Assessing the safety and cost-effectiveness of early nanodrugs

Assessing the safety and cost-effectiveness of early nanodrugs Timothy Vines and Thomas Faunce* This article provides a detailed examination of how the safety and cost-effectiveness elements of Australia’s drug regulatory system will respond to nanomedicines. The case study investigated involves Abraxane, a newly developed anti-cancer agent. The article concludes by proposing some responses to the challenges which nanomedicines are likely to present to international and domestic agencies. Additionally, it considers whether the recommendation of the Australian Productivity Commission to allow parallel submissions to the Pharmaceutical Benefits Advisory Committee (PBAC) and the Therapeutic Goods Administration (TGA) is appropriate when applied to new nanotherapeutics.

INTRODUCTION Nanotherapeutics is an emerging field of medicine. A number of early or “first generation” products have been listed for human use in the United States, Europe and Australia.1 Literature in the physical sciences and engineering discipline defines nanostructures as structures possessing at least one dimension less than 100 nanometres (nm).2 This definition has been adopted by several government agencies as generally appropriate for regulation of manufacturing processes and many reviews into the social impact of nanotechnologies also adopt this definition.3 The human body contains a variety of biological barriers which can be traversed by nanoparticles greater than 100 nm, such as the blood-brain barrier.4 Abraxane, as discussed below, is one such drug. It is common for research into nanotherapeutics to adopt a higher threshold of 1,000 nm to define nanotherapeutic agents.5 This article follows an Abraxane submission to Australia’s drug regulatory agencies. It focuses on the challenges that nanomedicines in general, and Abraxane in particular, will present not only to the * Timothy Vines, BA LLB (Hons) (ANU), Research Associate, College of Law; The Australian National University, Canberra; Dr Thomas Faunce, BA LLB (Hons), BMed, PhD, Associate Professor, College of Law and College of Medicine, The Australian National University, Canberra. Correspondence to: Dr Thomas Faunce, College of Law, The Australian National University, Canberra, ACT 2601, Australia; email [email protected]. 1

Wagner V et al, “The Emerging Nanomedicine Landscape” (2006) 24(10) Nature Biotechnology 1211; Committee on Human Medicinal Products (CHMP), Reflection Paper on Nanotechnology-based Medicinal Products for Human Use (EMEA, 2006), http://www.emea.europa.eu/pdfs/human/genetherapy/7976906en.pdf viewed 10 October 2008. 2 European Science Foundation (ESF), Nanomedicine – An ESF – European Medical Research Councils Forward Look Report (2005) p 20; Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR), The Appropriateness of Existing Methodologies to Assess the Potential Risks Associated with Engineered and Adventitious Products of Nanotechnologies (European Commission, 2005), http://ec.europa.eu/health/ph_risk/committees/04_scenihr/docs/scenihr_o_ 003.pdf viewed 8 August 2008; Royal Society and Royal Academy of Engineering, Nanoscience and Nanotechnologies: Opportunities and Uncertainties (2004) p 7. 3

Health and Safety Executive (HSE), Review of the Adequacy of Current Regulatory Regimes to Secure Effective Regulation of Nanoparticles Created by Nanotechnology (HSE, 2006), p 2, http://www.hse.gov.uk/horizons/nanotech/regulatoryreview.pdf viewed 24 October 2008; Ludlow K, Bowman D and Hodge G, A Review of Possible Impact of Nanotechnology on Australia’s Regulatory Framework Final Report (DIISR, 2007) p 9, http://www.innovation.gov.au/Section/Innovation/Documents/ MonashReport2008.pdf viewed 10 October 2008; Bruschi S and Thomas S, A Review of the Potential Occupational Health and Safety Implications of Nanotechnology for the Department of Employment and Workplace Relations (Australian Safety and Compensation Council, 2006), http://www.ascc.gov.au/NR/rdonlyres/AC17BA49-8BA1-43B8-BC08-219DE53781E6/0/ ASCCReviewOHSImplicationsNanotechnology2006.pdf viewed 24 October 2008. 4

Wagner et al, n 1 at 1212.

5

Desai N, “Public Meeting on Nanotechnology Materials in FDA Regulated Products”, presentation at FDA Public Hearing into

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Assessing the safety and cost-effectiveness of early nanodrugs

safety, but to the Pharmaceutical Benefits Scheme (PBS) cost-effectiveness evaluation process, a unique addition to the drug regulatory approval process in Australia which is of increasing international interest. The article begins with an overview of nanotechnology in relation to medicine, noting that nanotherapeutics is likely to be a significant growth area in the next 20 years.6 New technologies, such as Abraxis Bioscience’s (Abraxis) nab-technology and Elan’s NanoCrystal milling process, will be identified as examples of how nanotechnology operates as an “enabling technology”, allowing once unviable pharmaceutical products to be brought to the market.7 This may raise new challenges for patent registrars as it creates opportunities to “evergreen” soon-to-expire drug patents by reformulating them as nanomedicines. Continued commercial success for nanotherapeutics depends upon its ongoing acceptance by the community which, in turn, depends upon trust in government regulators. Surveys have found varying levels of public trust in the ability of such regulators to protect the community.8 Nonetheless, these surveys also reveal public optimism in the potential for nanoproducts to achieve positive health outcomes.9 Other drugs on the PBS which could be classed as nanomedicines include Caelyx.10 Abraxane, albumin-bound paclitaxel, is the latest nanodrug to enter Australia’s health regulatory regime. It is, however, the first nanodrug to explicitly refer to itself as “nano” and, with constituent particles of ±130 m, comes close to the more general threshold of “nanotechnology”.11 The second part of the article sets out to determine whether Abraxane represents a significantly different therapeutic class from previous taxanes, a group of chemotherapies. In doing so, the article analyses the decision of the United States Food and Drug Administration (FDA) to grant fast-tracked approval for Abraxane. This article considers to what extent the novelty of Abraxane will affect its progression through Australia’s drug regulatory regime. The third part outlines the key components of Australia’s therapeutics regulatory system likely to be relevant to a consideration of the challenge raised by Abraxane. Australia’s medicines regulatory system is built upon the National Medicines Policy (NMP).12 Two of the four objectives of the NMP are that Australians have access to safe and efficacious medicines at “a price affordable to the individual and community”.13 The Therapeutic Goods Administration (TGA) and Pharmaceutical Nanotechnology, Bethesda (10 October 2006), http://www.fda.gov/nanotechnology/meetings/transcript.pdf viewed 24 October 2008, p 187; ISO, IEC, NIST and OECD, International Workshop on Documentary Standards for Measurement and Characterization for Nanotechnologies, Final Report (2008) p 32; Wagner et al, n 1 at 1212; ESF, n 2, p 20. 6

Wagner et al, n 1; SCENIHR, n 2, p 5.

7

Prime Minister’s Science, Engineering and Innovation Council, Nanotechnology – Enabling Technologies for Australian Innovative Industries (2005); Ontario Health Technology Advisory Committee (OHTAC), Horizon Scanning Appraisal: Nanotechnology (2006) p 31: Elan Pharma International, Elan Technology Focus: Helping Bring Your Products to the Market (Elan Pharma International, 2007), http://www.elan.com/Images/Elan_Technology_07v1_tcm3-17145.pdf viewed 4 August 2008. 8 Market Attitude Research Services (MARS), Australian Community Attitudes Held About Nanotechnology – Trends 2005-2008 Final Report (DIISR, 2008), http://www.innovation.gov.au/Section/Innovation/Documents/ MARS%20Study%202008%20for%20website.pdf viewed 20 August 2008; cf Rejeski D, FDA and Nanotechnology: Public Perceptions Matter (Nanotechnology Project, 2006), http://www.nanotechproject.org/process/assets/files/2737/115_rejeskifda.pdf viewed 24 October 2008. 9

MARS, n 8.

10

Wagner et al, n 1 at 1217. Products check against information provided on Australian Register of Therapeutic Goods (ARTG) and Pharmaceutical Benefits Scheme (PBS) data: Department of Health and Ageing (DoHA), Australian Register of Therapeutic Goods (Medicines) (TGA, 2008), https://www.tgasime.health.gov.au/SIME/ARTG/ARTGPublicWeb.nsf/MEDpublic?OpenView viewed 24 October 2008; Department of Health and Ageing (DoHA), Pharmaceutical Benefits Scheme Product Search (PBS, 2008), http://www.pbs.gov.au/html/healthpro/home viewed 24 October 2008. 11

Desai, n 5, p 181.

12

Department of Health and Ageing (DoHA), National Medicines Policy (NMP) (DoHA, 2000), http://www.health.gov.au/ internet/main/publishing.nsf/Content/nmp-objectives-policy.htm/$FILE/nmp2000.pdf viewed 10 October 2008. 13

DoHA, n 12. The four objectives of the NMP are discussed further below.

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Benefits Advisory Committee (PBAC) seek to fulfil these objectives through assessing a new drug’s quality, safety and efficacy (QSE) along with its clinical cost-effectiveness.14 The next part critically analyses whether Abraxane will present novel QSE challenges for the TGA. It examines whether there are appropriate standards to establish the safety of nanoreformulations. Reflecting upon the United Kingdom’s parliamentary report into the influence of the pharmaceutical industry, this article here also examines some reforms to the way in which clinical data are collected and utilised by QSE agencies.15 It may be necessary to reassess clinical trial practice guidelines and this part explores some of the ethical implications which arise when exposing patients and volunteers to nanoparticles. This part is followed by a detailed analysis of the challenges Abraxane will present to the PBS cost-effectiveness process. Although considerable research is taking place on Engineered Nanoparticle (ENP) safety, the present authors examine whether there is a lack of evidence supporting the “cost-effectiveness” of new nanomedicines.16 Effectiveness is likely to be determined under this process by comparing Abraxane to previously listed taxanes. The role of reimbursement agencies as providers of low-cost access to medicines is critically analysed, specifically the cost-effectiveness evaluations performed by the PBAC and the expected requirements of nanodrugs under the Guidelines for Preparing Submissions to the Pharmaceutical Benefits Advisory Committee (the Guidelines).17 The authors’ methodology in this part was informed by attendance at a government and industry workshop run to explain the operation of the Guidelines.18 Whether the requirements of Section B of the Guidelines – which require full disclosure of all, not just “pivotal”, clinical trials – will address the “information imbalance” between existing drugs and new nanotherapies is examined.19 Based on the conclusions reached from an Abraxane submission to the TGA and PBAC, this article concludes by proposing some responses to the challenges which nanomedicines are likely to present to international and domestic agencies. Additionally, it considers whether the recommendation of the Australian Productivity Commission to allow parallel submissions to the PBAC and TGA is appropriate when applied to new nanotherapeutics.

NANOMEDICINE As a first step towards understanding the challenges nanotechnology will present to health technology regulators – and Australia’s medicinal drug policy – this part discusses the history and common definitions of nanotechnology. Richard Feynman’s 1959 speech, “There’s Plenty of Room at the Bottom”, prophesied the potential of the nanotechnology field.20 Academic discussion of contemporary nanotechnology research appears captivated by two central themes: size and novelty.21 The first consideration is that the effects, and effectiveness, of nanostructures are influenced by size. The second premise – novelty 14

Therapeutic Goods Act 1989 (Cth), s 4(1); National Health Act 1953 (Cth), s 101(3A).

15

House of Commons, Health Committee, The Influence of the Pharmaceutical Industry, Fourth Report, Vol 1, Session 2004-2005 (2005). 16

See generally, Bruschi and Thomas, n 3; Royal Society and Royal Academy of Engineering, n 2.

17

Department of Health and Ageing (DoHA), Guidelines for Preparing Submissions to the Pharmaceutical Benefits Advisory Committee [ver 4] (DoHA Guidelines) (DoHA, 2007), http://www.health.gov.au/internet/main/publishing.nsf/Content/ AECB791C29482920CA25724400188EDB/$File/PBAC4.2-3FINAL_13Mar08.pdf viewed 29 September 2008; Therapeutic Goods Administration (TGA), Literature-based Submissions: Points to Consider (TGA, 2003) p 9, http://www.tga.gov.au/docs/ pdf/litbsubs.pdf viewed 24 October 2008. 18 Comments made at a Practical Update on the PBAC Submission Guidelines Workshop, Sydney (4 September 2008) (ARCS Australia Conference). 19

ARCS Australia Conference, n 18.

20

Feymann R, “There’s Plenty of Room at the Bottom”, speech delivered at the Annual Meeting of the American Physical Society, CalTech (29 December 1959). 21

Ludlow, Bowman and Hodge, n 3.

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– is more debatable, especially when applied to nanoparticulates.22 Combustion, eg, gives rise to natural nanostructures and examples of nanostructures being incorporated into ceramics can be traced to the ninth century AD.23 Nanoparticles have been utilised for over two decades as contrast agents in medical imaging.24 Recent advances, however, have provided researchers with more effective tools to manufacture, assemble and manipulate ENPs and nanoscale structures. An open index of nanoproducts lists hundreds of products containing ENPs.25 Similarly, an increasing number of patents are being granted for nanotechnologies.26 Present market estimates of the United States National Science Foundation place the value of nanotechnologies at US$700 billion for 2008, with a projected world-wide value of US$1.5 trillion by 2015.27 Numerous authors have attempted to categorise nanotechnology by reference to particular “stages” or “generations” of nanoproducts.28 Thus, “first generation” products are often defined by the use of “static” ENPs, where the action of the particle does not change when interacting with a biological system. Under this definition, Abraxane would be classed as a first generation product, with the pharmakinetics of the albumin-bound-paclitaxel undergoing a similar process of absorption, distribution, metabolism and excretion once disassociated from the sterile human albumin.29 From a public health perspective, however, it is more important for regulatory and reimbursement agencies to first consider the clinical record of any proposed drug.30 The next consideration is its classification as “first” or “second” generation. In the following sections this article argues that such distinctions distract from the lack of uniform metrology or toxicological standards in this area. Reports of nanomedicine often hail the technology’s potential to help eradicate incurable diseases.31 Claims by the United States National Nanotechnology Initiative that “[i]t is conceivable that by 2015, our ability to detect and treat tumours in their first year of occurrence might totally eliminate suffering and death from cancer” are, however, discounted by many.32 Nonetheless, they represent the popularly held sentiment that nanotechnology will provide breakthroughs in treatment options.33 22

CHMP, n 1, p 2.

23

Australian Senate, Community Affairs Reference Committee, Workplace Exposure to Toxic Dusts (2006) at [7.10]; Darque-Ceretti E et al, “Gold Like Lustre: Nanometric Surface Treatment for Decoration of Glazed Ceramics in Ancient Islam, Moresque Spain and Renaissance Italy” (2005) 21(5-6) Surface Engineering 352 (Abstract).

24 Wagner et al, n 1 at 1213; Therapeutic Goods Administration (TGA), “TGA Rising to the Challenge of Nanomaterials in Medicine” (2007) 52 TGA News 1; Ontario Health Technology Advisory Committee (OHTAC), “Horizon Scanning: Nanotechnology” (2007) 22 E-Bulletin 1. 25

Woodrow Wilson Institute for Scholars, Index of Consumer www.nanotechproject.org/inventories/consumer viewed 24 October 2008.

Products

(Nanotech

Project,

2008),

http://

26

Kanama D, “Patent Application Trends in the Field of Nanotechnology” (2006) 21 Science and Technology Trends 77 at 80; Bawa R, “Nanotechnology Patenting in the US” (2004) 1 Nanotechnology Law and Business 31.

27

SCENIHR, n 2, p 5.

28

Renn O and Roco MC, “Nanotechnology and the Need for Risk Governance” (2006) 8 Journal of Nanoparticle Research 153; cf OHTAC, n 24.

29

Abraxis BioScience, Abraxane – Product Information (FDA, 2005), http://www.fda.gov/cder/foi/label/2005/021660lbl.pdf (2005) viewed 12 June 2008. 30 Villano JL et al, “Abraxane Induced Life-threatening Toxicities with Metastatic Breast Cancer and Hepatic Insufficiency” (2006) 24 Investigatory New Drugs 455. 31 Logothetidis L, “Nanotechnology in Medicine: The Medicine of Tomorrow and Nanomedicine” (2006) 10(10) Hippokratia 7 at 20; Ali Mansoori G, Mohazzabi P, McCormack P and Jabbari S, “Nanotechnology in Cancer Prevention, Detection and Treatment: Bright Future Lies Ahead” (2007) 4(2-3) World Review of Science, Technology and Sustainable Development 226 (Abstract). 32

Royal Society and Royal Academy of Engineering, n 2, p 23.

33

MARS, n 8, p 86; cf Friedman S and Egolf B, “Nanotechnology: Risks and the Media” (2005) (Winter) IEEE Technology and Science 5 at 6.

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Though figures differ, industry estimates that it costs US$500-800 million to develop a new medical entity (NME), run clinical trials and obtain final marketing approval.34 Development timelines, from Phase 1 studies to launch, vary from 8 to 13 years.35 Drug research is a high-investment, high-risk process, with only approximately 1 in 1,000 drugs passing preclinical stages.36 Almost half of Research and Development (R&D) expenditure occurs during this pre-clinical phase, before the proposed drug is granted (in the United States) investigational new drug (IND) approval. Only about one in eight Phase I NMEs eventually end up on the United States market.37 An inquiry into the pharmaceutical industry’s influence heard that “fewer than half of the new drugs approved in the United States can be expected to offer significant therapeutic advance and the number of new drugs is falling overall”.38 Many promising chemicals and therapeutic agents fail to proceed to a New Drug Approval (NDA) stage because of “insufficient stability and shelf-life, costly production, immunogenic and allergic potential, as well as poor bioavailability”.39 Whether Abraxane represents a rejuvenation of a pre-existing drug is considered below and claims that Elan’s NanoCrystals have assisted companies bring otherwise unviable drugs to the market are examined.

ABRAXANE’S

CLINICAL AND REGULATORY HISTORY

One in three Australian men and one in four women will be diagnosed with some form of cancer in the first 75 years of life.40 For women, breast cancer is the leading cause of cancer deaths, although mortality rates have been declining.41 Most patients are treated with various chemotherapies. As a common cancer, with a high prevalence in developed nations, it is an attractive target for new clinical treatments and therapies. Abraxane is a chemotherapy utilising a new “nanoparticle albumin-bound” (nab) drug delivery system. Developed by Abraxis BioScience (Abraxis), it is for the treatment of metastatic or recurrent breast cancer.42 Abraxane’s Product Information describes the drug’s mechanism of action as: an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. Paclitaxel induces abnormal arrays or “bundles” of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.43

Paclitaxel belongs to the taxane group of chemotherapies, so named for the yew tree (genus Taxus) from whose bark the chemical is synthesised.44 Abraxane’s nab delivery system helps 34 Nutley C, “The Value and Benefits of ICH to Industry”, paper produced as part of the International Conference on Harmonization of Technical Requirements of Pharmaceuticals for Human Use (2000) p 11. £500 million is quoted in House of Commons, Health Committee, n 15, p 17. 35 Adams C and Brantner V, New Drug Development: Estimating Entry from Human Clinical Trials (Federal Trade Commission Bureau of Economics Working Paper No 262, 2003) pp 9, 15; Nutley, n 34, p 11. 36

Quoted in Adams and Brantner, n 35, p 6.

37

Adams and Brantner, n 35, p 14.

38

Adams and Brantner, n 35, p 47.

39

Kratz F, “Albumin as a Drug Carrier: Design of Prodrugs, Drug Conjugates and Nanoparticles” (2008) 132(3) Journal of Controlled Release 171; doi:10.1016/j.jconrel.2008.05.010, p 3. 40 Australian Institute of Health and Welfare (AIHW) and Australasian Association of Cancer Registries (AACR), Cancer in Australia 2001 (2004) p xii. 41

AIHW and AACR, n 40, p 9; AIHW and National Breast Cancer Centre, Breast Cancer in Australia: An Overview (2006) p xv, App I.

42

Abraxis BioScience, n 29.

43

Abraxis BioScience, n 29.

44

Specifically the Pacific yew (Taxus brevifolia) and Canada yew (Taxus Canadensis).

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overcome the water-insolubility of paclitaxel by utilising the “endogenous albumin pathways”, resulting in increased intratumor concentrations of the active therapeutic substance.45 Unlike comparable paclitaxel-based medicines, such as Taxol, Abraxane’s formulation does not contain the excipient Cremophor, a solvent which limits maximum tolerated dosage and requires pre-medication.46 Abraxane is indicated in the United States and European Union for “[t]reatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy… [where] [p]rior therapy … included an anthracycline”.47 This makes Abraxane a third or fourth-line treatment. Abraxis is seeking the same listing from the Australian TGA.48 Phase II/III clinical studies demonstrated that a higher dosage of Abraxane can be tolerated by patients with less adverse effects, resulting in a slight improvement in overall treatment success rates.49 However, from the limited time horizon of the clinical trials it appears there is no increase in survival rates once the cancer again becomes “progressive”.50 International standard-setting bodies have agreed that, “as a minimum”, standards be implemented which discuss “size, zeta potential (surface charge) [and] solubility” as “predictor[s]” of toxicity for nanoparticles.51 Abraxane’s regulatory history demonstrates the operation of present European Medicines Agency (EMEA) and FDA guidelines in determining the safety of new nanoreformulations. Abraxane was approved under the abbreviated new drug application (ANDA) process.52 As a condition of submitting its ANDA, the FDA required Abraxis to demonstrate “bio-equivalence” with previous taxanes, rather than conduct a full “battery of safety tests”.53 A surprise finding during clinical trials was that many solid tumours excrete SPARC, a protein which allows tumours to spread and attracts albumin bound nutrients.54 As Abraxane utilises albumin, this has the potential to expand the drug’s clinical use. Nijhara and Balakrishnan refer to this as “[an] interesting new twist”, with the potential to turn Abraxane into a “blockbuster”. Yet it also highlights that a precautionary approach should be taken and nanoreformulations should not necessarily be

45 Green M et al, “Abraxane(R), a Novel Cremophor(R)-free, Albumin-bound Particle Form of Paclitaxel for the Treatment of Advanced Non-small-cell Lung Cancer” (2006) 17(8) Annals of Oncology 1263; Erin R et al, “Randomized Crossover Pharmacokinetic Study of Solvent-based Paclitaxel and nab-Paclitaxel” (2008) 14(13) Clinical Cancer Research 4200. 46

Bristol-Myers Squibb Pharmaceuticals, Taxol – Product Information (PBS, 2005), http://www.pbs.gov.au/pi/bqptaxol10505.pdf viewed 12 June 2008; Stinchcombe TE et al, “Phase I and Pharmacokinetic Trial of Carboplatin and Albumin-bound Paclitaxel, ABI-007 (Abraxane®) on Three Treatment Schedules in Patients with Solid Tumors” (2007) 60 Cancer Chemotherapy Pharmacology 759 at 760. 47 Evidence to the Oncology Drug Advisory Committee (ODAC), Hilton, Silver Spring, Maryland, 7 September 2006 (Abraxis BioScience) p 2. 48

Australian Drug Evaluation Committee (ADEC), ADEC 258th Meeting Resolutions (TGA, 2008), http://www.tga.gov.au/ docs/html/adec/adec0258.htm viewed 17 August 2008. 49 Gradishar W et al, “Phase III Trial of Nanoparticle Albumin Bound Paclitaxel Compared with Polyethylated Castor Oil Based Paclitaxel in Women with Breast Cancer” (2005) 23(31) Journal of Clinical Oncology 7794. 50

European Medicines Agency (EMEA), Assessment Report for Abraxane Doc Ref: EMEA/47053/2008 (EMEA, 2008) pp 31, 32, http://www.emea.europa.eu/humandocs/PDFs/EPAR/abraxane/H-778-en6.pdf viewed 28 October 2008.

51

ISO et al, n 5, pp 8-9.

52

Food, Drug and Cosmetic Act, 21 USC § 355.

53

Food, Drug and Cosmetic Act, 21 USC § 355; EMEA, n 50, p 17; Fromer M, ODAC Decides All Thumbs Ways Down for Abraxane Because Sponsor Requests to Omit Randomized Trial (Oncology Times, 2006) p 24, http://www.oncology-times.com/ pt/re/oncotimes/abstract.00130989-200609250-00013.htm;jsessionid= L5kGrdgWfp65pyBh3QSz1QQqv9XYG19yJjbnygBL0k6ZyBSxmmhG!949623904!181195628!8091!-1 viewed 18 October 2008; Nijhara R and Balakrishnan K, “Bringing Nanomedicines to Market: Regulatory Challenges, Opportunities, and Uncertainties” (2006) 2 Nanomedicine: Nanotechnology, Biology and Medicine 127. 54

Nijhara and Balakrishnan, n 53 at 134, 135.

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treated as bioequivalent with its bulk competitors.55 Indeed, adverse drug reactions (ADRs) – especially peripheral neuropathy – reported during clinical trials suggest that patients react differently to Abraxane than to Taxol.56 This was the view of some members of the Oncology Drug Advisory Committee (ODAC) when it denied Abraxis’ request to expand Abraxane’s listing without first conducting randomised clinical trials (RCT). One member expressed the view that he did not consider Abraxane bio-equivalent with Taxol.57 Although acknowledging the novel nanoformulation of Abraxane, Abraxis sought approval for a new indication based on existing clinical trials for Taxol.58 This was preferred by Abraxis over the “prohibitively costly” process of conducting its own “randomized controlled study to demonstrate the efficacy of Abraxane compared to Taxol as adjuvant treatment for node-positive breast cancer”.59 Both the ODAC and EMEA rejected the request for an enlarged listing.60 A lack of clinical trials establishing efficacy was a determining factor, yet the issue of Abraxane’s nanoformulation does not appear to have given the EMEA cause to pause. The committee freely acknowledged that Abraxis had not performed the “standard core battery of safety pharmacology tests”.61 As discussed above, under abbreviated approval pathways a drug is usually only required to demonstrate bio-equivalence. In furtherance of international harmonisation between QSE agencies which exists, especially, between the FDA and EMEA, it is perhaps reasonable for the EMEA to agree with the FDA and not require Abraxis to conduct a battery of tests to establish QSE.62 However, while the EMEA is correct in asserting that “paclitaxel is a well-known substance with well-defined safety and efficacy”, Abraxane’s nanoformulation is administered in a new way and has unique effects on solid mass tumours exhibiting the SPARC protein.63

OVERVIEW

OF THE

AUSTRALIAN

DRUG REGULATORY PROCESS

Regulation and pricing of Australian therapeutics is conducted by two independent agencies in a two-stage process.64 QSE evaluation of medicines and medical devices is the first stage, conducted by the TGA.65 Medicines approved by the TGA appear, along with their indications, on the Australian Register of Therapeutic Goods (ARTG).66 Submissions to the TGA are made by way of a “common technical document” (CTD) which sets out the relevant clinical data supporting a claim for therapeutic QSE.67

55 Nijhara and Balakrishnan, n 53 at 134, 135; Faunce T et al, “Sunscreen Safety: The Precautionary Principle, the Australian Therapeutic Goods Administration and Nanoparticles in Sunscreens” [2008] 2 Nanoethics 231; doi 10.1007/s11569-008-0041-z. 56

Stinchcombe et al, n 46; Villano et al, n 30.

57

Fromer, n 53.

58

Evidence of Abraxis BioScience, n 47, pp 2, 3.

59

Evidence of Abraxis BioScience, n 47, pp 4, 5.

60

EMEA, n 50, pp 5-6.

61

EMEA, n 50, p 17.

62

But see Therapeutic Goods Administration (TGA), Module 1 – Administrative Information and Prescribing Information for Australia (TGA, 2007), http://www.tga.gov.au/docs/pdf/euguide/tgamod1.pdf viewed 28 October 2008.

63

Nijhara and Balakrishnan, n 53 at 134; EMEA, n 50, p 17.

64

Productivity Commission, Annual Review of Regulatory Burdens on Business: Manufacturing and Distributive Trends (2008).

65

Therapeutic Goods Act 1989 (Cth); Therapeutic Goods Amendment (Medical Devices) Act 2002 (Cth); Therapeutic Goods (Charges) Act 1991 (Cth). 66

Therapeutic Goods Act 1989 (Cth), Ch 2.

67

Therapeutic Goods Administration (TGA), Australian Regulation of Prescription Medical Products (TGA, 2007), http://www.tga.gov.au/docs/html/pmeds_reg.htm viewed 24 October 2008.

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Under the Therapeutic Goods Act 1989 (Cth) it is an offence for an individual or “sponsor” to market or import for human use a therapeutic good, medical device or complementary medicine which has not been listed on the ARTG.68 Although this part of the article focuses on the drug safety regulation in Australia, the United States imposes similar obligations, requiring that: No person shall introduce or deliver for introduction into interstate commerce any new drug, unless an approval of an application filed pursuant to subsection (b) or (j) is effective.69

Filing under s 505(b) or (j) in the United States requires a submission to be made to the FDA. Under Australia’s Constitution, the TGA is restricted in its jurisdiction.70 Each State and Territory also maintains its own drug schedules and laws regulating chemicals and therapeutic goods.71 In order for the TGA to perform adequate QSE evaluations, sponsors are required to submit clinical data – collected through Phase I, II, III and, occasionally, IV studies.72 The European Union, the United States and Japan have moved towards a standardised format for marketing approval submissions via the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). In conjunction with the Good Manufacturing Practice guidelines, regulating drug manufacturing facilities; and the Good Clinical Practice Guidelines, which regulate clinical trial conduct and protocol requirements, the CTD has become the standard method of setting out QSE data.73 Australia’s marketing approval process, although “closely aligned” with the European Union, retains some unique QSE requirements.74 Following a listing on the ARTG, a sponsor can apply to the second stage of the regulatory approval process, the PBAC, for listing on the PBS.75 Australia’s reimbursement scheme – the PBS – is a globally unique institution ensuring “timely and affordable access” to life-saving medicines.76 Enshrined in the National Health Act 1953 (Cth) (the Act) it has served as a model for the equitable distribution of health resources and has been considered for adoption by several other nations.77 Section 101 of the Act creates the PBAC as a body independent of government and industry interference. Each year the PBAC receives, on average, 75 major submissions for new drugs, or new indications – of which 47% failed in 2006.78 The requirement for sponsor companies to demonstrate clinical cost-effectiveness, introduced in 1993, has been adopted by several international reimbursement agencies.79 Australia’s present public health care delivery system is composed of “three pillars”: public hospitals,80 Medicare (Australia’s universal public health insurance program),81 and the PBS.82 This 68

Therapeutic Goods Act 1989 (Cth), ss 19B, 19D-22.

69

Food, Drug and Cosmetic Act, 21 USC § 355.

70

Australian Constitution, s 51(i), (xx), (xxix) respectively.

71

For example, Medicines, Poisons and Therapeutic Goods Act 2008 (Cth).

72

Phase IV trials form a component of post-marketing surveillance. See Nijhara and Balakrishnan, n 53.

73

Department of Health and Ageing (DoHA), Australian Good Manufacturing Practice for Medicinal Products (2002). Based entirely upon Pharmaceutical Inspection Cooperation Scheme, Good Manufacturing Practice for Medicinal Products (3rd ed, 2002), to be read in conjunction with TGA, Australian Clinical Trial Handbook (TGA, 2006), http://www.tga.gov.au/ct/ cthandbook.pdf viewed 24 October 2008. 74

TGA, Module 1, n 62.

75

Submissions to the PBAC must be made in accordance with the DoHA Guidelines, n 17.

76

DoHA, National Medicines Policy, n 12.

77

Faunce T and Lexchin J, “Debate: ‘Linkage’ Pharmaceutical Evergreening in Canada and Australia” (2007) 4(8) Australia and New Zealand Health Policy; doi:10.1186/1743-8462-4-8. 78 Roughead E, Gilbert A and A Vitry, “The Australian Funding Debate on Quadrivalent HPV Vaccine: A Case Study for the National Pharmaceutical Policy” (2008) 88(2) Health Policy 250; doi:10.1016/j.healthpol.2008.03.012, 2. 79


80

Administered by the individual Australian States and Territories.

81

Funded, in part, through a 1% levy on the income of all middle to high income earners.

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system has been the product of 60 years of federal Labor and Coalition bipartisan support.83 Furthermore, the Commonwealth’s power to provide medical and dental services required a constitutional amendment.84 It thus maintains exceptional democratic legitimacy.85 Yet, a growing number of ever more expensive drugs are being listed on the PBS.86 Additionally, with an ageing population requiring greater levels of health care, the cost of the PBS has been increasing sharply over the past decade.87 It falls to the PBAC and the responsible federal Minister to decide whether a new drug (or indication) should be listed and, in pursuing their objectives, the long-term sustainability of the PBS should be borne in mind. A therapeutic drug’s sponsor must demonstrate “value for money” in order to have its therapeutic added to the PBS.88 Critics of the PBS’s cost-effectiveness mechanism argue that it restricts access to vital drugs where a patient disease does not fall within the indications recommended by the PBAC.89 Often, however, these studies are funded by the pharmaceutical industry, represented in Australia by Medicines Australia. Medicines Australia has been a vocal and persistent opponent of the stringent cost-effectiveness aspects of the PBS and even recommended its replacement with “medical savings accounts”.90 With the consequences of any change to the PBS to be felt by Australian patients and consumers through higher costs, any proposed reforms should be approached cautiously. Medicare Australia reports over 90% satisfaction with the PBS program based upon calls to the agency, and successive governments have been rewarded for supporting the PBS and punished whenever the public perceives that the “sacred cow” of Australian politics is threatened.91 Recommendations from the PBAC are considered by the Commonwealth Minister. If the cost to government is over $10 million per annum in any of the first four years of listing, approval must come from Cabinet. If successful, the drug is subsidised by the government at a price negotiated between the sponsor and the Pharmaceutical Benefits Pricing Authority (PBPA), with Australian patients paying a relatively small co-payment to the pharmacist.92 Underpinning the operation of Australia’s medicines regulatory system is the NMP, which sets out four objectives with the goal of promoting health outcomes for all Australians: • first, that Australians should have “timely access to the medicines that Australians need, at a cost individuals and the community can afford”; • secondly, that “medicines … [should meet]…appropriate standards of quality, safety and efficacy”; 82

Commonwealth, Senate, Debates (28 August 2008) p 14 (proof copy) (Senator Siewert).

83

Evidence to Parliament of Australia, Senate Community Affairs Committee, Inquiry into Draft National Health (Pharmaceutical Benefits – Charges) Regulations 2008 (Canberra, 8 September 2008), http://www.aph.gov.au/SENATE/ committee/clac_ctte/draft_regs_nat_hth_pharm_benefits_charges/submissions/sub03.pdf (Timothy Vines, Thomas Faunce). 84

Constitutional Alteration (Social Services) Act 1946 (Cth).

85

See Attorney-General (Vic) v Commonwealth (Pharmaceutical Benefits Case) (1945) 71 CLR 237. Post-referendum Act upheld in part in British Medical Association v Commonwealth (1949) 79 CLR 201. Medicare scheme and Pharmaceutical Benefits Scheme upheld in General Practitioners Society v Commonwealth (1980) 145 CLR 532. 86

Biggs A, The Pharmaceutical Benefits Scheme – An Overview (E-brief) (APH, 2003), http://www.aph.gov.au/library/ INTGUIDE/SP/pbs.htm viewed 24 October 2008. 87

The Intergenerational Report puts the increase in health expenditure as rising from 3.8% of GDP in 2006-2007 to 7.3% in 2046-2047: Treasury, Intergenerational Report 2007 (2007) p 49. See App II for projected growth in health costs.

88

DoHA Guidelines, n 17, p 5.

89

IMS Consulting, Australia’s Centralized Cost-effectiveness Requirements for Pharmaceuticals: Potential Implications for US Patients (2006); Allen Consulting Group, Drivers of Pharmaceutical Industry Investment: Understanding Australia’s Competitive Position (2006) p 7. 90

Allen Consulting Group, Medical Savings Accounts: A Discussion Paper (2004).

91

Lavelle P, Consumer Guide: Saving Money on Medicines (ABC Online, 2008), http://www.abc.net.au/health/consumerguides/ stories/2006/04/17/1837734.htm viewed 26 October 2008; Medicare Australia, Annual Report 2006-07 (2007) p 6, App III. 92 Department of Health and Ageing (DoHA), Pharmaceutical Benefits Pricing Authority Annual Report (DoHA, 2007) pp 5, 8, http://www.health.gov.au/internet/main/publishing.nsf/Content/68283772337B2BA7CA2573E7001C6CEA/ $File/Pharmaceutical%20Benefits%20Pricing%20Authority%202007%20WEB%20Single-page.pdf viewed 24 October 2008.

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• •

thirdly, that there should be a “quality use of medicines”; and finally, that “a responsible and viable medicines industry” should be maintained.93 Objective two is satisfied by the TGA’s QSE assessment, while the first objective falls to the PBAC and PBS. Under the National Strategy for the Quality Use of Medicines (QUM), responsibility for the “rational use of medicines” is shared, inter alia, between “health care consumers” (patients), practitioners, health and aged care facilities, pharmaceutical companies and the media.94 In fulfilling the NMP Abraxis will need to consider its promotion of Abraxane to all relevant stakeholders to ensure it does not contravene the spirit of the QUM. In subsequent parts of this article some activities which could threaten the NMP are examined. These include various forms of direct and indirect advertising, the undue influence upon and dissemination of misinformation to the medical profession, and patent evergreening.95 Government and industry recognise that the TGA’s QSE evaluations are of “the highest standard”.96 Various standing and sub-committees operate under the auspice of the TGA, facilitating consultation and discussion between industry and regulators, such as the “Industry Consultative Committee”. Despite industry complaints over a lack of transparency in TGA assessment procedures, the Productivity Commission found “no conclusive evidence” of any “widespread or systematic problems”.97 Industry has expressed concern over the PBAC listing process with at least one sponsor noting the “mismatch of early advice on our PBAC submissions and the PBAC’s final recommendations”.98 Sponsors have the ability to meet with the Pharmaceutical Benefits Branch (PBB) prior to lodging a submission with the PBAC. Given the clinical data available, it is foreseeable that the TGA will approve Abraxane for the same broad indication it has been granted in the United States and the European Union. Nonetheless, the PBAC may recommend a narrower indication to be subsidised by the government – such as for patients allergic to the comparator Taxol – and early discussions with the PBB would allow Abraxis to formulate a major submission more likely to be successful. Although some sponsors expressed frustration that PBB suggestions did not bind, nor predict, PBAC decisions, this is entirely consistent with the legislative scheme behind the PBAC, which makes it independent of government as well as industry.99 As the meeting with the PBB usually occurs prior to the establishment of a product’s clinical cost-effectiveness, it would be inappropriate for recommendations of the PBB to be binding on the PBAC who are presented with complete information. Even the drug multinational Pfizer, well known for its regulatory challenges, recognised the difficulty in enforcing PBB suggestions.100

NANOMEDICINE’S

CHALLENGES TO QUALITY, SAFETY AND EFFICACY REGULATORS

This section turns to challenges presented to QSE agencies by Abraxane specifically and nanomedicines in general. It considers whether Abraxane and other nanodrugs have sufficient clinical histories to demonstrate long-term safety. This part also explores whether trials of nanoreformulations should carry additional warnings for volunteers and patients. 93 Department of Health and Ageing (DoHA), National Strategy for the Quality Use of Medicines (QUM) (DoHA, 2002) p 1, http://www.health.gov.au/internet/main/publishing.nsf/Content/CA777524C860DFF2CA256F1800468B61/$File/natstrateng.pdf viewed 20 October 2008. For the NMP’s history see DoHA, About the National Medicines Policy and its Objectives (DoHA, 2008), http://www.health.gov.au/internet/main/publishing.nsf/Content/nmp-objectives-index.htm viewed 20 October 2008. 94

DoHA, n 93 (QUM), pp 10-11.

95

DoHA, n 93 (QUM), p 11. Evergreening is discussed below.

96

Productivity Commission, n 64, p 69.

97

Similar concerns about the PBAC process: ARCS Australia Conference, n 18. See also Productivity Commission, n 64, pp 69-70. 98

Pfizer, quoted in Productivity Commission, n 64, p 71.

99


100


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Presently, the FDA, EMEA and TGA examine each new drug on a product-by-product basis.101 However, some have suggested that they approach the task of assessing nanoreformulations with pre-existing knowledge and toxicological standards rather than adapting their assessment to account for novel technology.102 The Committee on Human Medicinal Products (CHMP), eg, asserts the EMEA’s assessment process is concerned with “principles of benefit/risk analysis, rather than solely … the technology per se”.103 Such an approach may not be appropriate for nanotherapeutics, where there exists a paucity of long-term nanotoxicology data.104 Further, as “[e]xperts are of the unanimous opinion that the adverse effects of nanoparticles cannot be predicted (or derived) from the known toxicity of material of macroscopic size”, and that ENPs can accumulate in secondary organs, there may be long-term effects which present benefit/risk analyses fail to consider.105 Moreover, evidence utilised by the TGA is derived from clinical studies almost exclusively commissioned, conducted and reported by the sponsor company.106 As these studies are crucial to a drug’s QSE assessment, there is a risk that pharmaceutical companies will suppress adverse or negative clinical findings. Speaking before the United Kingdom Health Committee, Professor David Healy stated: [T]hey [sponsor companies] take out the good bits of the data, the bits that suit them, and market that back to us and call it science, when clearly it is not.107

Investigations into a major United States pharmaceutical company resulted in a lawsuit alleging the company had suppressed negative clinical results. As part of the settlement, the company set up a public register of all trials.108 While the PBAC requires all relevant studies to be disclosed as part of its listing process, it is unknown to what extent the PBAC or TGA demand disclosure from sponsors of unpublished data.109 Nonetheless, from the treatment of PBAC submissions as “commercial-in-confidence” and the new requirements to protect confidential information in s 25A of the Therapeutic Goods Act 1989 (Cth), it appears that present attitudes are in favour of protecting sponsors’ clinical and economic data.110 Under the TGA’s risk management strategy, medicines can be classed as either “listed” or “registrable”.111 As with other taxanes, Abraxane would be a higher-risk “registrable” medication. The first stage of the QSE process involves the TGA assessing the “sources of risk … [such as] chemistry, … pharmacological and toxicological aspects” of the proposed drug.112 It is unknown against what benchmarks or safety thresholds new nanomedicines are being compared. Long-term toxicity, especially teratogenic and carcinogenic effects often takes many years to be established, which is why animal studies, preceding Phase I human clinical trials, continue for several years.113 101

CHMP, n 1, p 4.

102

Wagner et al, n 1 at 1217.

103

CHMP, n 1, p 4.

104

Faunce T, “Toxicological and Public Good Considerations for the Regulation of Nanomaterial-containing Medical Products” (2008) 7(2) Expert Opinion on Drug Safety 103.

105

SCENIHR, n 2, p 6; Helland A et al, “Nanoparticulate Materials and Regulatory Policy in Europe: An Analysis of Stakeholder Perspectives” (2006) 8 Journal of Nanoparticle Research 709 at 710.

106 Brook R, “Medicines Regulation in the UK: The Case for Reform” (2004) 13(5) Journal of Mental Health 431 at 435; House of Commons, Health Committee, n 15, p 44. 107

House of Commons, Health Committee, n 15, p 49.

108

House of Commons, Health Committee, n 15, p 52; Brook, n 106.

109

DoHA Guidelines, n 17, Section B.

110

Segal L, Osborne R and Day, “Matter Arising: Making All Data Available Would be Welcome” (2004) 181(6) MJA 339 at 340. 111 Department of Health and Ageing (DoHA), The Therapeutic Goods Administration’s Risk Management Approach to the Regulation of Therapeutic Goods (TGA, 2004) p 13, http://www.tga.gov.au/about/tgariskmnt.pdf viewed 20 October 2008. 112

DoHA, n 111, p 14.

113

House of Commons, Health Committee, n 15.

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Where a nanoreformulation relies upon an ANDA or Australian equivalent, the pre-existing data may not accurately reflect the new drug’s long-term toxicological profile. There still remain significant gaps in knowledge over the “pharmacokinetics” of nanoparticles; and “particle characterization protocols”, which factor in the “presence of biological coatings”.114 Moreover, a lack of knowledge concerning the operation of the protein “corona” around an ENP in a biological system leaves QSE agencies unsure of where the threats lie – from the nanoparticle, or the proteins which bind to its surface.115 Although measurement instruments and techniques, such as “transmission electron microscopy”, “scanning probe microscopy” and the “atomic force microscope”, have been utilised in characterising the internal structure of nanoparticles, it does not appear that QSE bodies require such detailed data regarding the nanoscale parts which constitute new products.116 Abbreviated pathways, such as that used by Abraxane, allow a new drug to enter the market on the basis of old data. This not only puts the general patient group at risk but also volunteers who may be induced to participate in a clinical trial on the assumption that it is simply to establish “bio-equivalence” rather than resolve toxicological concerns. Such deception would negate consent, violating the Declaration of Helsinki and Principles 1.28 and 2.1 of the ICH Good Clinical Practice: Consolidated Guidance which reads in part: 1.28 … a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject’s decision to participate.117

Nevertheless, these guidelines do not confer any new legal rights or obligations upon an aggrieved individual.118 The TGA’s risk assessment process suggests that the “sponsor of the therapeutic good is ultimately responsible for ensuring that the product is safe and effective for use by consumers”.119 A consequence of this is that the TGA’s post-marketing surveillance role is limited to responding to adverse effect reports from within Australian and other jurisdictions. Shortcomings in other jurisdictions’ QSE post-marketing surveillance have been identified. In the wake of the Vioxx product recall, British authorities acknowledging that their “Yellow Card ADR reporting system” and EudraVigilance were slow to identify problems.120 Litigation in the United States suggests the FDA was also slow to respond.121 Nonetheless, despite an absence of long-term patient safety data, Abraxane was approved by the FDA through an accelerated pathway, as it demonstrated bioequivalence with a pre-existing drug.122 114

ISO et al, n 5, pp 1, 2.

115

Lynch I et al, “The Nanoparticle-Protein Complex as a Biological Entity; A Complex Fluids and Surface Science Challenge for the 21st Century” (2007) 134-135 Advances in Colloid and Interface Science 167. 116 Royal Society and Royal Academy of Engineering, n 2, p 16; National Industrial Chemicals Notification and Assessment Scheme (NICNAS), NICNAS Information Sheet – Nanomaterials (NICNAS, 2006), http://www.nicnas.gov.au/Current_Issues/ Nanotechnology/Further_Information.asp viewed 29 October 2008. 117 International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance (FDA, 1996) pp 5, 8 (emphasis added), http://www.fda.gov/cder/guidance/index.htm viewed 29 June 2008; Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects, WMA GA 18th Ses Helsinki, Finland, June 1964 and WMA GA 59th Ses Seoul, Korea, October 2008. 118

ICH, n 117, fn 1.

119

DoHA, n 111, p 12.

120

House of Commons, Health Committee, n 15, p 31; Bartlett C, “Interview with Kent Woods, Chief Executive of the MHRA” (2008) Medicine Magazine Online, http://www.medicinemagazine.info/consumer/index.php viewed 29 June 2008.

121

Hill K et al, “The ADVANTAGE Seeding Trial: A Review of Internal Documents” (2008) 149 Annals of Internal Medicine 251; Bartlett, n 120.

122

Although see Villano et al, n 30; Till M, Simkin M and Maebius S, “Nanotech Meets the FDA: A Success Story About the First Nanoparticulate Drugs Approved by the FDA” (2005) 2(2) Nanotechnology Law and Business 163.

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Australia’s Office of Nanotechnology has called for an “evidence-based approach” to nanotechnology regulation.123 Moreover, the Office has called for agencies to apply the “precautionary principle” in developing appropriate safeguards.124 Yet, for an evidence-based approach to QSE regulation, it is insufficient for nanoreformulations to rely upon clinical data for older nonnanoreformulations. Absent a uniform definition of “nanoparticle” in the therapeutic context, it may not be in the interests of pharmaceutical companies to notify QSE assessors where their product contains particles less than 1,000 nm but greater than 100 nm. This could be especially so where disclosure is not mandated or would jeopardise fast-tracked approval. With a reduced requirement for patient information disclosure for ANDAs, it is questionable whether patients and volunteers are being afforded the opportunity to provide genuine informed consent to new nanodrugs whether in the clinical trial stage or otherwise.125 With amendments to the Therapeutic Goods Act 1989 (Cth), the TGA is now actively involved in protecting the interests of patent holders.126 This process, referred to as patent-linkage, was a product of the Australian-United States Free Trade Agreement (AUSFTA) and also extends to protecting the clinical data submitted as part of a QSE assessment process for five years.127 Conferring market exclusivity for 20 years, patents are designed, first, to reward innovation128 and secondly, to encourage the dissemination of knowledge through the disclosed patent specification.129 Attempts to “evergreen” a patent undermine both objectives. “Evergreening” involves tactics by pharmaceutical patent-holders (such as threatened (and actual) litigation and creating licensing arrangements) against generic companies which see the latter delay the release of their new product, thus maintaining the flow of royalties to the patent holder.130 Technical methods of evergreening include the creation of process, use or incremental innovation patents over dosage or drug delivery.131 Notwithstanding the terms of the AUSFTA,132 the Australian Parliament passed “anti-evergreening” amendments to the TGA legislation to allow the government to join a counter-claim against a plaintiff to a patent infringement action where the action is “vexatious or unreasonably pursued” and not commenced in “good faith”.133 Damages can be as high as A$10 million.134 123 Department of Innovation, Industry, Science and Research (DIISR), Australian Government Approach to the Responsible Management of Nanotechnology (DIISR, 2008) p 2, http://www.innovation.gov.au/Section/Innovation/Documents/ ObjectivesPaper.pdf viewed 24 October 2008. 124

DIISR, n 123; Faunce et al, n 55.

125

Food, Drug and Cosmetic Act, 21 USC § 355-1.

126

Therapeutic Goods Act 1989 (Cth), s 26B; Faunce and Lexchin, n 77.

127

AUSFTA, opened for signature 18 May 2004, 2005 ATS 1, Annex 2-C, Art 17 (entered into force 1 January 2005); see also Vaile M and Zoellick RB, Side Letters Chapter 2 PBS (Department of Foreign Affairs and Trade, 2004), http:// www.austlii.edu.au/au/other/dfat/treaties/2005/1/letters/02_pbs.pdf viewed 30 October 2008. Incorporated via US Free Trade Agreement Implementation Act 2004 (Cth); Therapeutic Goods Act 1989 (Cth), s 25A. 128

Commonwealth, House of Representatives, Parliamentary Debates (10 October 1990) p 2565 (Simon Crean, Minister for Science and Technology); Patents Act 1990 (Cth), s 67.

129

LaRoche K, Collard C and Chernys J, “Appropriating Innovation: The Enforceability of University Intellectual Property” (2007) 20 Intellectual Property Journal 135 at 140-141.

130

Chalmers R, “Evergreen or Deciduous? Australian Trends in Relation to the ‘Evergreening’ of Patents” (2006) 30 MULR 29; cf Faunce and Lexchin, n 77.

131

Faunce and Lexchin, n 77.

132

AUSFTA, Ch 17, opened for signature 18 May 2004, 2005 ATS 1 (entered into force 1 January 2005).

133

Therapeutic Goods Act 1989 (Cth), s 26C(5). These have been referred to as “the Latham amendments”: Pfizer Australia, Response to the Productivity Commission’s Draft Report on Regulatory Burdens on Business (Productivity Commission, 2008), http://www.pc.gov.au/__data/assets/pdf_file/0006/82455/subdr53.pdf viewed 28 October 2008; Therapeutic Goods Act 1989 (Cth), s 26C(4)(c), (3)(a)-(c) respectively. 134

Therapeutic Goods Act 1989 (Cth), s 26C.

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Nanoreformulations may represent an attractive method to extend a patent’s life and seek new data exclusivity.135 This may even occur where the nanoreformulation (such as Abraxane) relied upon existing clinical evidence, which it could not have accessed were data exclusivity an issue, to seek a fast-tracked approval pathway. Future nanoreformulations of paclitaxel – perhaps relying upon the safety data presented by Abraxis – may face a new patent thicket created around paclitaxel. Where an active ingredient is no longer under patent, a challenge for the TGA will be to only grant data exclusivity where required under the legislation, not simply at a sponsor’s request. Nanoreformulations such as Abraxane potentially represent a new technical method of evergreening, whereby out of patent therapeutic agents (such as paclitaxel) can be newly patented on the basis of a new nano-manufacturing process, or new drug-delivery system: such as Abraxais nab-technology. This is even though the clinical benefits of a new nanoreformulation may be insignificant. Elan’s NanoCrystal technology has been used initially by its licensees “on existing drugs that suffered from several problems … [to convert] … them into nanoparticulate forms”.136 As nanoreformulations of off-patent therapeutic substances seek new patent protection, several issues will arise for QSE agencies. Alphapharm Pty Ltd v H Lundbeck A/S (2008) 76 IPR 618 at [7] (Alphapharm) may provide a relevant analogy. In Alphapharm, Lundbeck sought a new patent over a purified “citalopram”, a molecule used in the treatment of depression. Citalopram is a “racemate mixture” of two enantiomers: (+)-citalopram and (-)-citalopram.137 The purified substance contained only (+)-citalopram which was therapeutically more active than citalopram itself (at [3]). Lundbeck sought to patent the purified enantiomer of its active pharmaceutical ingredient and to obtain a patent-term extension for delayed marketing approval, even though the new refined (+)-citalopram had been contained in the previously patented racemate mixture.138 Although the patent was eventually upheld, the follow conclusions can be drawn (at [409]). First, Abraxane could likely seek patent protection for the new manner of manufacturing nanoparticle albumin-bound (nab) paclitaxel, notwithstanding the long history of paclitaxel. Though paclitaxel is off-patent, the new formulation of it could satisfy the “non-obvious” or “novelty” test, as it would not have been obvious for a “non-inventive skilled addressee or team in the field of the invention” to have, as a “matter of routine”, taken steps towards creating a nanoreformulation of the drug by binding it to sterile albumin particles (at [176]-[178]). However, because Abraxane does not contain a new “pharmaceutical substance per se”, as required under the Patents Act 1990 (Cth), it would probably be ineligible for a patent extension to compensate for time spent proceeding through the TGA’s QSE process.139 If it were held that Abraxane could be granted a patent extension, one would be concerned that Abraxane did not then represent a “bioequivalent” substance to paclitaxel, and therefore was ineligible for ANDA fast-track approval. Secondly, because paclitaxel was listed on the ARTG more than five years ago, Abraxane is unlikely to be able to seek data exclusivity over the information submitted to the TGA.140 In the future, clinical evidence presented to the TGA by Abraxis could be used by generic manufactures to “springboard” their products onto the market. This is authorised by s 119A of the Patents Act 1990 (Cth), which provides a defence to patent infringement for companies utilising QSE data when filing for marketing approval for a generic medicine. Sustainability in the Australian, and global, health care system depends upon the therapeutic life-cycle: a new drug enters the market with a clinically significant benefit at a high price, it is made available by the government at a discounted price in situations where it is deemed cost-effective and, finally, the price of the drug drops as new medicines enter the market and the originator company works on developing a better formula. 135

Till et al, n 122.

136

Till et al, n 122 at 164.

137

Thalidomide is perhaps the most infamous of chiral racemate compounds: discussed in Eriksson T, Björkman S and Höglund P, “Clinical Pharmacology of Thalidomide” (2001) 57 European Journal of Clinical Pharmacology 365.

138

Patents Act 1990 (Cth), s 70.

139

Patents Act 1990 (Cth), s 70.

140

Therapeutic Goods Act 1989 (Cth), s 25A(2) especially s 25A(2)(c)(i), (e).

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ABRAXANE’S

CHALLENGES TO THE

PBAC

PROCESS

Having discussed some of the challenges to the QSE regime in Australia, this part identifies the relevant provisions of the Guidelines which will underpin an Abraxis submission to the PBAC. By following a hypothetical Abraxane submission, potential challenges to the PBS cost-effective process will be identified. The literature on cost-effectiveness of nanomedicines is not substantial.141 Although noting the absence of literature on the cost-effectiveness of nanomedicines, a 2006 study by Ontario’s Health Technology Advisory Committee excluded “first generation” nanotherapeutics such as Abraxane, instead focusing on “second generation” “multifunctional” nanomedicines.142 Based on a survey of other national health agencies, the report concluded that these second generation therapies would not be clinically available until 2010-2020.143 But cost-effectiveness issues will emerge prior to 2010 with the “innovative” status of nanomedicines likely to be the source of much confusion and potential litigation. Abraxane and other nanoreformulations will require an original, detailed and Australian relevant economic analysis, as part of a PBAC submission. The PBAC process ensures that medicines listed on the PBS are price-referenced according to the “effectiveness and cost of therapy involving the use of the drug … including by comparing the effectiveness and cost of alternative therapies”.144 In part this consideration is guided by the QUM, to ensure that a listed drug is prescribed and consumed in a “rational” manner.145 A positive recommendation from the PBAC must be accompanied by a specification as to whether the drug is “interchangeable on an individual patient basis”.146 Although an ambiguous standard, medicines deemed interchangeable are listed within a single Therapeutic Group with the government subsidising a drug up to the cost of the least expensive medicine in the group.147 Drugs used in the treatment of cancer – antineoplastic agents – form one such Therapeutic Group and Abraxane would, if added to the PBS, be price-referenced against drugs in the “ATC L01Antineoplastic Agents” group.148 First generation nanomedicines, such as Abraxane, have been referred to as “old wine in a new bottle”.149 Yet the new reformulations carry a high price, with Abraxane costing up to 25 times more than the pre-existing Taxol in the United States.150 It will need to justify those costs to the PBAC. Abraxis has legitimate claims to “patient-relevant” benefits: reduced hospital admission time, no pre-medication, and fewer hypersensitivity reactions.151 However, these considerations are “second141

Although see Faunce T, “Nanotherapeutics: New Challenges for Safety and Cost-effectiveness Regulation in Australia” (2007) 186 MJA 189.

142

OHTAC, n 7, pp 6, 7.

143

OHTAC, n 7, p 9; cf Renn and Roco, n 28 at 156.

144

National Health Act 1953 (Cth), s 101(3A).

145

DoHA, n 93 (QUM).

146

National Health Act 1953 (Cth), s 101(3BA).

147

Faunce T and Lofgren H, “Drug Price Reforms: The New F1-F2 Bifurcation” (2007) 30 Australian Prescriber 138 at 139; National Health Act 1953 (Cth), s 84AG(3); Pharmaceutical Benefits Pricing Authority (PBPA), Therapeutic Relativity Sheets (DoHA, 2008), http://www.health.gov.au/internet/main/Publishing.nsf/Content/79FFCFDE3F916A41CA256F180046E3EF/ $File/1%20July_%202008%20RELATIVITY%20SHEETS.pdf viewed 2 October 2008. 148

PBPA, n 147.

149

Hennenfent KL and Govindan R, “Novel Formulations of Taxanes: A Review. Old Wine in a New Bottle?” (2006) 17 Annals of Oncology 735 at 746. 150

Berenson A, “Hope, at $4200 a Dose”, New York Times (2006), http://www.nytimes.com/2006/10/01/business/yourmoney/ 01drug.html viewed 10 October 2008. On Australian prices, the difference would be $4,000+ per dose of Abraxane charged in the United States, compared to approximately $1,000 per dose of Taxol. 151

Hennenfent and Govindan, n 149 at 746.

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ary” and will only inform a PBAC determination.152 Companies seeking to list a drug on the PBS must demonstrate that the drug achieves satisfactory “health outcomes” in treating the health needs of the Australian community.153 As a sponsor seeking approval for in-hospital administration, Abraxis would find PBS listing commercially attractive. Public and private hospitals in Australia dispensed A$2.9 billion worth of medicines in 2005-2006.154 PBAC submission Guidelines list six sections to be addressed by a sponsor: sections A-F.155 Discussion between industry and government, however, focus on the application of sections A, B, C and D.156 Central to a PBAC determination is how a new drug compares with a comparator treatment.157 This raises difficulties for the PBAC as there may be no true “comparator drug” for nanoreformulations. While it is arguable that Abraxane should not be considered bio-equivalent with Taxol given its different mechanisms of action, based upon its treatment overseas it is foreseeable that the PBAC will consider Abraxane in light of other paclitaxel-based drugs. It is likely that “first generation” nanomedicines which do not contain mechanical or inorganic operating components will be able to easily identify familiar comparator drugs and treatments. Safety issues relevant to the PBAC will include increased toxicity arising from therapeutic ENPs, although an increase will not necessarily prevent the listing of a drug if it can demonstrate significant cost-effectiveness or if its use is to be restricted until after a less toxic treatment has been exhausted.158 Though future nanomedicines will probably not be so easy to assess, the Guidelines provide that, in circumstances where there is no comparator, the “current standard care” is to be the objective reference point.159 Through Section A, Abraxis will establish the “context for the submission”, setting out and describing the proposed uses of the new drug and identifying the comparator drugs and treatments.160 Turning to Section B of the Guidelines, Abraxis will be required to provide all clinical trials relevant to the listing, not merely those considered “pivotal” and provide them in the prescribed format.161 This is an important difference between the TGA and PBAC, with the former using “pivotal” trials to establish efficacy. Any study which Abraxane sought to exclude from consideration would be accompanied by an explanation as to why it should not be considered by the PBAC.162 Section B also provides for the inclusion of secondary “patient-relevant” outcomes, “perceptible to the patient”, such as an improved quality of life.163 The more important an outcome is to a patient, the “more relevant” it becomes.164 Ultimately, the purpose of Section B is to determine if the proposed drug is clinically 152


153


154

Pfizer Australia, Response to the Productivity Commission’s Draft Report on Regulatory Burdens on Business (Productivity Commission, 2008) p 7, http://www.pc.gov.au/__data/assets/pdf_file/0006/82455/subdr53.pdf viewed 28 October 2008. 155

A “no-worse-than” or cost-minimisation submission has different submission requirements: see Pt III, Section D(i) of the DoHA Guidelines.

156

A Mitchell, ARCS Australia Conference, n 18.

157


158


159


160


161

A submission will be rejected if all trials are not disclosed: A Mitchell, ARCS Australia Conference, n 18. DoHA Guidelines, n 17, pp 173-179.

162


163

DoHA Guidelines, n 17, pp 75-76.

164


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“superior” and therefore eligible to make a case for “cost-effectiveness” which allows it to seek a higher price than other drugs listed in the same Therapeutic Group.165 Section C requires the clinical data in Section B to be “translated” into an Australian relevant context.166 Further, Abraxis must “describe the methods used in premodelling studies to translate … the results of the evaluation of the clinical studies to the context of the requested listing”.167 It has been referred to as “the bridge” between the economic modelling of Section D and the clinical evidence of Section B and is discussed further below.168 Overseas clinical evidence must be “applied” to the proposed population with pre-existing data examined to determine any differences in clinical responses which could be expected were the drug indicated for use in Australia. Therefore, the statistically higher rate of cancers in Australia compared to other nations would be a factor which goes to the overall cost of Abraxane as this would impact upon the “circumstances of use”.169 Using the review of Smith et al, some other considerations in applying Abraxane’s clinical data would be the rates of free mammographic screening for older Australian women (which increases case diagnosis), local dietary and exercise habits as well as the use of oestrogen replacement therapy: all of which have been linked to an increase in breast cancer incidence.170 Additionally, Medicare itself is a factor, if the pre-existing study populations were not drawn from a country with universal health care, as that would impact upon the “patterns of health care resource provision”.171 Applied data must then be “extrapolated”. This involves extending the “time horizon” of the treatment use from the trial period to the end stage of a disease: usually the end of therapy or patient death.172 The Guidelines suggest that the “time horizon” for a cancer treatment should be measured in “full life expectancy”, a period longer than more “pivotal” clinical efficacy trials.173 At best, Abraxane provides an additional 10 weeks of progression-free survival time compared to generic paclitaxel.174 Yet, the PBAC does not ignore the obvious “patient-relevant” significance of an extra 10 weeks of life and the quality of that period remains a “secondary outcome” and an element which can be included when the data are “transformed” as the final requirement of Section C.175 Transformation involves accounting for patient-relevant outcomes against a set benchmark of “utilities”, the most common being Quality Adjusted Life Years (QALYs) gained.176 A submission to the PBAC must include either a claim to therapeutic superiority or demonstrate noninferiority. This claim is established in Section B and influences the economic analysis utilised in Section D. Abraxis, based on clinical evidence collected, is likely to submit a claim of therapeutic superiority and will be required to provide an “economic evaluation that focuses on changes in health outcomes and in the provision of health care resources due to the proposed drug”.177 Four methods of analysis are acceptable including: 165


166

DoHA Guidelines, n 17, p 91ff.

167


168


169

AIHW, “Cancer Death Rates Low in Australia Compared to Overseas, But Incidence High”, Press Release (15 December 2004), http://www.aihw.gov.au/mediacentre/2004/mr20041215a.cfm viewed 29 October 2008; DoHA Guidelines, n 17, p 91. 170

Smith C, Kricker A and Armstrong B, “Breast Cancer Mortality Trends in Australia: 1921 to 1994” (1998) 168 eMedical Journal of Australia 11.

171


172


173


174

EMEA, n 50.

175


176

DoHA Guidelines, n 17, pp 24, 91.

177


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•

a “cost-utility analysis”, presenting “the health outcome in terms of the life-years gained from the start of the analysis, with each life-year adjusted by a utility weight that is society’s preferences for the health outcome experiences in that life-year relative to full health”;178 or • a “cost-effectiveness analysis”, measuring “the incremental cost per extra unit of health outcome achieved”.179 For instance, if a new therapy demonstrates more of a given “health outcome” than its main comparator, it is considered more “cost-effective”. Additionally, a “cost-benefit analysis” or “cost-consequences analysis” can be supplementary to these two options. Given the evidence presented to the EMEA, it would appear that a “cost-utility analysis” could be submitted by Abraxane, as the increased median time to progression would represent additional QALYs.180 It is suggested that, given Abraxane’s price in the United States and the present use of paclitaxel-based taxanes, the PBAC would be unlikely to recommend Abraxane as a first- or second-line treatment. Unless clear therapeutic superiority was demonstrated, the population group for non-metastatic breast cancer patients would be too large to justify the cost of Abraxane. As a third- or fourth-line treatment, however, the population group would be small enough to support the indication sought by Abraxis in its submission to the TGA. A challenge to the PBAC and QSE agencies is the influence pharmaceutical companies exert over the collection of data submitted to the PBAC. Members of the Economics Sub-Committee and the Drugs Utilisation Sub-Committee provide the PBAC with an independent analysis of submitted data, crucial in an age where “intellectually redundant”, marketing oriented “seeding trials” can turn prescribers and patients into unwitting drug-lobbyists.181 As a novel technology with a positive “brand” association, nanomedicines such as Abraxane may be marketed in such a way as to undermine the PBAC process.182 Recent reforms such as the PBAC “public summary documents” and the provision of reasons for a negative listing have been welcomed by both industry and the community as providing greater transparency.183 However, the move to facilitating public comment on PBAC agenda items deserves to be critically examined.184 Following the latest Accesses to Medicines Working Group, PBAC meeting agendas will be available online six weeks prior to the meeting and the public able to submit comments online.185 While the Health Minister commented that the move would “increase the transparency of the PBS listing process and will benefit patients, carers, health professionals and consumer groups”, it is difficult to see what benefit can ultimately be gained.186 The public would have “two weeks to complete an online form” in which they could suggest how “they, their family and carers” would benefit if the drug were listed on the PBS.187 Two problems arise with this new system. First, the criterion by which a new drug is assessed by the PBAC remains unchanged under the National Health Act 1953 (Cth). Indeed, although the 178


179


180

EMEA, n 50.

181

Hill et al, n 121 at 253-254.

182

Rejeski D, FDA-Regulated Products Containing Nanotechnology Materials (Nanotech Project, 2006), http:// www.nanotechproject.org/process/assets/files/2714/112_pen_fdacomments_updated.pdf viewed 24 October 2008; Rejeski, n 8. 183


184

Lush N, Public Given a Voice at PBAC (PharmaInFocus, 2008), http://www.pharmainfocus.com.au/news.asp?newsid=2484 viewed 24 September 2008. 185

Department of Health and Ageing (DoHA), PBS Online Submission Form (DoHA, 2008), http://www.health.gov.au/internet/ main/publishing.nsf/Content/PBAC_online_submission_form viewed 28 October 2008. 186

Roxan N, “New Measures Give Public a Voice on Potential PBS Medicines”, Press Release (24 September 2008), http://www.health.gov.au/internet/ministers/publishing.nsf/Content/mr-yr08-nr-nr125.htm?OpenDocument&yr=2008&mth=9 viewed 20 October 2008. 187

Roxan, n 186.

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Guidelines may change to accommodate this new practice, it is this original legislative requirement for “the Committee [to] give consideration to the effectiveness and cost of therapy involving the use of the drug, preparation or class” which must ultimately determine whether a medicine succeeds in being listed.188 Secondly, it is a concern that patients with a legitimate desire to see a new preparation listed may have their hopes unfairly raised by this measure. PBS listing is an emotionally charged process which, as discussed above, presents some of the most difficult ministerial decisions. With new medicines, including nanomedicines, coming into the market, there is generally a community expectation that they will, at some point, be made available to the public. As the author suggested to the Senate, the public find a “cost-effectiveness” rationale for denying access to subsidised life-saving medicine unpalatable.189 This can only occur if the scheme’s costs are restrained through the “rational” use of medicines and the subsidy of only those drugs which show a clinically meaningful improvement over older, cheaper, medicines. Aside from arguments of increasing community participation – which will be futile under present legislation – there have been no strong arguments showing how this reform will improve the quality of PBAC decisions.190 While the comments made by the public may not themselves influence the PBAC, these reforms do threaten to turn vulnerable patients into lobbyists for the latest drug, as the 2007 listing of Gardasil demonstrated. When the Human Papilloma Virus (HPV) vaccine was initially denied a PBS listing, a media-driven campaign led to an extraordinary meeting of the PBAC and a subsequent positive recommendation.191 While the redetermination was made following the submission of additional information for the sponsor company, which had been sought by the PBAC, it still remains a concerning incident.192 The opening up of PBAC agenda items to public comment is likely to only increase the risk of public campaigns to have a new drug listed, notwithstanding the absence of any cost-effective benefits. Overall, the Guidelines ensure that the PBAC is presented with complete information, which would otherwise not be in the interests of the sponsor company to provide. Underpinning the requirement for full disclosure of trials and economic modelling (to a 95% confidence) is the belief that the Minister must have confidence in the decisions of the PBAC. The PBAC can only provide confident recommendations where the evidence submitted to it is full and complete.193 Interference with the PBAC process by well-meaning citizens or commercially-drive pharmaceutical companies could undermine ministerial and community confidence in the cost-effective arrangements underpinning the PBS. Abraxane is likely to be considered an “innovator” drug and it is foreseeable that the PBAC would, in the event of a positive recommendation, indicate that it be listed as an F1 therapeutic. With doubts expressed by authorities overseas over the therapeutic improvement provided by Abraxane, it may be that the F1-F2 bifurcation of the PBS will result in an overall increase in cost to the government if new, only slightly more effective nanomedicines, are protected from the full impact of price referencing.194 Evergreening, discussed above, may become seen as a method of preventing a F1 listed medicine moving to the F2 formulary – which entails a mandatory price cut. Though the facts occurred before the PBS bifurcation, the recent case of Apotex Pty Ltd (formerly GenRx Pty Ltd) v Les 188


189

Evidence to Parliament of Australia, Senate Community Affairs Committee (Canberra, 22 September 2008) p 9 (Timothy Vines).

190

Medicines Australia, “Patients Set to Gain from PBAC Transparency”, Press Release (24 September 2008), http://www.medicinesaustralia.com.au/pages/images/ MR%20Sept%202408%20Patients%20set%20to%20gain%20from%20PBAC%20transparency.pdf viewed 24 October 2008. 191

Roughead et al, n 78; Crossings S, Breast Cancer Media Frenzy Anything but Helpful (Crikey Online, 2008), http://www.crikey.com.au/Politics/20080715-Breast-cancer-wonder-drug-media-frenzy.html viewed 10 September 2008.

192

Roughead et al, n 78.

193


194

Hennenfent and Govindan, n 149.

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Laboratoires Servier (No 2) (2008) 76 IPR 99; [2008] FCA 607 (Apotex), suggests how a company may seek to undermine the PBAC process through misleading conduct. In Apotex the defendant was found to have breached s 52 of the Trade Practices Act 1974 (Cth) through a misleading and deceptive advertising campaign which targeted doctors, pharmacists and patients. Although direct-to-patient-advertising is generally prohibited in Australia, pharmaceutical companies can still market to doctors and pharmacist.195 If Abraxane is listed at a higher price than comparator drugs, Abraxis will need to ensure that information distributed to pharmacists and patients only makes “clinically relevant” claims (at [113]). Abraxane, as a chemotherapeutic agent, would only be available in hospital to admitted patients. As such, the chance of promotional material misleading patients is reduced. However, reports from the United States reveal that representatives of Abraxis have been successful in convincing practitioners to prescribe Abraxane, notwithstanding its significantly higher cost, without justifying the extra expense through claims of clinical superiority.196 Furthermore, as nanoreformulations extend to over-thecounter medicines, any tactics discouraging generic market entry and substitution should be monitored.

REFORMS

TO

AUSTRALIAN

DRUG REGULATION PROVOKED BY NANOMEDICINES

This article has examined Abraxane’s clinical history, indentifying some of the challenges it will present to Australia’s drug regulatory scheme and critically analysing, in turn, the current practices of the TGA and PBAC. Drawing upon the issues identified, this final section draws some conclusions on an Abraxane submission and proposes some reforms to the TGA and PBAC processes. From Abraxane’s clinical history in the United States and the European Union, it is reasonably foreseeable that Abraxane will be listed on the ARTG. Moreover, Abraxane’s approval by the FDA and EMEA suggests that Abraxis’s claim for a finding of “bio-equivalence” will also be accepted by the ADEC and TGA. This is a concern, given the functioning of the albumin nanoparticles around solid tumours.197 Nanoreformulation has rejuvenated paclitaxel, even if there is no improved overall patient survival time.198 Before a proper assessment of nanomedicine safety can be contemplated, QSE bodies will need to establish standard toxicological profiles and methods for ENP detection. This is not simply an issue of future concern as ENPs can be found in many present diagnostic, imaging and drug-delivery systems. While these remain less risky “static” ENPs, it is in the interests of industry – within a product liability framework – and governments to ensure that manufacturing standards are appropriate to the unique challenges of assembling and handling nanomaterials.199 With the ODAC in the United States expressing concern over the previous finding of “bio-equivalence”, the TGA should consider requiring additional clinical studies from Abraxane to establish a nanoreformulation specific toxicological profile. Second generation products will probably present even greater challenges and it is appropriate to review current risk/benefit frameworks and, where appropriate, apply precautionary principle methodologies to nanotechnology regulation.200 The overview of nanomedicine and QSE processes above identified the gaps in nanotherapeutic knowledge and critically analysed the present approach to risk-management adopted by the FDA and TGA. From the experience of Abraxane and products containing Elan’s NanoCrystals, the present arrangements do seem sufficient, with at least short-term clinical safety established through current Phase I, II and III trial requirements. 195

Therapeutic Goods Act 1989 (Cth), Pt. 5.1; Therapeutic Good Regulations 1990 (Cth), Pt 2.

196

Berenson, n 150.

197

Nijhara and Balakrishnan, n 53 at 134, 135.

198

Hennenfent and Govindan, n 149.

199

Allianz and Organization for Economic Cooperation and Development (OECD), Small Sizes That Matter: Opportunities and Risks of Nanotechnologies (3 June 2005), http://www.oecd.org/dataoecd/4/38/35081968.pdf viewed 1 April 2009.

200

Faunce, n 141.

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Without adequate post-marketing surveillance and long-term clinical studies, however, it is uncertain whether health regulators are prepared for unforeseen ADRs. The recent example of Vioxx demonstrates that post-market surveillance methods – in both the United States and United Kingdom – have serious flaws.201 While the TGA could consider the Rapid Alert System introduced in the European Union, a centralised system for reporting ADRs would greatly assist in quickly responding to problems, wherever they emerge.202 It is likely that rare and unusual side-effects will be first observed in the larger jurisdictions of the European Union and the United States and the TGA could benefit from their data. Although the PBAC is not presently charged with recording ADRs or monitoring a listed drug’s safety record, this is a function which the PBAC has expressed a desire to pursue.203 Ultimately, a drug’s PBS listing depends on its ARTG registration, which could be revoked by the TGA in the event of a safety breach. Post-listing surveillance for the PBAC could, if cost-recovery measures are passed, allow the agency to ensure that off-label prescribing (“leakage”) is minimised. From the evidence present in reported trials, the level of patient awareness of the nano-nature of Abraxane is unclear. “First in Man” (FIM) trials are only approved after QSE agencies are satisfied that a drug’s sponsor has conducted adequate animal tests.204 However, the operation of nanotherapeutics within the body may give rise to “species-specific” toxicology reactions which cannot be predicated beforehand.205 In the 2006 FIM trial of “monoclonal antibody TGN1412” serious ADR occurred which had not been seen before.206 Although not a nanodrug, the findings of the “Expert Scientific Group” remain relevant to the emerging nanotherapeutic field. As nanoreformulations are only required to show bio-equivalence, the trials performed to achieve that outcome may place a greater number of volunteers at risk than necessary. As such, it is appropriate that clinical test practice manuals contain adequate protections so that volunteers are adequately informed of the nano-related risks which could arise during testing. Such considerations recognise the important role of the trial doctor and investigator in ensuring that volunteers provide full, informed consent, in line with medical codes of ethics and the Declaration of Helsinki.207 The next part examined the process Abraxane would need to follow under the PBAC Guidelines to have Abraxane listed on the PBS. Although early nanomedicines may not present significant challenges to the PBAC, the novelty of the drug’s mechanism of operation will only exacerbate the “information imbalance” between the sponsored drug and other listed comparator drugs.208 Section B of the Guidelines will, hopefully, result in the PBAC having a complete picture of Abraxane’s cost-effectiveness. Is Abraxane four times more effective than Taxol? From clinical studies the answer would appear no. Although the measurable rate of tumour shrinkage and prolonged progression-free period suggest that Abraxis could establish a cost-effectiveness basis for Abraxane, it is likely that the PBPA will not recommend a price significantly greater than Taxol’s. Whether this will result in Abraxis withdrawing Abraxane from the PBAC is yet to be seen but, if such an action is taken, an evaluation of the present PBPA manual may need to be undertaken to ensure it takes account of new nanomedicines. Any such 201

House of Commons, Health Committee, n 15, p 31; Bartlett, n 120.

202

Committee for Proprietary Medicinal Products, Rapid Alert System (RAS) in Pharmacovigilance (EMEA), http:// www.eudra.org/emea.html viewed 14 May 2008. 203

Evidence to Parliament of Australia, Senate Committee on Community Affairs (Canberra, 15 July 2008) (Thomas Faunce, Timothy Vines), http://www.aph.gov.au/Senate/committee/clac_ctte/nat_hth_pharm_cost_recover_08/submissions/sub11.pdf viewed 30 October 2008. 204

Bartlett, n 120.

205

Expert Scientific Group on Phase One Clinical Trials, Final Report (2006) p 77.

206

Expert Scientific Group on Phase One Clinical Trials, n 205; Suntharalingam G et al, “Cytokine Storm in a Phase 1 Trial of the Anti-CD28 Monoclonal Antibody TGN1412” (2006) 355 NEJM 1018.

207

Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects, WMA, 1964, am 2008.

208


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inquiry should not be undertaken from an industry perspective but, instead, focus on whether present pricing arrangements for new nanoreformulations further the objectives of the NMP. An ongoing challenge is whether new nanoreformulations should constitute innovative drugs or merely “me-too” incremental improvements. Current literature on “me-too” drugs often describes their benefits as akin to a generic version of a patent-expired medicine.209 This argument is justified on the grounds that second and third “entrants” usually offer “better value” in that “the product must lead to better patient outcomes, or it must be less expensive”.210 Abraxane, however, as a reformulated version of a chemical entity already off-patent, is an example of where a “me-too” drug is more expensive than the alternatives.211 If this represents a continuing trend in pricing from nanoreformulations, then there will be serious consequences for the economic viability of any state-run medicine access program. Cost-effectiveness analysis and price referencing as performed in Australia but prohibited under United States federal law is one method in ensuring sustainable and transparent pricing by nanopharmaceutical companies. In the United States, where there is no equivalent to PBS price referencing, “me-too” drugs may very well serve as a price-reducing influence, although it will primarily be through off-patent generics that meaningful price savings occur.212 Australia’s PBAC and PBPA, however, ensure that the true value of any later entrant medication is justified by a sponsor. It remains to be seen whether Abraxis will be successful arguing that Abraxane should be listed as a F1 medicine, notwithstanding its abbreviated regulatory pathway. While the analysis of Abraxane’s clinical history suggests that it cannot be classed as a generic version of paclitaxel, its price should be referenced to other paclitaxel in its therapeutic group. Options exist for allowing Abraxane to cost more than the relevant bio-similar drugs, such as the Therapeutic Group Premium (TGP).213 Moreover, the group premium can be waived where there are “adverse effects occurring with all of the base-priced drugs”.214 Abraxane’s claim to therapeutic superiority is largely due to the removal of the toxic solvent, which as discussed, is responsible for serious ADR in some patients. Consequently, a TGP would allow Abraxis to charge more for Abraxane without the cost having to be borne by the patient. If the patient matched the class of patients who suffers ADR from traditional paclitaxel-based chemotherapies, they could access Abraxane at no extra cost. Should this occur, then the PBAC may seek to investigate the drug’s prescribing practice post-listing to ensure the TGP is not being waived inappropriately and recommend a risk-sharing arrangement, such as a “price-volume agreement”, were “leakage” identified.215 Industry has expressed dislike over the “anti-evergreening amendments” and the springboarding provisions of s 119 of the Patents Act 1990 (Cth).216 While the Productivity Commission expressed no opinion on these amendments, they remain an area for discussion in the Commission’s review into “burdens on innovation”.217 While somewhat cumbersome in their potential application, the 209

Lee T, “Perspective: ‘Me-Too’ Products – Friend or Foe?” (2004) 350(2) NEJM 211; cf Berenson, n 150.

210

Lee, n 209.

211

Berenson, n 150.

212

Lee, n 209.

213

PBS, Therapeutic Group Premium Policy (PBS, 2008), http://www.pbs.gov.au/html/healthpro/browseby/group-premium viewed 1 November 2008; see also PBS, Brand Premium Policy (PBS, 2008), http://www.pbs.gov.au/html/healthpro/browseby/ brand-premium viewed 1 November 2008. 214

PBS, n 213 (Therapeutic Group Premium Policy).

215

Pharmaceutical Benefits Pricing Authority (PBPA), PBPA Policies, Procedures and Methods (DoHA, 2007) p 31, http://www.health.gov.au/internet/main/publishing.nsf/Content/pbs-pbpa-policies-contents~pbs-pbpa-policies-ch3 viewed October 2008. 216

Pfizer, A Submission to the Productivity Commission’s Review of Regulatory Burden on Business (Productivity Commission, 2007), http://www.pc.gov.au/__data/assets/pdf_file/0003/79149/sub031.pdf viewed 29 October 2008, p 13.

217


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“anti-evergreening” amendments represent an important legitimate AUSFTA expectation by Australia in relation to the PBS and patent law: that market exclusivity is limited and is designed to disseminate knowledge, not just increase profits. Some of the contemporary challenges facing the PBS and the PBAC process were explored and the motives behind and effects of proposed reforms analysed. Reforms designed to increase transparency and timeliness of the PBAC are welcome and address some concerns of industry.218 Of the 47% of major submissions rejected by the PBAC, it is probable that some were rejected due to a breakdown in communication between the PBB and the sponsor company. Nanotherapeutics may need special guidance, as they will present unique cost-effectiveness questions especially where, as is the case of Abraxane, they are competing against bio-similar drugs in the same therapeutic group. Claims of improved transparency and timeliness, however, should not be used by industry in order to subvert the independence of the PBAC process. Proposed PBAC cost-recovery regulations, if passed by the Senate, appear well adapted to preventing undue influence. Fees will neither be set nor collected directly by the PBAC, but will instead be administered by the DoHA and paid into general revenue.219 With the PBAC’s workload increasing by 40% since 2004 and the complexity of new nanomedicines presenting new cost-effectiveness challenges, it is submitted that additional funding for the PBAC, derived from a service fee, would be of welcome assistance.220 Were cost-recovery mechanisms to be introduced, the PBAC should have its funding levels increased to allow it to assist sponsor companies where possible and conduct post-listing surveillance to ensure that a drug’s use in the field matches its listing. Off-label prescribing, while not illegal, can cause a leakage of funds from the PBS and increase the cost of a listed medication. Most leakage occurs in paediatrics and palliative care.221 It may be tempting for doctors, working with end-stage metastatic breast cancer patients to prescribe Abraxane for treatment outside its indication. Post-listing surveillance would allow the PBAC and DoHA to ensure that manufacturers do not encourage wasteful practices.

CONCLUSION Despite an absence of relevant international nano-specific safety standards and methodologies, nanotechnologies are already present in consumer products and medicines. Abraxane represents only the first explicit nanomedicine. Many more products containing ENPs are already on the market. To ensure public safety and community acceptance of nanotechnologies, greater disclosure is required by manufacturers and more particle size specific information should be requested by regulators. It is doubtful whether the QSE role of the TGA, which also extends to monitoring foreign compliance with the GMP guidelines, would be improved by creating “cost-effectiveness” as a parallel rather than in-series responsibility as it is now. As noted by the Productivity Commission, a product may be listed on the ARTG with a wide range of uses but only recommended for subsidy by the PBAC for a narrower population group. Submitting “parallel” submission to the TGA and PBAC could result in confusion for both sponsor companies and the PBAC in knowing what restriction or indication they should seek and approve.222 A second consequence of the general absence of uniform standards for detecting and categorising ENPs is that reimbursement agencies – such as the PBS – might find it challenging to identify 218


219

Proposed s 99YBA(4) of the National Health Amendment (Pharmaceutical and Other Benefits Cost-Recovery) Bill 2008 (Cth) indicates that fees set under the regulations would be “payable to the Commonwealth”; Evidence to Parliament of Australia, Senate Community Affairs Committee (Canberra, July 2008) p 12 (DoHA), http://www.aph.gov.au/Senate/committee/ clac_ctte/draft_regs_nat_hth_pharm_benefits_charges/submissions/sub05.pdf viewed 28 October 2008. 220

Lush N, PBAC Workload up 40% Since 04 (PharmaInFocus, 2008), http://www.pharmainfocus.com.au/news.asp?newsid= 2451 viewed 10 September 2008. 221

Parliament of Australia, Senate Community Affairs Committee, Final Report into the National Health (Pharmaceutical and Other Benefits Cost Recovery) Bill 2008 (2008) p 8.

222

Department of Health and Ageing, quoted in Productivity Commission, n 64, p 79.

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appropriate comparator drugs to assess the cost-effectiveness of nanoreformulations. However, the PBAC Guidelines go some way towards ensuring the PBS can identify a relevant standard treatment. Reforms aimed at improving PBAC transparency deserve consideration, but also scrutiny. The ability of the public to comment on the proposed listing of a drug by the PBAC raises significant concerns about industry influence. More importantly, in exposing already vulnerable individuals to further heartache and frustration, the reforms seem counterproductive in increasing community acceptance of PBAC decisions. Breast cancer is a sensitive topic within the Australian community and this article has identified several ways in which a company marketing a drug, such as Abraxane, could undermine the NMP through patent evergreening, misleading doctors or recruiting patients to lobby the government through the online comment submission process. Abraxane and new nanomedicines present some unique QSE concerns, along with new challenges to cost-effectiveness assessment. Their innovative status should be determined on a case-by-case basis in which the PBAC retains the capacity to find drugs like Abraxane suitable at some point for an F2 listing (should the F1-F2 PBS categories persist). The challenges posed by nanomedicines will only increase over the next 20 years as combination therapies confuse the boundary between drug and device. Although a cure for all cancers may always remain elusive, it is realistic to expect great things from the nanopharmaceutical field.

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