‘FAST TRACK’ REGULATORY APPROVAL OF NANOTHERAPEUTICS: ISSUES FOR PUBLIC SAFETY
Steven Andrew Speldewinde
A paper submitted for Honours Thesis ANU College of Law, The Australian National University
30 October 2006 Word Count: 1
Table of Contents Acknowledgements............................................................................................................................. 3 Abstract............................................................................................................................................... 4 Introduction........................................................................................................................................ 5 Chapter 1 Nanotherapeutics: 'Fast-Tracking' and Risk-Benefit Analysis of Safety and Efficacy .............. 8 1.1 Nanotherapeutics: Unknown Safety Issues........................................................................... 10 1.2 Safety and Efficacy of Nanotherapeutics: Risks and Benefits of 'Fast-Tracking'.................. 11 1.3 Industry Leverage for 'Fast-Tracking' Nanotherapeutics .................................................... 12 Chapter 2 'Fast-Tracking' Nanotherapeutics in Australia: Increased Reliance on the FDA? ................. 15 2.1 Clinical Trials: the Development of Safety Evaluation for Nanotherapeutics.....................16 2.2 'Fast-Track' TGA Approval of FDA Approved Nanomedicines? ......................................... 19 Chapter 3 'Fast-Tracking' Convergent Nanotherapeutics: Medicines v Devices.........................................22 3.1 Contrasting the Approval of Nanomedicines and Nanodevices............................................. 23 3.2 'Fast-Tracking' Convergent Nanotherapeutics...................................................................... 25 Chapter 4 'Fast-Tracking' of Nanotherapeutics: Importance of Postmarket Regulation ..........................28 4.1 Problems with Conditioning 'Fast Track' Approvals on Postmarketing Regulation ............ 29 4.2 Advances in Nanotherapeutics: Increased Pressure on Postmarket Regulation.................. 32 4.3 An Inter-agency Review Board for Postmarket Regulation of Nanotherapeutics..................33 Conclusion......................................................................................................................................... 36 Bibliography......................................................................................................................................38
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Acknowledgements
Acknowledgements I would like to thank Dr. Tom Faunce for his guidance and ideas for writing this paper, and Kellie Johnston for all her help with research. I would also like to thank my Dad, Mum, Brother and Grandparents for all their help and support throughout my University career. Finally I would like to make special mention of my Grandpa, Don Phillips who is no longer with us, but whose outlook on life continues to be an inspiration to me.
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Abstract
Abstract The advent of nanotechnology is likely to revolutionise both the development and regulation of innovative therapeutic products. This paper provides a conceptual analysis of the manner in which industry may 'fast-track' approval of nanotherapeutic products, including nanomedicines and nanomedical devices, and the associated regulatory issues with respect to the maintenance of a high standards of public healthcare in Australia. The emphasis of this paper is on the regulatory framework of Australia's Therapeutic Goods Administration (TGA) however analysis of the United States Food and Drug Administration's regulatory framework provides valuable insight, of increased relevance following our respective countries commitment 'to advance existing dialogue between the FDA and TGA' under Annex 2C(4) of the Australia and United States Free Trade Agreement.
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Introduction
INTRODUCTION The advent of nanotechnology is likely to revolutionise both the development and regulation of innovative therapeutic products. This paper examines the proposition that the United States Food and Drug Administration (FDA) and Australia's Therapeutic Goods Administration (TGA) are under increasing pressures to adopt 'fast-track' approval pathways for innovative nanotherapeutics and that this pressure, may result in compromised standards of safety and efficacy for such products. 'Fast-tracking' will be defined, in this paper, as 'any regulatory pathway or process that industry may utilise to secure more rapid and cost-effective access to the market for a therapeutic product'. However 'fast-tracking' may also be described from the patients point of view, as any regulatory pathway or process that allows speedier access to much needed innovative therapies. Nanotherapeutics may be broadly defined to include products resulting from the application of nanotechnologies to medicines, medical devices, and biotechnologies. It is likely to be characterised by
its ability to create greater levels of convergence between these fields.1
Nanotechnology refers to the study, manipulation and application of materials at the nanoscale (1100 nanometres), called nanoparticles.2 Nanoparticles have a number of unique properties that make them attractive to developers of medical technologies, for example, they have a greater surface area to mass ratio when compared with larger sized compounds of the same chemistry, rendering them more biologically active, and their small size facilitates uptake into potentially sensitive target sites such as bone marrow, lymphnodes, spleen, heart and central nervous system.3 As of mid 2006, 130 nano-based drugs and drug delivery systems and 125 devices or diagnostic tests are in pre-clinical, clinical or commercial development.4 Examples of Australian products in development include; Alchemia's VAST, a nanoscale drug discovery tool which may be used to identify candidates for therapeutic indications for cancer, CeramiSphere's sol-gel 1 See generally: Roco, M.C. & Bainbridge, W.S. (Eds), Converging Technologies for Improving Human Performance (2002) 2 One nanometre is equal to one-billionth of a metre. To put this in perspective, a human hair is approximately 80,000nm wide. See generally: United Kingdom, Royal Society Report, Nanoscience and Nanotechnologies: Opportunities and Uncertainties (2004).: See also: Brumfiel, G. 'A Little Knowledge...' (2003) 246 Nature 424 3 Nanomedicine: An European Science Foundation â&#x20AC;&#x201C; European Medical Research Councils (EMRC) Forward Look Report (2005) European Science Foundation,. <http://www.esf.org/publication/214/Nanomedicine.pdf> at 17 September 2006 4 Nanotechnology in $32 Billion Worth of Products: Global Funding for Nanotech R&D Reaches $9.6 Billion (2006) Lux Research, Inc. <www.luxresearchinc.com/press/RELEASE_TNR4.pdf,> at 27 September 2006.
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Introduction encapsulation, a technology where active molecules are encapsulated in nanosized ceramic particles allowing advanced drug delivery, and Xceed Biotechnologies' 'Novosorb' biodegradeable bone cement. The University of Wollongong is developing bio-nanotechnological artificial nerve sell communication systems, and Starpharma Holdings' VivaGel, a dendrimer based microbicide gel which may be used in the prevention of sexually transmitted diseases such as AIDS.5 Clearly nanotherapeutics represents an area of research and development with high potential for both public health benefit and economic profit. Every major pharmaceutical company in the world has begun to engage in nanotechnology research.6 The market size for nanotechnology based drug delivery systems alone in 2005 was $980 million and is expected to grow by 54% annually over the next five years.7 The risks associated with nanotherapeutics can essentially be divided into two categories; a) toxicological risks, which may exist at all stages of a products life-cycle, production, distribution, consumption and end of life, but, for the purposes of this paper will be confined to consumption risks borne by the consumer and b) financial risks, which, are generally borne by corporate investors. In relation to the first category, the Therapeutic Goods Act 1989 (Cth) provides a national framework for the regulation of therapeutic goods in Australia to ensure their quality, safety, efficacy and timely availability.8
The framework is based on a risk management approach,
designed to ensure public health and safety while at the same time freeing industry of unnecessary regulatory burdens, a key focus being 'to ensure that consumers have timely access to medicines'. 9 This statement encompasses the fundamental dichotomy faced by therapeutics regulators between the interests of public health, in maintaining high safety, quality and efficacy standards for, and of having timely access to, innovative therapeutic products. The second of these interests provides industry with a point of leverage from which to pursue their interest in gaining 'fast-track' access to the market and hence a financial return on their investment in research and development. The manner in which industry may exercise this leverage and the potential for this to compromise standards of safety and efficacy will be explored in this paper 5 Invest Australia, Australian Government, Australian Nanotechnology: Capability and Commercial Potential (2nd ed 2005). Available at http://investaustralia.hyperlink.net.au/media/IR_Nano_NanotechReport.pdf, last accessed 17/9/06. 6 Herrera, S. The Big Science of Nanomedicine, Red Herring Magazine (2000) <http://www.redherring.com/mag/issue84/mag-nano-84.html> at 17 September 2006- ****find better reference*** 7 Lux Research, Inc., The Nanotech Report (4th Ed 2006) p. 106. 8 Regulation of Therapeutic Goods in Australia (2005) Therapeutic Goods Administration <http://www.tga.gov.au/docs/html/tga/tgaginfo.htm> at 29 October 2006 9 Id.
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Introduction In the first chapter, I will examine, through consideration of the evolutionary history of industry leverage over the FDA, whether 'fast-tracking' compromises risk-benefit analysis in relation to nanotherapeutics,.
Further I will consider the manner in which advances in
nanotherapeutics may enable industry to increase its leverage over regulatory agencies. In the second chapter, I will critically examine the proposition that there is significant pressure on the TGA to harmonise its regulatory framework with that of the FDA under Annex 2C(4) of the Australia and United States Free Trade Agreement (AUSFTA). I will then consider whether a reliance on FDA evaluations that may compromise safety and efficacy standards for nanotherapeutics in Australia. In the third chapter I will examine whether the disparate evaluative rigour between regulatory approval of medicines and that of medical devices, in combination with increased convergence between these fields resulting from advances in nanotherapeutics, provides a further mechanism by which industry may exert leverage to secure 'fast-track' regulatory approval. In the final chapter, I will examine the issues of whether advances in nanotherapeutics are likely to result in an increased reliance on the post-marketing phase of regulation, and whether this is likely to increase the leverage of industry to promote 'fast-tracking' of approvals at the premarketing phase. However I will conclude by putting the case that Annex 2C(4) of AUSFTA provides an opportunity for the TGA and FDA to regain some leverage over industry, by creating an inter-agency review board, responsible for the development of an effective safety evaluation framework for nanotherapeutics and, an effective post-market regulatory system for such products.
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Chapter 1
CHAPTER 1 NANOTHERAPEUTICS: 'FAST-TRACKING' AND RISK-BENEFIT
ANALYSIS OF SAFETY AND EFFICACY Risk-benefit analysis pervades all stages of therapeutics regulation both in the TGA, the FDA and similar organisations worldwide. Risk refers to a possible future harm, where harm is defined as a setback to interests.10 Benefit refers to something of positive value, usually in life, health and welfare.11 Analysis of these risks involves an evaluation of the ratio between the probability and magnitude of a potential harm and the probability and magnitude of a potential benefit.12
From a regulatory standpoint, risk-benefit analysis is based on utilitarian or
consequentialist principles. Traditionally regulatory bodies, such as the TGA and FDA, protect the public welfare by placing the burden of proof on manufacturers; to meet rigorous outcome standards in demonstrating the safety and efficacy of new therapeutic products.13 However, in some circumstances, utilitarian risk-benefit analysis may conflict with the autonomous risk-benefit analysis of individuals, or particular sub-groups of patients. Furthermore, utilitarian benefits will not be realised where the satisfaction of this burden of proof becomes to costly and thus stifles innovative research into new therapeutic products. 'Fast-tracking, as previously mentioned' represents 'any regulatory pathway that industry may utilise to secure more rapid and cost-effective access to the market for a therapeutic product'. However 'fast-tracking' may also be described, from the patients point of view, as any regulatory pathway or process that allows speedier access to much needed innovative therapies. The 'accelerated approval' pathway was adopted in response to the intense political pressure imposed on the FDA by patient advocacy groups during the AIDS epidemic in the 1980's. 14 For groups facing imminent death from a serious disease, the magnitude of risk associated with a particular experimental treatment is considerably diminished in comparison to the potential benefit 10 11 12 13
Beauchamp, T. & Childress, J. Principles of Biomedical Ethics (2001) Id. Id. Greenberg, M. 'AIDS, Experimental drug approval, and the FDA new drug screening process' (2000) 3 New York University Journal of Legislation and Public Policy 295 14 Id.
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Nanotherapeutics: 'Fast-Tracking' and Risk-Benefit Analysis of Safety and Efficacy of the treatment even where the probability of that benefit actually accruing is unknown.15 Such groups may see rigorous pre-approval safety and efficacy testing procedures as overly paternalistic, risk-averse and exacerbating a healthcare crisis by impeding access to new medications.16 Such groups are powerful lobbying agents and this has not escaped the notice of the pharmaceutical industry who funds many such activities.17 The FDA's response to this pressure represented an evolutionary change in the FDA's risk-benefit analysis for new drugs. By allowing patients access to drugs with less well developed safety and efficacy profiles, the FDA shifted the focus of public protection from protection against risks caused by new drugs, to protection against the risks associated with not being able to access potentially beneficial drugs.18 Processes involved with â&#x20AC;&#x2DC;fast trackingâ&#x20AC;&#x2122; in relation to pharmaceutical products in the US FDA involves these common features: a) a shorter review time, b) closer collaboration between industry and the FDA prior to approval, whereby clinical trial protocols are developed in consultation with the FDA and data is submitted to, and evaluated by the FDA whilst further phases of clinical trials are conducted, and c) a shorter clinical trials process through the adoption of surrogate endpoints for efficacy.19 A surrogate endpoint is an indication that is said to be correlated to the clinical end-point for the treatment of a disease, for example; reduction in the size of a tumour is a surrogate end-point for the treatment of cancer.20 In this chapter I will consider, using examples, whether 'fast-tracking' compromises riskbenefit analysis of safety and efficacy in relation to nanotherapeutics. In the first section I will consider the current state of knowledge in relation to the safety of nanotherapeutics. In the second section I will consider the risks and benefits of 'fast-tracking' nanotherapeutics in relation to public health. In the final section I will examine whether the FDA's reliance on industry funding in combination with advances in nanotherapeutics may provide industry with leverage to pursue its interest in 'fast-tracking' nanotherapeutics.
15 Id. 16 Id. 17 See for example: Hughes, G. & Minchin, L., 'Drug Firms Fund Disease Awareness' Sydney Morning Herald 13 December 2003 18 See: Shulman, S. & Kuettel, A. 'Drug Development and the Public Health Mission: Collaborative Challenges at the FDA, NIH, and Academic Medical Centres' (2005) 53 Buffalow Law Review 663. 19 See generally: Above n18: see also: Above n13 20 See generally: Fleming, T., 'Surrogate Endpoints and FDA's Accelerated Approval Process' (2005) 24 Health Affairs 67
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1.1 Nanotherapeutics: Unknown Safety Issues
1.1
Nanotherapeutics: Unknown Safety Issues
Whilst it is likely that standard models of safety assessment will apply to nanotherapeutics, within these models, data needs and technical questions might be very different given the special biological, chemical and physical properties that arise at the nanoscale.21 These issues are currently being studied in the emergent field of nanotoxicology. Nanotoxicology can be defined as safety evaluation of engineered nanostructures and nanodevices.22
This is a broad definition which
extends to include the industrial and environmental safety of nanoproducts.
Within the sub-
discipline of nanomedicine toxicological effects may exist at all stages in the lifecycle of a nanomedical product, production, distribution, clinical administration/consumption and end of life.23 Relevant considerations in the development of a safety evaluation framework for nanotherapeutics include, the unique physiochemical properties of the nanoparticles, routes of exposure (oral, dermal and injection)and, translocation, accumulation and retention rates at critical target sites.24 It is likely that the biological activity of nanoparticles will depend on physiochemical properties that may not be routinely considered in toxicity screening studies, including, particle size and distribution, agglomeration state, shape, crystal structure, chemical composition, surface area, surface chemistry, surface charge and porosity.25 To date there has been a lack of fundamental studies into the mechanisms of interaction of nanoparticles with cells and their components, including their effects on blood vessels, the skin, heart and nervous system.26 However the studies that have been performed raise a number of pertinent considerations in safety assessment of nanotherapeutics. nanoparticles in the body is unknown.
The ultimate fate of
Studies have suggested that nano-sized particles can
translocate across the plasma membranes of epithelial cells by unconventional means, nanoparticles may compromise respiratory function in the lungs, the capacity of nanoparticles to cross human skin is largely unknown and nanoparticles preferentially accumulate at the sub-cellular level in the 21 Miller, J., 'Beyond Biotechnology: FDA Regulation of Nanomedicine' (2003) 4 Columbia Science and Technology Law Review 5 22 Oberdorseter, G. et al. 'Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles' (2005) 113 Environmental Health Perspectives 7 23 Nanomedicine: An European Science Foundation â&#x20AC;&#x201C; European Medical Research Councils (EMRC) Forward Look Report (2005) European Science Foundation,. <http://www.esf.org/publication/214/Nanomedicine.pdf> at 17 September 2006 24 Above n21 25 Id. 26 United Kingdom, Royal Society Report, Nanoscience and Nanotechnologies: Opportunities and Uncertainties (2004
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1.1 Nanotherapeutics: Unknown Safety Issues mitochondria potentially inhibiting mitochondrial function.27 Of further concern is the extent to which results of cellular and immunological studies in animal models can be translated to humans, as there are distinct intra and interspecies variations.28 Finally the long-term consequences of the introduction of nanoparticles into the body are unknown, of particular concern may be the relative absence of studies into the effect of nanoparticles on reproduction.29 Thus it would appear that, at this point the safety evaluation framework for nanotherapeutics is underdeveloped and thus risks associated with such products may not be able to be adequately assessed prior to regulatory approval. In the next section I will consider the risks and benefits of 'fast-tracking' the approval of nanotherapeutics, in light of these concerns.
1.2
Safety and Efficacy of Nanotherapeutics: Risks and Benefits of 'Fast-Tracking'
Starpharma, a Melbourne based company, was recently granted 'fast-track' status by the FDA for its nanotherapeutic VivaGelTM, which is a topical microbicide gel incorporating nanoscale molecules called dendrimers.30
Dendrimers are synthetic, three dimensional molecules, with
branching parts that bind to receptors on the surface of virus's such as HIV and Genital Herpes and inactivate them by preventing them from attaching to the host cells, which they are trying to infect31.
Thus when applied to the vagina, prior to sexual intercourse it may prevent the
transmission of sexually transmitted diseases.32 Fast-track status was granted in the form of placing 27 Australian Safety and Compensation Council Report, Australian Government, A Review of the Potential Occupational Health & Safety Implications of Nanotechnology (2006) â&#x20AC;&#x201C; in the view of the author of this report mitochondrial accumulation represents a smoking gun from a molecular toxicology perspective. Mitochondria are the energy producers of a cell. 28 Moghimi, S., Hunter, A. & Murray, J., 'Nanomedicine: current status and future prospects' (2005) 311 The FASEB Journal 19 29 Australian Safety and Compensation Council Report, Australian Government, A Review of the Potential Occupational Health & Safety Implications of Nanotechnology (2006) 30 Greenblat, E., 'US to fast-track Starpharma's HIV gel' Australian Financial Review 1 October 2006 See also: R&D Projects The Starpharma Website <http://www.starpharma.com/framemaster.htm> at 28 October 2006. 31 See: R&D Projects The Starpharma Website <http://www.starpharma.com/framemaster.htm> at 28 October 2006 See also: Bryan, J., 'What Role will dendrimer-based drug technology have in the future?' (2004) 273 The Pharmaceutical Journal 793. Available at http://www.pharmj.com/pdf/articles/pj_20041127_newdrugtechnologies05.pdf at 28 October 2006. 32 See: Nanotech RX â&#x20AC;&#x201C; Medical applications of Nanoscale Technologies: What Impact on Marginalised Communities (2006) ETC Group Report <http://www.etcgroup.org/upload/publication/593/01/etc06nanotechrx.pdf > at 17 September 2006.
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1.2 Safety and Efficacy of Nanotherapeutics: Risks and Benefits of 'Fast-Tracking' VivagelTM on the FDA's 'accelerated approval' pathway, which is designed to accelerate the clinical trials process for innovative drugs designed to treat serious and life-threatening conditions.33 This pathway allows Starpharma to develop clinical trial protocols in collaboration with the FDA, adopt surrogate end-points, and submit trial data for review during the clinical trials process, all with a view to expediting the approval process.34 VivaGelTM has the potential to be a very beneficial preventative treatment for sexually transmitted diseases such as AID's, a disease that is serious and life-threatening, and the very same disease that caused patient advocacy groups to pressure the FDA for speedier access to innovative treatments. However it is questionable as to whether these benefits are best realised via 'fast-track' approval. VivaGelTM is a preventative treatment, that is likely to be frequently and widely used by healthy people, as opposed to those facing imminent death from AID's. Further, given the potential long-term risks associated with nanoparticles, along with the fact that there are other preventative measures, such as condoms, which have been shown to be both safe and effective, 'fast-track' approval based on surrogate end-points for efficacy and an underdeveloped safety evaluation, may unjustifiably compromise public health, in this situation. More generally it could be argued that, given the underdeveloped safety evaluation framework for nanotherapeutics, high standards of efficacy must be maintained in order to ensure that the public are not exposed to potential risks without an associated benefit and, further that the terms 'serious and life-threatening' should be given close regulatory scrutiny, in the context of granting access to designated 'fast-track' regulatory pathways. In the next section we will see that 'fast-tracking' is pervasive even outside such designated pathways and that advances in nanotechnology are likely to give industry increased leverage to pursue fast-track pathways.
1.3
Industry Leverage for 'Fast-Tracking' Nanotherapeutics
From industriesâ&#x20AC;&#x2122; point of view, the development of a new therapeutic product is expensive and time consuming. Reliable and objective data on the costs of pharmaceutical production is difficult to obtain. Reasonable estimates not created by pharmaceutical industry apologists, place it 33 See: Above n30 34 Above n18
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1.3 Industry Leverage for 'Fast-Tracking' Nanotherapeutics at approximately $US403 million in 2000 for an average innovative product. 35 On average a new drug takes 9 years to get to the market and it is risky, with more than 80% of drug candidates fail between the Investigational New Drug application (IND) and the New Drug application (NDA).36 The introduction, in 1992, of user fees in return for services that the FDA had up until that time been providing for free, provided industry with the perfect opportunity to shape regulatory procedures in such a way as to reduce their risks, associated with the development of new drugs. Industry negotiated with the FDA to come to a quid pro quo agreement whereby the introduction of user fees would be accompanied by a commitment by the FDA to expedite the review of new drug applications.37 The effect of this agreement is encapsulated by the following quote by the then director of the FDA taken from a 1999 newsletter "In exchange [for the user fees], FDA makes a commitment to meet certain goals for review times. [The agency] has exceeded almost all of the goals, and it expects to continue to exceed them. Basically, the number of new approved drugs has doubled, and the review times have been cut in half."38 The renegotiation of the fee structure every five years along with the willingness of the FDA to link fees with performance goals continues to give industry a substantial say in the way in which the fees will be spent.39 It has been suggested that the introduction of user fees has essentially created a system whereby industry is paying for the services of the FDA. This leads to concerns that industry may be able to exert undue influence over the FDA, compromising its objectivity and independence in product approvals.40 One reasonable conclusion, especially in light of recent scandals such as Vioxx, is that the FDA may be compromising safety and efficacy concerns in order to meet demanding targets for approval times and that this may be the result of a 'cosiness' between the FDA and industry.41 The FDA has recognised, at least implicitly, by increasingly conditioning approval for new medicines on the conduct of postmarketing studies, that the end product of fasttrack development and evaluation may be a less well developed safety and effectiveness profile.42 Furthermore, it has been suggested that FDA funding would need to be increased by more than 50% 35 See eg: Costs of Research and Development CP Tech <http://www.cptech.org/ip/health/econ/rndcosts.html> at 29 October 2006 and references contained therein. DiMAsi Grabowski and Hansen with qualifications ********** 36 Ferrari, M. & Downing, G., 'Medical Nanotechnology: Shortening Clinical Trials and Regulatory Pathways?' (2005) 19 Biodrugs 4 37 Mathews, A., W., 'Drug Firms Use Financial Clout to Push Industry Agenda at FDA' The Wall Street Journal 1 September 2006 38 Willman, D. 'How a New Policy Led to Seven Deadly Drugs', L.A. Times, 20 December 2000 39 Above n18. 40 Id. 41 Id. 42 Id.
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1.3 Industry Leverage for 'Fast-Tracking' Nanotherapeutics in order to acquire the resources needed to build its own expertise and gather the necessary premarket data required to get ahead of the commercialisation of nanotherapeutics.43 The consequences of this are twofold. Firstly, the FDA will have to negotiate with industry to provide this funding increase, meaning that the adoption of a risk averse precautionary approach to the regulation of nanotherapeutics, whilst it acquires the requisite resources to develop an effective safety evaluation framework, is not a viable option, in terms of the funding structure of the FDA. Not to mention the fact that such a strategy will potentially stifle innovation in potentially beneficial nanotherapeutics, and is thus undesirable when analysed from a utilitarian risk-benefit point of view. Compounding the already substantial leverage industry is likely to have to pursue its interest in 'fast-tracking' approval processes, is the secondary consequence that, at least initially, the FDA and other regulatory bodies, including the TGA, will face a deficit of knowledge as compared to industry, regarding fundamental aspects of nanotherapeutic design and function. This means that industry may be able to frame nanotherapeutics, particularly those characterised by convergence of technologies, in a manner that is most likely to result in 'fast-track' approval. A critical examination of the manner in which these issues may affect the TGA's regulation of nanotherapeutics will form the basis of the next two chapters. In the next Chapter I will examine the proposition that, whilst the TGA might equally be susceptible to industry funding leverage, such leverage may also be characterised by increased reliance on FDA assessment of safety and efficacy.
43 Taylor, M. R., Regulating the Products of Nanotechnology: Does FDA Have the Tools It Needs? (2006) Project on Emerging Nanotechnologies <http://www.nanotechproject.org/82/10506-regulating-the-products-ofnanotechnology> at 29 October 2006
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Chapter 2
CHAPTER 2 'FAST-TRACKING' NANOTHERAPEUTICS IN AUSTRALIA: INCREASED
RELIANCE ON THE FDA? In this chapter I plan to critically examine two mechanisms by which industry may exercise leverage over the TGA with a view to fast-tracking the approval of innovative nanotherapeutics and discuss whether this may compromise the maintenance of a sovereign, high quality and efficient regulation capacity in Australia. These mechanisms may be characterised by an increased reliance on the FDA to develop and carry out safety and efficacy evaluations of nanotherapeutics and may be developed through Australia's commitment under Annex 2C(4) of AUSFTA ““to advance the existing dialogue between the Australian Therapeutic Goods Administration and the U.S. Food and Drug Administration with a view to making innovative medical products more quickly available to their nationals”.44 The 1997 KPMG review of the TGA identified three levels of information sharing between regulatory agencies that may facilitate 'fast-track' approvals. Level 1, is the “exchange of evaluation reports following independent evaluation by both [agencies]”, level 2, is the “exchange or supply of an evaluation report, with the recipient country using the report in part or in whole instead of undertaking its own evaluation”, and level 3, is that “countries agree that they will [divide and] share the evaluation of an application”.45 In the first section I will outline differences in the manner in which clinical trials are approved in Australia and the United States. I will then examine whether an unofficial, 'level 3' style sharing of clinical trial evaluation between Australia's Human Research Ethics Committees (HREC's) and the FDA, may impede the TGA's development of a safety evaluation framework for nanotherapeutics. In the second section I will identify pathways within the TGA's regulatory framework for medicines that are likely to be targeted with a view to making, innovative, FDA approved nanomedicines, more quickly available in Australia and the potential for this to compromise high standards of safety and efficacy for nanotherapeutics in Australia. 44 Australia and United States Free Trade Agreement , Annex 2C(4), 1 January 2005 45 The Department of Health & Family Services, Australian Government, KPMG - Review of Therapeutic Goods Administration on behalf of the Department of Health & Family Services (1997), pp. 69-70.
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2.1 Clinical Trials: the Development of Safety Evaluation for Nanotherapeutics
2.1
Clinical Trials: the Development of Safety Evaluation for Nanotherapeutics
Regulatory oversight of the clinical trials phase of therapeutics development is becoming increasingly important as a means of ensuring public safety. The FDA's adoption of designated 'fast-track' approval pathways (see Chapter 1) mean that clinical trials are no longer a precursor to regulatory approval but increasingly an integral part of it. Regulatory review of clinical trial protocols for emergent technologies such as nanotherapeutics provides an important opportunity for regulatory agencies to develop expertise and input in the design of safety evaluation frameworks. Given that the TGA does not have the equivalent of FDA designated 'fast-track' approval pathways, in this section I will consider whether there may be an unofficial 'level 3' style division of evaluation, facilitated by industry 'fast-track' tactics, with respect to the approval of clinical trials, between Australia's HREC's and the FDA. The FDA has a closer and more detailed involvement in the clinical development program of products than the TGA and consequently a considerably more expanded bureaucracy. Before a clinical trial can go ahead in the US the sponsor must submit a Investigational New Drug (IND) application which includes data on toxicity and pharmacologic effect obtained from animal studies, as well as details regarding trial design.46 The FDA scientifically reviews the application and if it does not raise any objections within 30 calendar days the trial may commence. The FDA does not recover any costs from the applicant for this review.47 Once the initial IND has been approved subsequent clinical trials involving the same product must be notified to the FDA but do not go through another FDA approval process.48 All clinical trials are subject to separate ethics approval by an Institutional Review Board, similar to HREC review in Australia.49 Approval to conduct a clinical trial in Australia may be obtained under either the Clinical Trial Notification (CTN) scheme or Clinical Trial Exemption (CTX) scheme.50 The initial choice of 46 Till, M., Simkin, M. & Maebius, S. 'Nanotech Meets the FDA: A Success Story about the First Nanoparticulate Drugs Approved by the FDA' (2005) 2 Nanotech. Law & Business 163 47 Banscott Health Consulting Pty Ltd, Report of the Review of Access to Unapproved Therapeutic Goods (2005) Jointly Commissioned by the TGA & NHMRC. available at http://www.tga.gov.au/consult/2005/cltrialrevrep.pdf, at 17 September 2006 48 Id. 49 Id. 50 Department of Health and Aged Care, Australian Government, Human Research Ethics Committees and the Therapeutic Goods Legislation (2001) available at <http://www.tga.gov.au/docs/pdf/unapproved/hrec.pdf> at 29
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2.1 Clinical Trials: the Development of Safety Evaluation for Nanotherapeutics which scheme to utilise is made by the company that is developing the product (the sponsor).51 Under the CTN scheme, the sponsor notifies the TGA that an application to conduct a clinical trial has been made, but the actual review of the application is undertaken by a HREC.52 The CTN scheme was introduced with the intention that it would be used for trials that did not require detailed scientific evaluation or which had already been evaluated and approved for clinical trials in the US or UK.53 This is reflected by the fact that HREC's, where they believe that more detailed scientific analysis is required, may refer an application to the TGA for review under the CTX scheme and by the differing cost structure. CTN review for all phases of clinical trials costs $240 per trial site, whereas CTX reviews cost $1240 for phase I trials and $15 300 for phase II and III trials.54 An application under the CTX scheme is similar to an IND application at the FDA, in that an application detailing data on toxicity and pharmacologic effect obtained from animal studies, as well as details regarding trial design is submitted to the TGA for scientific evaluation. However unlike the FDA's IND review, the TGA charges a fee for this evaluation and has a much longer review period, 75 days as compared with the FDA's 30 days55, however it has been suggested that, once approved, it is up to five times cheaper to run a clinical trial in Australia than in the US. 56 Following the introduction of the CTN scheme in 1991, the number of CTX approved trials has dwindled to only a few per year, whilst the number of CTN approved trials has steadily increased.57 A number of inferences regarding a potential industry strategy for obtaining approval to conduct clinical trials, for nanotherapeutics, may be drawn from the preceding information. First, where a product is being developed for a serious or life-threatening condition, the best option for the sponsor is to seek accelerated approval status from the FDA, as this secures speedier access to the US market. In this situation clinical trial protocols, often utilising surrogate rather than clinical end-points will be developed and approved in consultation with the FDA but the actual clinical trials may be conducted in Australia to reduce costs. It would appear that a strategy of this type was adopted by Melbourne based company, Starpharma, for its product VivaGel TM, which, as we have seen, was recently granted accelerated approval status by the FDA. On 24 August 2006 Starpharma announced the commencement of phase I clinical trials in Australia following successful review by 51 52 53 54 55 56 57
October 2006 Id. Above n47 Id. Id. Id. Id. Id.
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2.1 Clinical Trials: the Development of Safety Evaluation for Nanotherapeutics the FDA and approval by local ethics committees.58 Second, there is likely to be significant differences in the type of review between a HREC and FDA or TGA review under the CTX scheme. When reviewing an application under the CTN scheme, HREC's are likely to primarily focus on trial design and the ethical conduct of research, as such, the review may be less rigorous in terms of pharmacological, toxicological and chemical data than the TGA or FDA.59 With this in mind, we may predict that, a legitimate strategy for the sponsor of a nanotherapeutic product, would be to submit an initial application under Australia's CTN scheme, on the assumption that it will not be subject to stringent scientific review. Finally, if the HREC does refer the application to the TGA for scientific review, under the CTX scheme, it is likely that the sponsor would withdraw the application and seek approval under the FDA's much more time and cost effective IND scheme. Thus there may be an unofficial 'level 3' style sharing of clinical trial review between Australian HREC's and the FDA, with very minimal scientific review being conducted by the TGA. The consequence of this in terms of the regulation of nanotherapeutics in Australia, are twofold. First Australian research participants are being exposed to the potential toxicological risks associated with nanotherapeutics where those risks have either, not been subject stringent scientific evaluation at all, or have been assessed by the FDA with no input from the TGA. The second consequence is that if the present state of affairs continue, the TGA may not be given an opportunity to gain expertise in, and have input into the development of, a safety evaluation framework for the burgeoning area of nanotherapeutics, a corollary of this is that the TGA may become more reliant on FDA marketing approval evaluations, which will be discussed further in the next section. The TGA essentially has two options to address this situation: â&#x2014;?
take a more active role in the monitoring of clinical trials, which would involve expanding it bureaucracy the costs of which would have to be recovered,60 or
â&#x2014;?
push for the establishment of 'level 1' style information sharing between it and the FDA, an option that will be discussed further in Chapter 4.
58 R&D Projects The Starpharma Website <http://www.starpharma.com/framemaster.htm> at 28 October 2006 59 Above n47 60 Id.
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2.2 'Fast-Track' TGA Approval of FDA Approved Nanomedicines?
2.2
'Fast-Track' TGA Approval of FDA Approved Nanomedicines?
Regulation of prescription medicines, by the TGA and FDA, is characterised by the requirement that the quality, safety and efficacy of the product be evaluated by the relevant regulatory agency, prior to being approved for marketing. A nanotherapeutic product will be classified as a medicine (from here on in 'nanomedicine') under the TGA's regulatory framework if; it is represented to achieve, or is likely to achieve, its principal intended action by pharmacological, chemical, immunological or metabolic means in, or on, the body of a human or animal.61 Currently the majority of prescription drugs are evaluated by the TGA following submission of a 'category 1' application, detailing quality, safety and efficacy data based on both clinical and pre-clinical study reports, for which the statutory review period for the approval of prescription medicines is 255 working days.62 The Department of Foreign Affairs and Trade has stated that Australia's commitment under Annex 2C(4) of AUSFTA, does not require the TGA to approve FDA approved products. This statement is in line with recommendation 2.1 of the KPMG Review which states that â&#x20AC;&#x153;The Government should re-affirm its commitment to maintain a sovereign, high quality and efficient drug regulation capacity in Australiaâ&#x20AC;?.63 Nonetheless the TGA is likely to be under considerable pressure to approve new medical products such as nanotherapeutics in accordance with international benchmark times, such as those set by the FDA, or risk falling behind internationally. 64 Further given that the US drug market is the largest in the world and thus industry is likely to seek access to this market first it is likely that industry will seek to exercise leverage to obtain 'fast-track' TGA approval of FDA approved drugs. In this section I will examine the manner in which Annex 2C(4) of AUSFTA may be used as a leverage mechanism by industry to target existing TGA 'fast-track' approval pathways with a view to gaining speedier approval for, innovative, FDA approved, nanotherapeutics. There are two potential fast-track pathways are for nanomedicines that contain a new 'active pharmaceutical ingredient'. These are medicines whose therapeutically active component is not 61 Department of Health and Ageing, Australian Government, Australian Medical Devices Guidance Document Number 35: Device Medicine Boundary Products (2005) 62 Department of Health and Ageing, Australian Government, Australian Regulatory Guidelines for Prescription Medicines (2004) 63 Above n45 64 Working Group for the Prime Minister's Science, Engineering and Innovation Council, Australian Government Nanotechnology: Enabling Technologies for Australian Innovative Industries, (2005).
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2.2 'Fast-Track' TGA Approval of FDA Approved Nanomedicines? already listed on the Australian Register of Therapeutic Goods (ARTG).65 Such products will generally be evaluated as normal 'category 1' applications however in some circumstances they may be candidates for fast-tracking as either 'category 2' applications or 'priority evaluations', a special type of 'category 1' application. At present, gaining FDA marketing approval for a nanomedicine does not result in 'fasttrack' TGA approval. For example, Emend速 is a nanoparticulate drug containing a new active pharmaceutical ingredient, developed by Merck, was granted marketing approval by the FDA on 26 March 2003.66 Following FDA approval Merck submitted a regular 'category 1' application to the TGA which was approved late in 2005.67
The two and a half year delay between US and
Australian marketing approval may have been alleviated, to some extent, by adoption of 'level 2' information sharing between the FDA and TGA, whereby an FDA evaluation report alone will activate the 'category 2' pathway. Under the current regulations, a nanomedicine will be a candidate for a 'category 2' application, which have a statutory review period of 175 days, where it has been independently, approved by two acceptable countries, which include, the United States, Canada, Sweden, the Netherlands and the United Kingdom.68 The application involves the submission of the reports of both countries along with quality, safety and efficacy data as per a 'category 1' application.69 A nanomedicine will be a candidate for 'priority evaluation' where; it is indicated for treatment or diagnosis of a serious, life-threatening or severely debilitating disease or condition and there is clinical evidence that the medicine may provide an important therapeutic gain.70 These are very similar conditions to those required for a product to receive 'fast-track' status via the 'accelerated approval' pathway in the FDA. Thus nanotherapeutics that receive 'fast-track' status from the FDA are ideal candidates for 'priority evaluation' by the TGA. Indeed the TGA's regulatory framework already allows data packages for such medicines to be submitted in the United States format rather than the usual European Union format which is required for most other applications.71
Under the TGA's current regulatory framework 'priority evaluations' are still
65 Above n62 see: Appendix 1. 66 FDA Approves New Drug to Combat Nausea and Vomiting for Cancer Patients Getting Chemotherapy, Food and Drug Agency <http://www.fda.gov/bbs/topics/NEWS/2003/NEW00886.html> at 29 October 2006 67 Australian Register of Therapeutic Goods no's. 95332,95333,95773,95744,95755,96671 68 Above n62 69 Id. 70 Id. 71 Id.
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2.2 'Fast-Track' TGA Approval of FDA Approved Nanomedicines? 'category 1' applications and as such have a statutory evaluation time of 255 days, but the TGA is committed to performing the evaluation as rapidly as possible.72 In Chapter 1 we saw that VivagelTM, was granted 'fast-track' status at the FDA, thus potentially. making it a candidate for 'priority evaluation' by the TGA. However we considered whether the benefits of 'fast-track' approval, based on surrogate end-points for efficacy, justified the potential risks associated with nanotherapeutics in this situation. Drawing from this, we may hypothesise that if the TGA were, under Annex 2C(4) of AUSFTA, to automatically give FDA approved nanomedicines access to the 'category 2' pathway or those receiving designated 'fast-track' status from the FDA, 'priority evaluation' status, a result that is likely to be targeted by industry, there is potential for Australia's sovereign capacity to maintain high standards of safety and efficacy to be compromised. Of particular concern, in this respect, is whether FDA risk-benefit analysis based on its interpretation of 'serious or life-threatening' will necessarily be applicable in Australian circumstances, and the increasing trend of the FDA conditioning approval on the conduct of postmarketing studies73, meaning that any reliance of the TGA on FDA pre-marketing evaluation is consequently reliant on an effective system of postmarketing regulation, an issue which is likely to become increasingly important in the regulation of nanotherapeutics, and will be examined in Chapter 4.
In the next section I will critically examine the proposition that the regulatory
knowledge deficit in relation to nanotherapeutics may give industry leverage in framing classification of such products to achieve 'fast-track' approval.
72 Id. 73 See Generally: Steenburg, C., 'The Food and Drug Administration's use of Postmarketing (Phase IV) Study Requirements: Exception to the Rule? ' (2006) 61 Food and Drug Law Journal 295
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Chapter 3
CHAPTER 3 'FAST-TRACKING' CONVERGENT NANOTHERAPEUTICS: MEDICINES V
DEVICES In the previous section I identified two TGA 'fast-track' approval pathways that industry may target, using leverage derived from Annex 2C(4) of AUSFTA, to obtain speedier access to the Australian market for FDA approved new medicines. In this section I will examine the manner in which industry may attempt to secure 'fast-track' approval for nanotherapeutics by framing such products as essentially similar to existing therapeutic products. However I will conclude that the success of this strategy is likely to be dependant on whether the product is classified as a medicine or a device. This conclusion will form the basis for an examination of whether the disparate rigour of premarket regulatory review between medicines and devices may provide industry with leverage to 'fast-track' regulatory approval for convergent nanotherapeutics.
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3.1 Contrasting the Approval of Nanomedicines and Nanodevices
3.1
Contrasting the Approval of Nanomedicines and Nanodevices
In this section I will consider two case studies of nanotherapeutic products, Rapamune速 and NanossTM. Rapamune速, is a nanoparticulate reformulation of an approved medicine and is thus a candidate for approval as an 'essentially similar' medicine. NanossTM is a precipitation of calcium phosphate nanocrystals which may be used to form implants used in orthopaedic surgery. 74 Calcium phosphate has been used in the medical devices with non-load bearing applications for years, however Nanoss' nanocrystalline structure provides it with increased strength and bioactivity enabling it to mimic the properties of natural bone crystals, which, may grow around, and eventually replace the implant.75 An 'essentially similar' medicine is a product that, has the same qualitative and quantitative composition in terms of active substances, is in the same pharmaceutical form (eg. oral dosage as opposed to injection), and is bioequivalent, unless it differs significantly from the original product as regards to safety or efficacy in light of scientific knowledge. 76 An application for an 'essentially similar' medicine, does not require the submission of safety and efficacy data where appropriate studies showing bioequivalency have been submitted.77 Such applications are still 'category 1' applications however the TGA has a non-statutory target time frame of 45 working days for evaluation of these applications.78 However, typically a nanoparticulate form of an existing drug will not be bioequivalent, due to a combination of factors associated with the advantages of nanoparticulate reformulation including, enhanced bioavailability, reduced toxicity and smaller and more stable dosage forms.79 Thus it is unlikely that this pathway could be utilised to secure 'fasttrack' approval of nanoparticulate reformulated medicines. In fact, Rapamune速, was approved following a evaluation of a regular 'category 1' application by the TGA and NDA by the FDA.80 Nevertheless it may be advisable for the TGA to take into account the significantly different 74 Baluch, A., 'Angstrom Medica: Securing FDA approval and Commercializing a Nanodevice' (2005) 2 Nanotech Law & Business 168 75 Id. 76 Above n62 77 Id. 78 Id. 79 Till, M., Simkin, M. & Maebius, S. 'Nanotech Meets the FDA: A Success Story about the First Nanoparticulate Drugs Approved by the FDA' (2005) 2 Nanotech. Law & Business 163 80 Australian Register of Therapeutic Goods no's: 73921, 79504, 97766, 104340, 125629, 125630: see also: Till, M., Simkin, M. & Maebius, S. Nanotech Meets the FDA: A Success Story about the First Nanoparticulate Drugs Approved by the FDA. 2 Nanotech. L. & Bus 163 2005
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3.1 Contrasting the Approval of Nanomedicines and Nanodevices properties of nanoparticles and subject all nanoparticulate reformulations to 'category 1' applications, even if bioequivalence is shown. By way of contrast, Angstrom Medica's success in framing its product NanossTM as essentially similar, to pre-existing calcium phosphate implants, and obtaining FDA approval as a 'class II' medical device, reflects the disparate rigour of regulatory evaluation between medical devices and medicines. A nanotherapeutic product, classified as a medical device (from here on in nanomedical device) includes, any instrument, apparatus, implement, machine, appliance, implant, software, material or other similar or related article intended for diagnosis, treatment, monitoring, prevention, alleviation or compensation for an injury, handicap or disease, contraception, disinfection of medical devices or in vitro diagnosis, that does not achieve its principal intended action by pharmacological, chemical, immunological or metabolic means, but may be assisted in its function by such means.81 The contrast between devices and prescription medicines, is that, whereas the regulation of prescription medicines, is characterised by the requirement that the quality, safety and efficacy of the product be evaluated by the relevant regulatory agency, prior to being approved for marketing, the regulation of medical devices is characterised to some extent, by industry self-regulation, whereby the sponsor of the device is able to some extent, frame the level of regulatory risk assessment applied to the product. The sponsor must first, classify the device as, class I; low risk, class IIa; low-medium risk, class IIb; medium-high risk, class III; high risk, according to its intended use, the level of risk and the degree of invasiveness in the human body.82 The sponsor then makes a declaration, notifying the TGA, that the device complies with the 14 essential principles, including that the product's safety and efficacy have been proven in clinical trials.83 Following this notification, all devices may be subject to an audit by the TGA, in which the TGA reviews, among other things, a summary of the clinical trial evidence used to establish conformity with the 14 essential principles.84 However whilst most medium-high risk products (including all class III devices) are subject to an audit, most low-medium risk products are automatically listed on the ARTG as approved products. 85 In gaining
81 Above n61 82 Department of Health and Ageing, Australian Government, Australian Medical Devices Guidance Document Number 25: Classification of Medical Devices (2005) 83 Department of Health and Ageing, Australian Government, Australian Medical Devices Guidance Document Number 2: Application Audits (2005) 84 Id. 85 Id.
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3.1 Contrasting the Approval of Nanomedicines and Nanodevices approval as a class II medical device Nanoss TM was not subject to the FDA equivalent of an audit.86 Two conclusions may be drawn from this. First, given that, most of the risks associated with nanotherapeutics to the interaction of free nanoparticles with processes in the body (see chapter 1.1), the unique aspects of safety evaluation for nanodevices, such as Nanoss, which incorporate fixed nanoparticles, are likely to be associated with the end of the products lifecycle. 87 In light of this, it may be prudent for the TGA to audit all implantable nanodevices to ensure that sponsors have adequately assessed the safety of their product at this stage. The second conclusion we can draw is, that even where a nanodevice is subject to an audit, safety and efficacy evaluation, is far less rigorous than for prescription medicines. The significance of this in terms of potential industry leverage to secure 'fast-track' approval for convergent nanotherapeutics will be examined in the next section.
3.2
'Fast-Tracking' Convergent Nanotherapeutics
The distinction between a medicine and a medical device under the TGA's regulatory framework essentially turns on the words 'principle intended action'. Where a therapeutic product achieves its 'principle intended action' by pharmacological, chemical, immunological or metabolic means it will be regulated as a medicine; where a therapeutic product is merely assisted in its function by such means or achieves its 'principle intended action' by another means it will be regulated as a medical device. The TGA has recognised that some therapeutic products do not fit neatly within either definition and provides a list of device/medicine boundary products that have been approved and whether they were classified as a medicine or a device.88 However, this list provides little assistance in determining the classification of new therapeutic products.
The
distinction is likely to become increasingly important in the regulation of nanotherapeutics, as the development of therapeutics on the nanoscale allows manufacturers to combine components of devices and medicines into a single therapy89 and, as we have seen regulatory evaluation of 86 Above n74 87 United Kingdom, Royal Society Report, Nanoscience and Nanotechnologies: Opportunities and Uncertainties (2004) 88 Above n61 89 Miller, J., 'Beyond Biotechnology: FDA Regulation of Nanomedicine' (2003) 4 Columbia Science and Technology
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3.2 'Fast-Tracking' Convergent Nanotherapeutics medicines is far more comprehensive than regulatory evaluation of medical devices. Illustrative of this point is the convergent nanotherapeutic product being developed by the US company, Nanospectra Biosciences, 'gold nanoshells'.
These nanoshells are essentially
nanosized particles of silica, coated in gold nanoparticles, which when injected into the blood stream, naturally congregate at tumour sites.
The nanoshell then acts as a 'nanolens', capturing
infra-red light and focusing it around itself allowing tumours to be detected and imaged. In vivo diagnostic imaging agents are listed by the TGA as boundary products and are currently regulated as medicines.90 However, having served its diagnostic, function the gold nanoshell may be used to destroy the tumour, by shining an infra-red laser on the tumour site, where the nanoshells have congregated, the area around the nanoshells heats up and the tumour 'cooks',91 the effect is similar to that of an 'implantable radioactive source', which are placed within tumours in order to destroy them, these are also listed as boundary products by the TGA but are currently regulated as devices 92. Thus gold nanoshells have two distinct modes of action, both of which are recognised by the TGA as blurring the distinction between medicines and devices and both of which are currently classified differently by the TGA. Unlike the TGA, the FDA explicitly recognises 'combination products' and assigns regulatory jurisdiction based on the mode of action that is expected to make the greatest contribution to the overall intended therapeutic effects of the combination product'. 93 Given that the destruction of tumours is likely to make the greatest contribution to the overall intended therapeutic effect of gold nanoshells it would appear likely that an application of this definition would result in them being regulated as medical devices. However it is arguable that the risks associated with free nanoparticles, in vivo, should be subject to the more comprehensive safety and efficacy evaluation associated with prescription medicines approval. It would thus be prudent for both the TGA and FDA to adopt a regulatory definition for nanotherapeutics, distinguishing between products that incorporate nanoparticles in fixed structures, such as Nanoss, be classified as devices, whilst products that involve the use of free nanoparticles, such as gold nanoshells, be classified as medicines. The FDA has taken a step toward such a definition, providing that where a product has
90 91 92 93
Law Review 5 Above n61 Above n32 Above n61 'Definition of Primary Mode of Action of a Combination Product', (2005) 70 Federal Register 160 available at <http://www.fda.gov/OHRMS/DOCKETS/98fr/05-16527.htm> at 29 October 2006
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3.2 'Fast-Tracking' Convergent Nanotherapeutics two modes of action, and neither mode is subordinate to the other, it will be assigned to the jurisdictional area with the most expertise in evaluating the most significant safety and effectiveness questions presented by the product.94 The difficulty associated with classifying convergent nanotherapeutics as medicines or devices provides industry with considerable leverage to secure 'fast-track' approval for such products. Rather than attempting to secure approval for multiple modes of action for one product, which would require the submission of data to demonstrate the safety and efficacy for all modes of action, which is likely to be both time consuming and costly. Industry may choose to, initially, only provide data demonstrating safety and efficacy for the mode of action that is most likely to secure 'fast-track' access to the market. The problem for regulators, as we shall see in the next chapter, is that, once the product is approved for marketing it is difficult to maintain regulatory control over unapproved uses.
94 Id.
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Chapter 4
CHAPTER 4
'FAST-TRACKING' OF NANOTHERAPEUTICS: IMPORTANCE OF POSTMARKET REGULATION In this chapter I will critically analyse, in light of FDA experiences, a number of problems with post-marketing regulation in its current form and critically examine whether advances in nanotherapeutics are likely to place increased importance on the post-marketing phase of regulation. In the final section I will put forward the case that Annex 2C(4) of AUSFTA provides an opportunity to restructure regulatory relations between the TGA and FDA with a view to creating a forum for 'level 1' style information sharing facilitating, the development of a safety evaluation framework for nanotherapeutics and, an effective post-market surveillance system for such products.
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4.1 Problems with Conditioning 'Fast Track' Approvals on Postmarketing Regulation
4.1 Problems with Conditioning 'Fast Track' Approvals on Postmarketing Regulation Prior to receiving regulatory approval, the safety and efficacy of therapeutic products is evaluated based on data obtained from clinical trials, which generally involve no more than a few thousand volunteers, forming a largely homogenous group, treated under carefully controlled conditions, by highly trained medical practitioners.95
However following approval a new
therapeutic product may be prescribed or used by many hundreds of doctors on thousands of patients. Thus it is almost redundant to say that â&#x20AC;&#x153;even the most extensive clinical investigations will reveal only a fraction of the information that emerges during the course of a therapeutic product's general marketing and useâ&#x20AC;?.96 In light of this post-marketing evaluation of therapeutic products may be required to detect unexpected side effects and interactions and to determine their long term safety and efficacy.97 Evaluation of these risks post-marketing is likely to be particularly important for nanotherapeutics given that the safety evaluation framework for such products, is lagging significantly behind their commercial development98.
There are essentially two methods for
evaluating such risks following regulatory approval, post-marketing surveillance and phase IV studies. Sponsors of approved therapeutic products are required, under the regulatory framework of both the TGA and FDA, to conduct a limited form of post-marketing surveillance, whereby they must maintain records of, and report, any adverse safety reports for their product of which they become aware.99 Generally sponsors will become aware of such matters, as a result of adverse event reporting from doctors, healthcare institutions and others in the field. 100 Thus the data is collected rather haphazard making epidemiological evaluation particularly difficult.101 Further, whilst acute adverse reactions are likely to be reported, it is unlikely that long-term adverse effects, or those that occur as an increase in already common conditions, will be detected by this 95 Steenburg, C., 'The Food and Drug Administration's use of Postmarketing (Phase IV) Study Requirements: Exception to the Rule? ' (2006) 61 Food and Drug Law Journal 295 96 Id. 97 Meyboom, R.H.B., 'Good practice in postmarketing surveillance of medicines' (1997) 19 Pharmacy World & Science 186 98 See: Above n43. 99 Department of Health and Ageing, Australian Government, Australian Regulatory Guidelines for Prescription Medicines (2004) See also: Postmarketing Surveillance Programs, Food and Drug Agency <http://www.fda.gov/cder/regulatory/applications/postmarketing/surveillancepost.htm> at 29/10/06 100Above n95 See also: Above n97 101Above n95
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4.1 Problems with Conditioning 'Fast Track' Approvals on Postmarketing Regulation mechanism.102 Phase IV studies may be defined to include all post-approval studies to obtain data concerning safety, efficacy or new uses for the product103 and may take the form of formal trials or active monitoring efforts.104 There are essentially three situations in which phase IV studies will be conducted. The FDA has explicit regulatory authority to condition approval on the conduct of phase IV studies, in order to verify that the clinical efficacy, predicted on the basis of pre-approval surrogate endpoints, where a medicine has been approved under the 'accelerated approval' pathway.105 In these circumstances the FDA has the authority to pull the drug off the market, where the sponsor does not perform the tests or the predicted benefits are not realised.106 However the FDA is now conditioning the approval of about half of all New Drug Applications on the conduct of phase IV studies.107
It is suggested that conditioning approval on phase IV studies may represent a
compromise for review panels, subject to considerable pressure to fast-track approvals, where safety and efficacy concerns arise from ambiguities in pre-marketing data.108 Outside of the 'accelerated approval' pathway the FDA's authority to condition approval on, and enforce the conduct of, phase IV studies is somewhat questionably derived from its 'records and reports' provision,109 which is similar to the Conditions Standard and Specific Applying to Registered or Listed Therapeutic Goods under Section 28 of the Therapeutic Goods Act 1989 and requires that the sponsor provide the TGA with periodic safety update reports containing information relevant to the safety of approved therapeutics, including the status of post-marketing studies.110 Whether or not this provision gives the TGA the authority to condition approval on, and enforce the conduct of phase IV studies, is outside the scope of this paper.
However it is
worthwhile noting that in the FDA context, a recent investigation by the Office of the Inspector General revealed that 35% of the periodic safety update reports that should have been submitted in the fiscal year 2004, were either missing or did not contain information regarding phase IV study 102Id. 103 Dohram, J., 'Rethinking and Restructuring The FDA Drug Approval Process in Light of the Vioxx Recall' (2005) 31 Journal of Corporation Law 203 104Above n95 105Id. 106Id. 107Department of Health and Human Services, Office of Inspector General, United States Government, FDA's Monitoring of Postmarketing Study Commitments (2006). available at <http://oig.hhs.gov/oei/reports/oei-01-0400390.pdf> at 29 October 2006 108Above n95. 109Id. 110Above n107
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4.1 Problems with Conditioning 'Fast Track' Approvals on Postmarketing Regulation commitments.111 The report concluded that the FDA lacks an effective management information system for monitoring phase IV study commitments.112 Further it appears that the FDA has few options, short of withdrawing marketing approval, available to force sponsors to carry out their postmarketing commitments.113 Whilst this is a substantial threat in theory, in practice, the FDA is unlikely to withdraw approval unless a medicine is shown to be unsafe through adverse event reporting which as we have seen is difficult to evaluate.114 It would appear likely that the TGA is in a similar situation in these respects. The final situation is where, the sponsor of a therapeutic product voluntarily conducts a phase IV study. Such studies are most commonly conducted by companies wishing to test a therapeutic product for a new treatment indication or to show increased efficacy of their product compared to other similar products on the market. However, such studies may also reveal safety issues. For example Vioxx® was found to be unsafe and voluntarily recalled by Merck in 2004 because it was found to increase the risk of heart attacks or strokes, following the results of two phase IV studies, the 2001 VIGOR study which was designed to assess the gastrointestinal safety of Vioxx® relative to that of an older drug (naproxen)115 and, the 2000 APPROVe study, designed to study the protective effects of Vioxx® in preventing colon polyps.116 It is questionable whether Vioxx® should have been approved at all given that there was data, available to the FDA prior to approval, of increased risk of cardiovascular events occurring in patients receiving Vioxx® compared to the control group.117 However this data was dismissed as statistically insignificant based on the size of the trial and further was not considered reason enough, by the FDA, to condition approval on the conduct of phase IV studies.118 The Vioxx® scandal highlights the difficulty of identifying and imposing critical phase IV studies prior to approval, even where there is evidence to suggest the need for further investigation and further highlights the fact that regulatory agencies may be unable or unwilling to force sponsors to conduct specified phase IV investigations in response to evidence that comes to light post-marketing.119 111Id. 112Id. 113Above n95 114Id. 115 Bombardier, C. et al., 'Comparison of Upper Gastrointestinal Toxicity of Refecoxib and Naproxen in Patients with Rheumatoid Arthritis,' (2000) 343 New England. Journal of. Medicine 1520 116 Above n103 117 Above n95 118 Id. 119 Id.
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4.1 Problems with Conditioning 'Fast Track' Approvals on Postmarketing Regulation Thus we might conclude that there are two significant problems with post-marketing regulation in its current form; 1) pre and post-marketing identification of critical safety issues requiring further study post-marketing and, 2) imposition and enforcement of phase IV obligations. In the next section I will argue that these problems must be addressed given the increased importance of the post-marketing regulatory phase, in light of advances in nanotherapeutics.
4.2
Advances in Nanotherapeutics: Increased Pressure on Postmarket Regulation
We have already seen that there have been relatively few studies assessing the unique properties of nanoparticles and thus the safety evaluation framework for nanotherapeutics is lagging significantly behind their commercialisation. This means that regulatory agencies do not currently have a strong scientific foundation on which to base regulatory approval decisions for nanotherapeutics but at the same time agencies may be under increasing pressure to fast-track the approval of such products. This places increased pressure on the post-marketing regulatory phase because it is being relied upon to not only identify and assess critical safety issues for individual products but also as one of the primary means of developing a safety evaluation framework for nanotherapeutics more generally. For example we may envision circumstances in which adverse safety reports for a particular nanotherapeutic product call into question the safety of not only that product but a particular class of nanotherapeutics.
Such adverse reports may come about as a result of post-marketing
surveillance or as a result of clinical trial data obtained from a nanotherapeutic product in development. The maintenance of high safety standards for nanotherapeutics in this situation requires that regulatory authorities be able to identify not only the source of the safety concern but also whether this concern applies to only this particular product or arises due to a use of nanoparticles that is characteristic of a number of products, for example, nanoparticulate drug reformulations.
If the concern does potentially affect a class of nanotherapeutics, regulatory
agencies must have the authority to impose phase IV study requirements, placing the burden on sponsors of such products, to demonstrate that their approved product, still meets the requisite high
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4.2 Advances in Nanotherapeutics: Increased Pressure on Postmarket Regulation safety requirements for continued marketing approval. The necessity of such authority is further highlighted by the fact that an underdeveloped safety evaluation framework for nanotherapeutics is likely to make it even harder to identify critical phase IV studies on which marketing approval may be conditioned. The pressure on the post-marketing regulatory phase is compounded by the fact, as discussed in Chapter 3, that advances in nanotherapeutics are likely to result in an increase in convergent products that challenge the regulatory distinction between medicines and devices. Where a combination product is approved for a single 'mode of action' but may have multiple modes of action, as in the case of gold nanoshells, a number of scenarios may unfold. The first is that the sponsor may voluntarily undertake phase IV studies to establish the safety and efficacy of the products second mode of action, this would be advantageous to the sponsor in terms of potential increased sales and patent extensions. However as we have seen with Vioxx速 they may also reveal safety concerns that do not become immediately apparent to regulators. The second scenario is that once the product is on the market, and further, potentially clinically beneficial modes of action are revealed, the product may increasingly be used for unapproved purposes. Regulatory agencies may potentially pre-emptively address this concern through close scrutiny of the clinical trials conducted by the sponsor prior to seeking regulatory approval for a specific mode of action, providing the regulator with an opportunity to halt or condition approval subject to safety and efficacy testing for all potential modes of action. Where pre-emptive action is not available the maintenance of high safety and efficacy standards for further modes of action will be reliant on post-market surveillance of unapproved uses and the authority to impose phase IV study requirements on sponsors where unapproved uses are revealed.
4.3
An Inter-agency Review Board for Postmarket Regulation of Nanotherapeutics
In light of the concerns highlighted in the previous Chapters of this paper, it is arguable that the most significant concern for the TGA, if it is to maintain sovereign high standards of safety and efficacy for nanotherapeutic products in Australia, is the disjunction between an underdeveloped
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4.3 An Inter-agency Review Board for Postmarket Regulation of Nanotherapeutics safety evaluation framework and the potential for significant industry leverage to ensure 'fast-track' approvals for such products. In this Chapter we have examined the potential for postmarketing studies to in some respects resolve this disjunction but analysis has revealed that the current postmarketing regulatory frameworks of the FDA, explicitly and the TGA by implication, do not provide the requisite control to the respective regulatory agencies over this phase of regulation. In chapter two, we saw that Annex 2C(4) would likely be used for the purpose of expanding a number of TGA regulatory pathways with a view to 'fast-tracking' FDA approved medicines in Australia. Concomitant with 'fast-track' commitments under this agreement, is a commitment to 'advance existing dialogue between the TGA and FDA'. Thus I would suggest that Annex 2C(4) provides an opportunity for the agencies to work together to establish an independent review board, that would facilitate the advancement of this dialogue by creating a forum for 'level 1' style information sharing between the TGA and FDA particularly in the clinical trials and post-marketing phases of regulation. An Australian and United States Independent Review Board (AUSIRB) may address a number of the safety and efficacy concerns associated with fast-track approval of nanotherapeutics and the associated increased pressure on post-market regulation if it is established with the following terms of reference.
All clinical trial applications and scientific review of these
applications by the FDA or TGA under the CTX scheme (although this is rare as discussed in Chapter 2) as well as data obtained following the conduct of such clinical trials should be immediately submitted to AUSIRB and made readily accessible for investigation and peer review by researchers with relevant expertise.120 Further pre-market approval evaluations by both the TGA and FDA should be submitted to AUSIRB facilitating access to these reports by both agencies. AUSIRB should take primary responsibility for post-marketing surveillance and identification of safety issues and unapproved uses, by instituting a form of active monitoring based on fostering interactions with the broader scientific community, including healthcare workers and academia, whereby safety concerns and adverse event reports should be submitted directly to AUSIRB and again made immediately available to both the TGA and FDA as well as interested independent researchers.121 Facilitation of interaction between agencies and the broader scientific committee enables 120Above n103 121Id.
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4.3 An Inter-agency Review Board for Postmarket Regulation of Nanotherapeutics identification and evaluation of safety issues that may have broad application to nanotherapeutics and, in particular, may allow evaluative frameworks for long-term safety concerns to be developed based on surrogate indicators of long-term bio-accumulation rates. Based on this information AUSIRB could make recommendations to the TGA and FDA on phase IV studies that should be conducted for nanotherapeutic products. However the TGA and FDA must be invested with regulatory authority to impose and enforce such studies post-marketing. Most importantly AUSIRB would provide a centralised database of information upon which a safety evaluation framework for nanotherapeutics could be developed providing a basis for more effective pre-marketing regulation of this exciting new technology, without the need for the adoption of a risk averse precautionary halt to nanotherapeutic approvals thus achieving a compromise between ensuring safety and efficacy whilst providing Australians with timely access to therapeutic products.
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Conclusion
CONCLUSION Nanotechnologies have the potential to revolutionise the development of innovative and beneficial therapeutic products. In this paper I have examined the proposition that the FDA and TGA are under increasing pressure to 'fast-track' approval of innovative nanotherapeutics and that this pressure may compromise high standards of safety and efficacy which have been established to protect public health.
Analysis of the risks and benefits associated with 'fast-tracking'
nanotherapeutics, in Chapter 1, revealed that even though, the framework for assessing the safety risks of nanotherapeutics was underdeveloped, this did not justify the adoption of a risk averse regulatory approach which would likely stifle innovation thus nullifying the potential public health benefits of this technology. The discussion revealed that industry has a number of mechanisms by which it may exercise leverage over regulatory agencies to 'fast-track' approvals for nanotherapeutics. Examination of the manner in which such mechanisms may affect the TGA's regulation of nanotherapeutics in Chapters 2 and 3 showed that the TGA may become more reliant on FDA evaluation of safety and efficacy particularly given Australia's commitments under Annex 2C(4) of AUSFTA and further that the convergent nature of nanotherapeutics provide industry with a further mechanism by which to pursue 'fast-track' approval. In the final Chapter analysis of the FDA's increased reliance on postmarketing regulation revealed that, whilst postmarketing regulation may provide a mechanism by which regulatory industry may regain some leverage over industry in response to fast-track pressures, the current regulatory framework for postmarketing regulation was ineffective. This formed a basis for putting the case that Annex 2C(4) of AUSFTA may facilitate the development of an Interagency Review Board, which would be responsible for developing an effective safety evaluation framework for nanotherapeutics based on extracting, collating and evaluating the maximum amount of information from each stage of the regulatory process. On the basis of this discussion I will conclude by suggesting that if Australia is to maintain sovereign, high standards of public healthcare in the wake of advances in nanotherapeutics, the TGA must reconcile the dual goals of ensuring high standards of safety and efficacy, and providing timely access to innovative therapeutic products. To do this, the Australian Goverment should take a proactive stance toward utilising mechanisms, such as Annex 2C(4) of AUSFTA, to allow the Word Count:
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Conclusion TGA to efficiently develop the requisite evaluative framework for nanotherapeutic products.
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