA's approach to regulating medical devices, noting, in particular, the impact of the growing number and complexity of devices and combination products. (208) Another recent report, by a task force within the FDA, found that it is difficult for staff "to share scientific knowledge ... in part due to staffing limitations, and to tap meaningful scientific expertise in a timely manner." (209) All of this is consistent with an assessment published in 2008 that concluded:

Even if the current situation is better than this assessment suggests, it is still cause for grave concern.

Additional resources will be needed urgently to address these capacity issues. The challenges of building capacity go beyond the need for financial resources, however. Capacity is determined several components, including the authority and organization of the agency, financial resources, and human resources; (211) human resources include both the number and qualifications of personnel. (212) Particularly in a relatively small jurisdiction like Canada, it may be difficult to recruit sufficient numbers of qualified personnel with adequate expertise to deal with applications for complex products. Even finding external experts to provide assistance and advice to the regulatory agency may be difficult in a very specialized field. Addressing these limitations will require a strategy, backed by sufficient resources, to strengthen the pool of scientific expertise. Recent investments in safety and effectiveness research are encouraging, but still fall far short of what is needed. (213) The renewed attention to advancing "regulatory science" in the U.S. may provide a useful model. (214)

Any regulatory agency, even if well-resourced, would be hard pressed to develop adequate expertise in all of the specialized areas needed to regulate tissue engineering and other complex novel technologies. Particularly given that many biotechnology research and manufacturing networks are multinational if not global, cooperation between regulatory agencies will be increasingly important. One of the motivations behind the development of the EU ATMP Regulation and its implementation has been that "as new technologies arise, many, if not all, member states accept that their competent authorities may not have enough expertise to assess them, yet if they pooled this expertise across the EU this problem would be reduced." (215) Further efforts to share information and expertise will be critically important as the technology develops further. The existing formal mechanisms for harmonization may not be particularly well suited to this field, however, given that they reflect the traditional divide between drugs/biologics and devices. (216)

For any new technology, it will be a challenge to determine what data is required to show safety, efficacy, and quality of a product. (217) if is probably fair to say, with respect to uncertainty about data requirements, that "the hurdle is not the regulation but rather the science," (218) in the sense that the uncertainty results from our incomplete understanding of the science underlying a product, rather than any uncertainty or other problem with the regulations themselves. However one describes it, though, this uncertainty will be a challenge for regulatory agencies as well as researchers and manufacturers. Meeting this challenge will require a substantial investment in financial and human resources to enhance the capacity of regulatory agencies. If governments expect to reap the economic benefits of progress in biomedical technology, (219) they must be prepared to provide these resources. It is not enough to invest in research and development; we also need to invest in regulatory capacity and mechanisms of international cooperation so that the products of research and development can be assessed in a timely and effective manner.

III. Conclusion

Regulating tissue engineered products is just one of many challenges currently facing regulatory agencies that oversee therapeutic products. However, it is an important one, given the potential impact of tissue engineering for patients and for the development of medicine. It also highlights some common issues, like legislative reform and strengthening capacity, where progress would benefit not only tissue engineering but virtually any field developing medical products.

At present, Canada's regulatory framework is not particularly well-placed to deal with tissue engineered products. Legislative and policy reform are needed to address several issues. It has long been recognized that novel cell and tissue therapies might be developed and used experimentally with individual patients, in ways that do not fit the conventional model of mass manufacture and testing in phased clinical trials. However, no mechanism currently exists to accommodate these. The hospital exemption in the EU ATMP Regulation could provide a model, though its implementation within our federal system may prove challenging. Our therapeutic products legislation-recently described as "antiquated" (220)--needs to be updated to conform, at least, to current practice. This would include, for example, amending the definition of biologics and creating a category of combination products. For combination products in particular, however, there is a danger that reforming our legislation to give effect to current policy could end up enshrining a regulatory model that has already been widely criticized as outdated and ineffective. Tissue engineered products provide an excellent case study against which to test regulatory approaches like the PMOA criterion, because of the ways in which they exemplify the convergence and interaction of emerging technologies. Any new regulatory framework should be prepared to address products like these that depend on the interaction of different technologies and modes of action to achieve their therapeutic purpose.

Canadian researchers and regulatory authorities can benefit from the considerable work done elsewhere, for example by the FDA and the EMA, to develop and adapt regulatory standards for emerging biomedical technologies like stem cell therapy, gene therapy, and nanotechnology. It is obvious, however, that much work remains to be done by regulatory agencies and researchers alike to address scientific questions surrounding the risks and benefits of novel types of therapies. Furthermore, in the area of tissue engineering, we need not only to understand the safety and efficacy issues associated with distinct areas of technology like nanotechnology or genetic modification, but also the complex interactions between each of them, all of them together, and between the integrated product and the body after implantation. This complexity will make assessments of safety, efficacy, and quality more challenging than ever.

Legislative and policy developments will be helpful in addressing these challenges, but none will allow tissue engineered products to be adequately regulated without the necessary capacity. Unfortunately, recent assessments of the financial and human resources of agencies like Health Canada and the FDA are not encouraging. There have been some promising developments, such as efforts to increase agency funding and to stimulate and invest in the development of regulatory science. However, if our society is to reap the full benefits of tissue engineering and other exciting medical technologies, we will need much greater investment in regulatory capacity. We will also need to explore and invest in mechanisms of cooperation and harmonization that will allow regulatory agencies to combine their resources and expertise. The complex challenges of regulating tissue engineering not only show the importance of efforts to pool relevant expertise, but suggest that new mechanisms may be required--for example, transcending the drug/device divide that currently persists in international harmonization organizations, and learning from the specialized expert committee created in Europe by the ATMP Regulation.

The challenges of regulating tissue engineered products are daunting, but meeting them will be worthwhile. If this revolutionary technology can deliver even part of what it seems to promise for patients, it would be short-sighted not to invest in its success. The improvements in legislation, policy, and regulatory capacity that are required could also have widespread benefits for other emerging therapies, and bolster confidence in our ability to regulate more effectively the next "next generation" of biomedical technology.

(1) Josh Fischman, "How to Build a Body Part" (1 March 1999) Time Magazine, online: .

(2) U Meyer, "The History of Tissue Engineering and Regenerative Medicine in Perspective" in Ulrich Meyer et al, eds, Fundamentals of Tissue Engineering and Regenerative Medicine (Berlin: Springer, 2009) 5 at 8; Nicholas D Evans, Eileen Gentleman & Julia M Polak, "Scaffolds for Stem Cells" (2006) 9:12 Materials Today 26 at 28.

(3) Robert Langer & Joseph P Vacanti, "Tissue Engineering" (1993) 260 Science 920 at 920.

(4) British Standards Institution, Regenerative Medicine--Glossary (April 2008), online: British Standards Institution at 6.

(5) Chris Mason & Peter Dunnill, "A Brief Definition of Regenerative Medicine" (2008) 3:1 Regenerative Medicine 1 at 4.

(6) Heather L Greenwood et al, "Regenerative Medicine: New Opportunities for Developing Countries" (2006) 8 International Journal of Biotechnology 60 cited in Mason & Dunnill, ibid., at 4.

(7) See e.g. Giuseppe Orlando et al, "Regenerative Medicine and Organ Transplantation: Past, Present, and Future" (2011) 91:12 Transplantation 1310 at 1312; Rob B de Vries et al, "Ethical Aspects of Tissue Engineering: A Review" (2008) 14:4 Tissue Engineering: Part B 367 at 367; N de Isla et al, "Introduction to Tissue Engineering and Application for Cartilage Engineering" (2010) 20 BioMedical Materials and Engineering 127 at 127-128.

(8) See e.g. US Food and Drug Administration, Draft Guidance for Industry and Food and Drug Administration Staff : The Content of Investigational Device Exemption (IDE) and Premarket Approval (PMA) Applications for Low Glucose Suspend (LGS) Device Systems (22 June 2011), online: Food and Drug Administration (regarding a device known as an "artificial pancreas").

(9) Meyer, supra note 2 at 8.

(10) Ibid.

(11) Ibid at 9.

(12) Ibid.

(13) Langer & Vacanti, supra note 3.

(14) Robert M Nerem, "Regenerative Medicine: The Emergence of an Industry" (2010) Journal of the Royal Society Interface S771 at S771-S772.

(15) Ibid. at S772-S773; Michael J Lysaght & Anne L Hazlehurst, "Tissue Engineering: The End of the Beginning" (2004) 10 Tissue Engineering 309.

(16) See Orlando et al, supra note 7 at 1311-12.

(17) Anthony Atala et al, "Tissue-Engineered Autologous Bladders for Patients Needing Cystoplasty" (2006) 367:9518 Lancet 1241.

(18) Atlantida Raya-Rivera et al, "Tissue-Engineered Autologous Urethras for Patients Who Need Reconstruction: an Observational Study" (2011) 377:9772 Lancet 1175.

(19) Paolo Macchiarini et al, "Clinical Transplantation of a Tissue-Engineered Airway" (2008) 372:9655 Lancet 2023.

(20) Michelle Roberts, "Windpipe Transplant Breakthrough", BBCNews (19 November 2008) online: BBC News .

(21) Anthony Hollander et al, "The First Stem Cell-Based Tissue-Engineered Organ Replacement: Implications for Regenerative Medicine and Society" (2009) 4:2 Regenerative Medicine 147.

(22) Silvia Baiguera et al, "Tissue Engineered Human Tracheas for in vivo Implantation" (2010) 31 Biomaterials 8931.

(23) University College London, "UCL Surgeons Perform Revolutionary Transplant Operation" (19 March 2010), online: UCL Centre for Stem Cells and Regenerative Medicine .

(24) Sam Lister, "'Milestone Moment' as Boy Undergoes Transplant to Regenerate Trachea", The Times (20 March 2010) online: The Times .

(25) Karolinska Institutet, News Release, "First Successful Transplantation of a Synthetic Tissue Engineered Windpipe" (7 July 2011) online: .

(26) Pedro M Baptista et al, "The Use of Whole Organ Decellularization for the Generation of a Vascularized Liver Organoid" (201l) 53:2 Hepatology 604; Alejandro Soto-Gutierrez et al, "A Whole-Organ Regenerative Medicine Approach for Liver Replacement" (2011) 17:6 Tissue Engineering: Part C 677.

(27) Silvia Baiguera et al, "Development of Bioengineered Human Larynx" (2011) 32:19 Biomaterials 4433.

(28) Thomas H Petersen, Elizabeth A Calle & Laura E Niklason, "Strategies for Lung Regeneration" (2011) 14:5 Materials Today 196; Thomas H Petersen et al, "Tissue-Engineered Lungs for in Vivo Implantation" (2010) 329:5991 Science 538; Harald C Ott et al, "Regeneration and Orthotopic Transplantation of a Bioartificial Lung" (2010) 16 Nature Medicine 927.

(29) Frederic G Sala et al, "A Multicellular Approach Forms a Significant Amount of Tissue-Engineered Small Intestine in the Mouse" (2011) 17:13-14 Tissue Engineering: Part A 1841.

(30) Amanda Pedersen, "Lab-grown Blood Vessels Help Hemodialysis Patients" (2011) 15:134 Medical Device Daily 1.

(31) Kerstin M Galler & Rena N D'Souza, "Tissue Engineering Approaches for Regenerative Dentistry" (2011) 6:1 Regenerative Medicine 111.

(32) Also exciting are the potential uses of tissue engineering in research, such as providing disease models to study ora source of tissue on which to test other medical products (as an alternative to animal testing): see Anthony Holmes, Robert Brown & Kevin Shakesheff, "Engineering Tissue Alternatives to Animals: Applying Tissue Engineering to Basic Research and Safety Testing" (2009) 4:4 Regenerative Medicine 579. These applications could be extremely important but raise different issues, so the discussion in this article will focus on direct clinical applications of tissue engineering.

(33) See Shane M Ward, "Global Harmonization of Regulatory Requirements for Premarket Approval of Autologous Cell Therapies" (2000) 55:2 Food & Drug LJ 225; Melissa K Carpenter & Larry A Couture, "Regulatory Considerations for the Development of Autologous Induced Pluripotent Stem Cell Therapies" (2010) 5:4 Regenerative Medicine 569; Maureen L Condic & Mahendra Rao, "Regulatory Issues for Personalized Pluripotent Cells" (2008) 26:11 Stem Cells 2753.

(34) Carole A Heath, "Cells for Tissue Engineering" (2000) 18 Trends in Biotechnology 17-19 at 17.

(35) Ibid.

(36) Kazutoshi Takahashi et al, "Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors" (2007) 131:1-12 Cell 1.

(37) See Marie Csete, "Translational Prospects for Human Induced Pluripotent Stem Cells" (2010) 5:4 Regenerative Medicine 509; Sean M Wu & Konrad Hochedlinger, "Harnessing the Potential of Induced Pluripotent Cells for Regenerative Medicine" (2011) 13 Nature Cell Biology 497 at 498-500.

(38) David Williams, "Benefit and Risk in Tissue Engineering" (2004) 7:5 Materials Today 24 at 27.

(39) See e.g. Stelios T Andreadis, "Gene-Modified Tissue-Engineered Skin: The Next Generation of Skin Substitutes" (2006) 103 Advances in Biochemical Engineering/Biotechnology 241; Meredith Lloyd-Evans, "Regulating Tissue Engineering" (2004) 7:5 Materials Today 48 at 54.

(40) Silvia Baiguera, Martin A Birchall & Paolo Macchiarini, "Tissue-Engineered Tracheal Transplantation" (2010) 89:5 Transplantation 485 at 487.

(41) Ibid; Evans, Gentleman & Polak, supra note 2 at 28.

(42) Mason & Dunnill, supra note 5 at 1-2.

(43) See e.g. Petersen, Calle & Niklason, supra note 28.

(44) Williams, supra note 38 at 27.

(45) Marissa Peck et al, "Tissue Engineering by Self-Assembly" (2011) 14:5 Materials Today 218.

(46) See e.g. Macchiarini et al, supra note 19; Petersen et al, supra note 28.

(47) Peter M Crapo, Thomas W Gilbert & Stephen F Badylak, "An Overview of Tissue and Whole Organ Decellularization Processes" (2011) 32:12 Biomaterials 3233.

(48) Ibid at 3233.

(49) Evans, Gentleman & Polak, supra note 2 at 29-30.

(50) Williams, supra note 38 at 27; Mark H Lee et al, "Considerations for Tissue-Engineered and Regenerative Medicine Product Development Prior to Clinical Trials in the United States" (2010) 16:1 Tissue Engineering: Part B 41 at 45; Diane Longley & Pat Lawford, "Engineering Human Tissue and Regulation: Confronting Biology and Law to Bridge the Gaps" (2001) 5:2 Medical Law International 101 at 104.

(51) Cassandra M Kelleher & Joseph P Vacanti, "Engineering Extracellular Matrix through Nanotechnology" (2010) 7 Journal of the Royal Society Interface S717 at S724-25.

(52) Catherine Prescott, "Regenerative Nanomedicines: An Emerging Investment Prospective?" (2010) 7 Journal of the Royal Society Interface S783 at S783.

(53) Health Canada, Interim Policy Statement on Health Canada's Working Definition for Nanomaterials, (2010), online: Health Canada at 1-2; US Food and Drug Administration, Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology: Guidance for Industry (Draft Guidance) (14 June 2011), online: US Food and Drug Administration [Nanotechnology Draft Guidance].

(54) Prescott, supra note 52 at S783.

(55) Tal Dvir et al, "Nanotechnological Strategies for Engineering Complex Tissues" (2011) 6 Nature Nanotechnology 13 at 13.

(56) Kelleher & Vacanti, supra note 51 at S718.

(57) Ibid at S718-S720.

(58) Ibid.

(59) Ibid at S721.

(60) Ibid.

(61) Ibid at S722.

(62) Ibid.

(63) Ibid.

(64) Ibid at S724.

(65) Ibid at S723.

(66) de Vries et al, supra note 7 at 370-71.

(67) See e.g. Ibid at 368-69; Prescott, supra note 52 at S786; P Gelhaus, "Ethical Issues in Tissue Engineering" in Meyer et al, supra note 2, 23; Leen Trommelmans, Joseph Selling & Kris Dierickx, "An Exploratory Survey on the Views of European Tissue Engineers Concerning the Ethical Issues of Tissue Engineering Research" (2009) 15:3 Tissue Engineering Part B: Reviews 241; Mette Ebbesen & Thomas G Jensen, "Nanomedicine: Techniques, Potentials, and Ethical Implications" (2006) Journal of Biomedicine and Biotechnology 1; Heather L Greenwood & Abdallah S Daar, "Regenerative Medicine" in Peter A Singer, ed, The Cambridge Textbook of Bioethics (Cambridge: Cambridge University Press, 2008) 153.

(68) Greenwood & Daar, ibid at 156.

(69) Longley & Lawford, supra note 50 at 105.

(70) RSC 1985, c F-27 [F&DA].

(71) Ibid, s 2.

(72) Health Canada, Access to Therapeutic Products: The Regulatory Process in Canada (Ottawa: Health Canada, 2006) online: Health Canada at 26.

(73) F&DA, supra note 70, Schedule D.

(74) See e.g. Health Canada, "Biologics, Radiopharmaceuticals and Genetic Therapies" (2008), online: Health Canada .

(75) Food and Drug Regulations, CRC, c 870.

(76) F&DA, supra note 70, s 2.

(77) Medical Devices Regulations, SOR/98-282 [MDR].

(78) Safety of Human Cells, Tissues and Organs for Transplantation Regulations, SOR/2007-118.

(79) Ibid, s 3.

(80) Ibid.

(81) Food and Drug Regulation, supra note 75, Part C, Division 5.

(82) Ibid, Part C, Division 8.

(83) Ibid, s C.08.002(2).

(84) Ibid, Part C, Division 2.

(85) The definition includes such diverse products as: "pacemakers, artificial heart valves, hip implants, synthetic skin, medical laboratory diagnostic instruments, test kits for diagnosis and contraceptive devices." Health Canada, "Sale Medical Devices in Canada" (November 2007), online: Health Canada at 1.

(86) MDR, supra note 77, s 6, Schedule 1.

(87) Ibid, s 9 (manufacturer's obligation), ss 10-20 (safety and effectiveness requirements).

(88) Ibid, s 44.

(89) Ibid, s 26.

(90) Ibid, s 32.

(91) Ibid, Schedule I, Part 1, Rule 14(1)(a). The only exception is it such a device is "intended to come into contact with intact skin only": Ibid, Schedule 1, Part 1, Rule 14(2).

(92) Ibid, s 32(4)(i).

(93) Ibid, s 32(4)0).

(94) See nn 19-25, above, and accompanying text.

(95) Lloyd-Evans, supra note 39 at 50.

(96) Williams, supra note 38 at 28.

(97) May M Smith & Anthony AG Ridgway, "Tissue-Engineered Products: The Canadian Approach" (1997) 3:1 Tissue Engineering 85 at 86-87.

(98) See Health Canada, Guidance Document for Cell, Tissue and Organ Establishments: Safety of Human Cells, Tissues and Organs for Transplantation (Ottawa: Health Products and Food Branch, 2009) at 12-13.

(99) See Barbara von Tigerstrom, "The Food and Drug Administration, Regenerative Sciences, and the Regulation of Autologous Stem Cell Therapies" (2011) 66 Food & Drug L J 479 at 489-90.

(100) Assisted Human Reproduction Act, SC 2004, c 2.

(101) Reference re Assisted Human Reproduction Act, 2010 SCC 61. A full discussion of this decision and the relevant federalism issues is beyond the scope of this paper. For a discussion of some implications of the Reference decision for federal health legislation, including the Food and Drugs Act regime, see Barbara von Tigerstrom, "Federal Health Legislation and the Assisted Human Reproduction Act Reference" (2011) 74 Sask L Rev 33.

(102) Assisted Human Reproduction Act, supra note 100, ss 10, 11, 13. Reference re Assisted Human Reproduction Act, ibid at para 22 l, 265-73, 285-87, 294.

(103) Currently, Health Canada has a Therapeutic Products Directorate, which contains a Medical Devices Bureau and various units dealing with drugs, and a Biologics and Genetic Therapies Directorate, which deals with biologics and other cells and tissues.

(104) See International Conference on Harmonisation, "Vision" (2011), online: International Conference on Harmonisation ; Global Harmonization Task Force, "About GHTF" (30 June 2011), online Global Harmonization Task Force ; Health Canada, "Statement from the International Medical Device Regulators' Forum" (3 November 2011), online: Health Canada .

(105) See Kiki B Hellman & David Smith, "The Regulation of Engineered Tissues: Emerging Approaches" in John P Fisher, Antonios G Mikos & Joseph D Bronzino, eds, Tissue Engineering (Boca Raton, FL: CRC Press, 2007) 17-1 at 17-7 (Table 17.2).

(106) See ibid at 17-4; Lloyd-Evans, supra note 39 at 49.

(107) 21 CFR [section] 3.2(e)(1) (2010).

(108) 21 CFR [section] 3.2(e)(2)-(4) (2010).

(109) US Food and Drug Administration, Frequently Asked Questions About Combination Products, (2011) online: US Food and Drug Administration .

(110) US Food and Drug Administration, "Summary of Safety and Effectiveness Data: Infuse[R] Bone Graft: P050053" (9 March 2007), online: US Food and Drug Administration .

(111) US Food and Drug Administration, "Summary of Safety and Effectiveness Data: Vitagel[TM] Surgical Hemostat: P050044" (9 March 2007) online: .

(112) 21 CFR [section] 3.4(a) (2010).

(113) 21 CFR [section] 3.2(m) (2010).

(114) 21 CFR[section] 3.4(b)(2010).

(115) 21 CFR [section] 3.4(c) (2010).

(116) Bill C-51, An Act to amend the Food and Drugs Act and to make consequential amendments to other Acts, 2nd Sess, 39th Parl (2007-2008), cl 3(6) (The Bill was at the Second Reading stage when Parliament dissolved in September 2008; it has not yet been reintroduced).

(117) Ibid.

(118) See e.g. Natalie Bellefeuille et al, "Modernizing Canada's Regulatory Regime for Pharmaceuticals and Biologics" (2010) 16 Health Policy Research Bulletin 17; Health Canada, Health Canada Responds to Concerns about Therapeutic Product Regulatory Modernization Technical Discussions: Letter to the Editor (21 January 2011), online: Health Canada .

(119) Health Canada, Policy: Drug/Medical Device Combination Products, (2006), online: Health Canada [Combination Products Policy].

(120) Ibid at 1.

(121) Ibid at 2.

(122) Ibid at 2-3.

(123) Ibid at 3 (The parallel provisions in the US are at 21 CFR [section][section] 3.7-3.8).

(124) Mark Lavender, "Regulating Innovative Medicine: Fitting Square Pegs in Round Holes" (2005) Duke L & Tech Rev 1 at para 36 [footnote omitted].

(125) Ibid.

(126) Greenwood & Daar, supra note 67 at 156.

(127) See nn 39 and 51, above, and accompanying text.

(128) Jordan Paradise et al, "Evaluating Oversight of Human Drugs and Medical Devices: A Case Study of the FDA and Implications for Nanobiotechnology" (2009) 37:4 JL Med & Ethics 598 at 604.

(129) Laure Brevignon-Dodin, "Regulatory Enablers and Regulatory Challenges for the Development of Tissue-Engineered Products in the EU" (2010) 20:3-4 BioMedical Materials and Engineering 121 at 124; see also Longley & Lawford, supra note 50 at 104.

(130) Lavender, supra note 124 at para 34; Susan Bartlett Foote & Robert J Berlin, "Can Regulation Be As Innovative as Science and Technology? The FDA's Regulation of Combination Products" (2005) 6 Minn JL Sci & Tech 619 at 638-39.

(131) Combination Products Policy, supra note 119 at 4.

(132) Ibid at 3.

(133) Ibid at 4.

(134) Ibid.

(135) Lavender, supra note 114 at paras 43-44; Foote & Berlin, supra note 130 at 641.

(136) Foote & Berlin, supra note 130 at 642.

(137) Ibid at 642-43.

(138) Ibid at 644.

(139) EC, Regulation (EC) No 1394/2007 on Advanced Therapy Medicinal Products and Amending Directive 2001/83/EC and Regulation (EC) No 726/2004, [2007] O J, L 3241121 [ATMP Regulation].

(140) Ibid at art 2.1(a).

(141) Ibid at art 2.1(b).

(142) Christopher A Bravery, "Regulating Interface Science Healthcare Products: Myths and Uncertainties" (2010) 7 Journal of the Royal Society Interface S789 at S790-91.

(143) EC, Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use, [2001] O J, L 311/67; EC, Council Directive 90/385/EEC of 20 June 1990 on the approximation of the laws of the Member States relating to active implantable medical devices, [1990] O J, L 189/17; EC, Council Directive 93/42/EEC of 14 June 1993 concerning medical devices, [1993] OJ, L 169/1.

(144) Directive 90/385/EEC, ibid, at art 6(a); Directive 93/42/EEC, ibid, at art 5(c).

(145) ATMP Regulation, supra note 139 at art 5.

(146) Ibid at art 8.

(147) Ibid at art 8.4.

(148) Ibid at art 2.1(d) (The definition also includes products whose cell and tissue component contains non-viable cells or tissues if their action is primary: ibid at art 2.1(d)).

(149) This would include most it not all of what are currently thought of as tissue engineered products, but the definition of tissue engineered product in the Regulation does not correspond to current common usage of the term "tissue engineering" (see Bravery, supra note 142 at $791, comparing the EU definition to the BSI definition quoted above in text accompanying n 4); it could apply to any cell or tissue therapy that uses "engineered" cells or tissues (i.e. those that are substantially manipulated or for non-homologous use: ATMP Regulation, supra note 139 at art 2.1(c)).

(150) Ibid at art 6 (The requirements are contained in Directive 93/42/EEC, Annex I and Directive 90/385/EEC, Annex 1).

(151) ATMP Regulation, supra note 139 at art 9.2; See also art 7.

(152) Ibid. at arts 9.3, 9.4.

(153) Miroslav Mikolasik, "The European Union's Advanced Therapies Proposal: The Rapporteur's Perspective" (2007) 9:3-4 Pharmaceuticals Policy and Law 317 at 322.

(154) See e.g. Committee for Advanced Therapies (CAT) and the CAT Scientific Secretariat, "Challenges with Advanced Therapy Medicinal Products and How to Meet Them" (2010) 9 Nature Reviews: Drug Discovery 195 at 199.

(155) ATMP Regulation, supra note 139 at art 2.2.

(156) Ibid at arts 2.4-2.5.

(157) Barbara J von Tigerstrom, "The Challenges of Regulating Stem Cell-Based Products" (2008) 26:12 Trends in Biotechnology 653 at 655.

(158) ATMP Regulation, supra note 139 at art 28.2.

(159) Ibid at art 28.2.

(160) Ibid at art 21.2.

(161) Ibid at arts 4-5.

(162) Bravery, supra note 142 at S792.

(163) Lloyd-Evans, supra note 39 at 49.

(164) Donald W Fink, "FDA Regulation of Stem Cell Based Products" (2009) 324 Science 1662 at 1662.

(165) Ibid at 1662; Jeffrey L Fox, "FDA Scrutinizes Human Stem Cell Therapies" (2008) 26:6 Nature Biotechnology 598 at 599; Robert A Preti, "Bringing Safe and Effective Cell Therapies to the Bedside" (2005) 23:7 Nature Biotechnology 801 at 802.

(166) Committee for Advanced Therapies (CAT) and the CAT Scientific Secretariat, supra note 154 at 197; Fink, supra note 164 at 1663; Fox, supra note 165 at 599.

(167) For a review of safety, efficacy, and quality issues with stem cell-based products, see Barbara von Tigerstrom & Erin Schroh, "Regulation of Stem Cell-Based Products" (2007) 15 Health LJ 175 at 181-86.

(168) Dina Gould Halme & David A Kessler, "FDA Regulation of Stem-Cell-Based Therapies" (2006) 355:16 New Eng J Med 1730 at 1734.

(169) Ibid at 1734.

(170) See e.g. US Food and Drug Administration, Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products, (2011), online: US Food and Drug Administration ; US Food and Drug Administration, Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs) (2008), online: US Food and Drug Administration .

(171) European Medicines Agency, Guideline on Human Cell-Based Medicinal Products, (21 May 2008), Doc Ref EMEA/CHMP/410869/2006 online: European Medicines Agency .

(172) European Medicines Agency, Reflection Paper on Stem Cell-Based Medicinal Products, (14 January 2011) Doc Ref EMA/CAT/57113412009 online: European Medicines Agency .

(173) Health Canada, Guidance for Industry: Guidance Document on the Regulation of Medical Devices Manufactured from of Incorporating Viable or Non-Viable Animal Tissue or their Derivative(s) (Ottawa: Health Canada, 2004), online: Health Canada .

(174) US Food and Drug Administration, Guidance for Industry: Source Animal, Product, Preclinical, and Clinical Issues Concerning the Use of Xenotransplantation Products in Humans (Final Guidance), (2003), online: US Food and Drug Administration ; European Medicines Agency, Guideline on Xenogeneic Cell-Based Medicinal Products (1 January 2010), online: European Medicines Agency .

(175) See e.g. Andreadis, supra note 39 at 254-58.

(176) See e.g. US Food and Drug Administration, Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs) (2008), online: US Food and Drug Administration ; US Food and Drug Administration, Guidance for Industry: Gene Therapy Clinical Trials--Observing Subjects for Delayed Adverse Events (2006), online: US Food and Drug Administration .

(177) See e.g. European Medicines Agency, Guideline on Quality, Non-Clinical and Clinical Aspects of Medicinal Products Containing Genetically Modified Cells (Draft) (20 May 2010), Doc Ref EMA/CHMP/ GTWP/671639/2008 online: European Medicines Agency .

(178) See n 140, above, and accompanying text.

(179) James S Murday et al, "Translational Nanomedicine: Status Assessment and Opportunities" (2009) 5:3 Nanomedicine: Nanotechnology, Biology, & Medicine 251 at 259.

(180) Prescott, supra note 52 at S785.

(181) US Food and Drug Administration, "Nanotechnology: A Report of the U.S. Food and Drug Administration Nanotechnology Task Force" (25 July 2007), online: US Food and Drug Administration at 12.

(182) Robin Fretwell Wilson, "Nanotechnology: The Challenge of Regulating Known Unknowns" (2006) 34:4 JL Med & Ethics 704 at 706; US Food and Drug Administration, "Nanotechnology: A Report of the U.S. Food and Drug Administration Nanotechnology Task Force" (25 July 2007), online: US Food and Drug Administration at 16-19.

(183) Wilson, supra note 182 at 708.

(184) Ibid at 704.

(185) Gary E Marchant, Douglas J Sylvester & Kenneth W Abbott, "What Does the History of Technology Regulation Teach Us about Nano Oversight?" (2009) 37:4 JL Med & Ethics 724 at 724.

(186) Ebbesen & Jensen, supra note 67 at 7. This discussion seems to imply that these concerns are overstated, with the most extreme concerns based on "science fiction" rather than "sound science" (ibid.).

(187) Health Canada, Interim Policy Statement on Health Canada's Working Definition for Nanomaterials, supra note 53; US Food and Drug Administration, Nanotechnology Draft Guidance, supra note 53.

(188) See e.g. US Food and Drug Administration, News Release, "FDA Takes 'first step' Toward Greater Regulatory Certainty around Nanotechnology" (9 June 2011) online: US Food and Drug Administration ; US Food and Drug Administration, "Nanotechnology: A Report of the U.S. Food and Drug Administration Nanotechnology Task Force" (25 July 2007), online: US Food and Drug Administration ; European Medicines Agency, Reflection Paper on Nanotechnology-Based Medicinal Products for Human Use (29 June 2006), online: European Medicines Agency :

(189) Barbel R Dorbeck-Jung & Nupur Chowdhury, "Is the European Medical Products Authorisation Regulation Equipped to Cope with the Challenge of Nanomedicines?" (2011) 33:2 Law & Pol'y 276 at 295.

(190) Paradise et al, supra note 128 at 621.

(191) Lee et al, supra note 50 at 44.

(192) Ibid.

(193) Ibid.

(194) Ibid at 47.

(195) Ibid at 48.

(196) Bravery, supra note 142 at $792.

(197) Office of the Auditor General of Canada, "Chapter 8: Allocating Funds to Regulatory Programs--Health Canada" in Report of the Auditor General of Canada to the House of Commons (November 2006), online: Office of the Auditor General of Canada at 1, 11-12.

(198) Ibid at 1.

(199) Ibid at 14.

(200) Office of the Auditor General of Canada, "Chapter 6: Regulating Medical Devices--Health Canada" in Status Report of the Auditor General of Canada to the House of Commons (2011), online: Office of the Auditor General of Canada at 10-11, 14-16.

(201) Ibid at 11-13.

(202) Ibid at 12.

(203) Fees in Respect of Drugs and Medical Devices Regulations, SOR/2011-79; see Regulatory Impact Analysis Statement, (13 April 2011) C Gaz II, 815-17.

(204) A cost-recovery model raises concerns about potential conflicts of interest: see e.g. Paul C Hebert et al, "Can Health Canada protect Canadians from unsafe drugs?" (2011) 183:10 Canadian Medical Association Journal 1125 at 1125.

(205) Lavender, supra note 124 at para 49.

(206) Leslie Pray & Sally Robinson (Rapporteurs), Challenges for the FDA: The Future of Drug Safety, Workshop Summary (Washington, DC: National Academies Press, 2007) at 15; see also Peter Barton Hutt, "The State of Science at the Food and Drug Administration" (2008) 60:2 Admin L Rev 431 at 432.

(207) Paradise et al, supra note 128 at 617.

(208) See especially Institute of Medicine, Medical Devices and the Public's Health: The FDA 501(k) Clearance Process at 35 Years (Washington, DC: National Academies Press, 2011) at 119-24.

(209) US Food and Drug Administration Center for Devices and Radiological Health, Task Force on the Utilization of Science in Regulatory Decision Making: Preliminary Report and Recommendations (August 2010), online: US Food and Drug Administration at 4.

(210) Hutt, supra note 206 at 432.

(211) S Ratanawijitrasin & E Wondemagegnehu, Effective drug regulation: A multicountry study (World Health Organization, 2002), online: World Health Organization at 39.

(212) bid at 45. In this multicountry study, staff shortages appeared to be "a serious problem" in all countries studied, with the majority experiencing difficulties with recruiting staff: ibid.

(213) Hebert et al, supra note 204 at 1125.

(214) See US Food and Drug Administration, Strategic Priorities 2011-2015: Responding to the Public Health Challenges of the 21st Century (2011), online: US Food and Drug Administration at 5-7. "Regulatory science" is defined in this document as "the development and use of new tools, standards, and approaches to more efficiently develop products and facilitate the evaluation of product safety, effectiveness, quality, and performance" (at 5, n 2).

(215) Bravery, supra note 142 at $789.

(216) See above n 104 and accompanying text.

(217) Bravery, supra note 142 at $794.

(218) Ibid at $791.

(219) See Timothy Caulfield, "Stem Cell Research and Economic Promises" (2010) 38:2 JL Med & Ethics 303 at 304-305.

(220) Hebert et al, supra note 204 at 1125.

Barbara von Tigerstrom, The research for this article was funded in part by a public policy impact grant from the Stem Cell Network, Canada. The author gratefully acknowledges research assistance by Adryan Toth (LL.M. Candidate, University of Saskatchewan) and useful comments from an anonymous reviewer.
A tissue engineered product may contain cells or tissues of human
   or animal origin, or both. The cells or tissues may be viable of
   nonviable.

   It may also contain additional substances, such as cellular
   products, bio-molecules, biomaterials, chemical substances,
   scaffolds or matrices.

   Products containing or consisting exclusively of non-viable human
   or animal cells and/or tissues, which do not contain any viable
   cells or tissues and which do not act principally by
   pharmacological, immunological or metabolic action, shall be
   excluded from this definition. (141)


In terms of both personnel and the money to support them, the
   agency is barely hanging on by its fingertips. The accumulating
   unfunded statutory responsibilities imposed on the FDA, the

   extraordinary advance of scientific discoveries, the complexity of
   the new products and claims submitted to the FDA for premarket
   review and approval, the emergence of challenging safety problems,
   and the globalization of the industries that the FDA
   regulates--coupled with chronic underfunding by Congress--have
   conspired to place demands upon the scientific base of the agency
   that far exceed its capacity to respond." (210)
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