Innovations from 'Down-Under': a Focus on Prescription to Non-Prescription Medicine Reclassification in New Zealand and Australia

ORIGINAL ARTICLE SelfCare 2012;3(5):88-107

Advancing the study&understanding of self-care

INNOVATIONS FROM ‘DOWN-UNDER’: A FOCUS ON PRESCRIPTION TO NON-PRESCRIPTION MEDICINE RECLASSIFICATION IN NEW ZEALAND AND AUSTRALIA

NATALIE GAULD*, FIONA KELLY**, LYNNE EMMERTON†, LINDA BRYANT††, STEPHEN BUETOW‡ * PhD Candidate, Department of General Practice and Primary Health Care, University of Auckland, New Zealand **Honorary Senior Lecturer, School of Pharmacy, University of Auckland, New Zealand †Associate Professor, School of Pharmacy, Curtin Health Innovation Research Institute, Perth, Western Australia †† Honorary Lecturer, Department of General Practice and Primary Health Care, University of Auckland, New Zealand ‡Associate Professor, Department of General Practice and Primary Health Care, University of Auckland, New Zealand

ABSTRACT BACKGROUND: Australia and New Zealand (NZ) contribute to the international trend of medicines reclassification from prescription to non-prescription availability (switch). Both countries have been acknowledged as being as advanced or even more so than the United Kingdom (UK) in availability of medicines without prescription, despite not making some of the recent innovative UK switches.

OBJECTIVE: To derive a measure of progressiveness in switch; to compare the progressiveness of switch between NZ and Australia; and to compare NZ and Australia switch activity with the UK.

METHODS: Records of medicines classification meetings in Australia and NZ from 2000 to 2011 were analysed with respect to all switch considerations (whether approved or not approved). Switches in Australia and NZ were compared with those in the UK. A new measure, ‘innovative switches’, was developed to provide a useful measure of switch progress.

RESULTS: Australia demonstrated ‘switch innovation’ in the early 2000s, including the ‘first-in-world’ switch of orlistat, but has slowed down since. Recently NZ has become more innovative than Australia with first- in-world switches of oseltamivir, famciclovir and calcipotriol. Switches driven by sponsors, and also non- sponsors, and exemption to prescription supply have facilitated consumer access to medicines in NZ. However, medicines that were switched in the UK but not Australasia indicate locality-specific barriers.

CONCLUSIONS: Australia and NZ have both been progressive with medicines reclassification in the past 12 years, albeit with fewer innovative switches in Australia recently. NZ has become more innovative since 2004 and is now one of the more progressive countries in this trend. Our ‘innovative switch’ framework demonstrates potential for ongoing monitoring of international developments.

Key words: Self medication; Nonprescription drugs; Reclassification; Pharmacy; Pharmacist Prescribing; Advisory Committees.

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INTRODUCTION

Australia and New Zealand (NZ) contribute to the international trend for reclassification or down-scheduling of medicines from prescription to non-prescription availability, also known as ‘switch’.

Both countries have three levels of non-prescription access1-3. Pharmacist Only Medicines (Schedule 3 or S3 in Australia) require a pharmacist’s involvement in supply, and cannot be directly accessed by consumers. Pharmacy Medicines (Schedule 2 or S2 in Australia) are generally only available from pharmacies and can be self-selected in NZ, and in some Australian jurisdictions. General sales medicines (unscheduled medicines in Australia) can be sold in non- pharmacy outlets such as supermarkets and convenience stores.

The Advisory Committee on Medicines Scheduling (ACMS) in Australia, and the Medicines Classification Committee (MCC) in NZ advise the respective Governments on classification of medicines4,5. In Australia, the ACMS also makes recommendations on advertising of Pharmacist Only Medicines. Ultimate authority rests with the Minister of Health’s Delegate (in NZ) or the Secretary of the Department of Health and Ageing’s Delegate (in Australia). The ACMS evolved from the decision-making National Drugs and Poisons Scheduling Committee (NDPSC) in Australia in mid-2010. The committee composition, decision-making process, and matters considered by each committee in making a recommendation vary between Australia and NZ, and are presented as Appendices 1 and 2.

Australia and NZ have attempted to harmonise the scheduling of medicines since the late 1990s under Trans-Tasman Harmonisation (TTH)6,7. The intention has been to harmonise to the less- restrictive schedule, while considering public health and safety issues and/or jurisdictional needs7.

Australia8,9 and NZ8 have been found to be advanced in non-prescription availability of medicines relative to selected developed countries. Using World Self-Medication Industries (WSMI) tables (September 2003), the Gilbert et al.8 review of schedules for 119 medicines found NZ and Australia ahead of the United Kingdom (UK), Canada, France and the United States (US) in numbers of medicines available without prescription. The authors concluded that more medicines tended to be available off-prescription in countries with a pharmacy- only or pharmacist-only category, rather than a single non-prescription category, and that two pharmacy categories may be more enabling than one pharmacy category. However, they noted the limitation of confirming the accuracy of only the Australian classifications. Our check of the WSMI tables updated 19 December 2008 (as per the lead author’s personal communication with the Association of the European Self-Medication Industry (AESGP) on 15 July 2009) found 20 discrepancies for NZ that may have changed findings by Gilbert and others, especially if inaccuracies also occurred for other countries. The US Government Accountability Office (GAO) used the WSMI tables (1 February 2007) to compare classification status across 86 medicines approved in all five selected countries9. Australia and the UK had the most medicines available without prescription (n=63 in each country), followed by the

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US (n=44), Italy (n=43) and the Netherlands (n=41). As Australia had fewer open-availability (unscheduled) medicines than the US or UK, the GAO considered that the benefits of ‘behind- the-counter’ medicine availability were unclear. Since the GAO checked regulatory information against the WSMI tables (finding discrepancies around medicines approvals), its numbers are probably accurate.

However, the WSMI tables treat all drugs as equal and do not necessarily reflect the progress that, for example, the UK has made with innovative switches of medicines such as simvastatin, sumatriptan and azithromycin. Blenkinsopp and Bond, in 2005, identified the UK as the most progressive country in the world in terms of switch, although the reason for their judgement was unclear10. This view was supported by McCreedy from the Medicines and Healthcare products Regulatory Agency in 200911. Using WSMI tables to ascertain advancement may reflect historical classifications and switches rather than current activity. Further, in 2010, Australia was described by the industry group Australian Self-Medication Industry as ‘extremely risk-averse’ in switch12, which is at odds with the findings of Gilbert et al.8 and the USGAO9. Thus, there is a need to derive an appropriate measure of progressiveness or switch innovation, in order to compare this process between countries.

The term ‘first-in-class switches’ was used by Soller et al. and showed clearly how limited the US has become in switch activity, with only four such reclassifications since 200013. These authors defined first-in-class switches as ‘uniquely pushing the boundary of OTCness’, wanting to differentiate these switches from the easier follow-on switches, and noting that such switches raise a higher level of concern than the easier ‘me-too’ or ‘follow-on’ switches. Mann agreed, noting the difficulties faced in switching simvastatin in the UK as a first-in-class switch14.

In drug development, a first-in-class medicine has a novel mode of action, whereas a follow- on medicine uses an existing mode of action15. However, for reclassification first-in-class switches may not push any boundaries, and follow-on switches could push boundaries. For example, the UK reclassification of topical griseofulvin has a different mechanism of action to the already-switched azoles and polyenes16, but does not push boundaries. A switch of diclofenac, allowing 150mg per day (full dose)16 after the ibuprofen low-dose switch, would probably push boundaries in most countries, yet would be deemed a follow-on switch rather than first-in-class. A non-prescription medicine with a new indication previously untreated in the non-prescription arena can be deemed to push boundaries, for example domperidone, being indicated to treat nausea and vomiting in the UK17. Finally, some medicines have no clear class, such as ketotifen (an antihistamine and mast cell stabiliser) and acetylcysteine (a mucolytic and nutritional)16.

In measuring innovation in drug development, Schmid and Smith (2005) used US Food and Drug Administration (FDA) priority reviews (for registering new chemical entities) to measure significant advantage over existing medication18, but regulators do not similarly prioritise non- prescription medicines. Thus, a new measure is needed to show progressiveness or innovation in switch.

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OBJECTIVES

Our study had three aims:

1. To derive a measure of progressiveness or innovation in reclassifying through identifying key switches.

2. To compare the progressiveness of Australia and NZ in switching medicines.

3. To ascertain if Australia and NZ are more advanced than the UK in switch.

METHODS

Meeting records for classification committees in Australia and NZ were reviewed by the lead author (NG) in terms of approved and rejected switches, recorded decisions, and reasons for the decisions. A period of 12 years was identified in line with available records and trends in reclassification rates. NZ’s MCC usually meets twice per year, so 24 MCC meeting minutes were scanned (up to 40 pages each). Australia’s ACMS (and formerly the NDPSC) meets three times per year (four times in 2000). Thus, 37 records of meetings were reviewed for Australia (up to 280 pages each). The switches were analysed further, tabulated, and then compared with the list of recent reclassified medicines from the Medicines and Healthcare products Regulatory Authority in the UK (List C)19.

Given our concerns about comparing reclassifications between countries using either WSMI tables or first-in-class switches, we have developed a new mechanism that adapts the FDA priority criteria for new chemical entities20 into a mechanism to identify ‘innovative’ switches. Our framework defines an innovative switch as one having the potential to provide – in the treatment, prevention, or diagnosis of a disease – either:

1. safe and effective therapy where no satisfactory non-prescription therapy yet exists in the same country; or

2. a clinically-significant improvement compared to current non-prescription therapies in the same country.

The italics indicate our revisions to the FDA criteria.

Recognising the subjectivity in determining ‘clinically-significant improvement’, we modified examples provided by the FDA (Table 1). The FDA bases this judgement on clinical trials or other scientifically-valid information. In contrast, the scope of the project required us to use the clinical judgement of the four pharmacist authors (NG, LE, FK, and LB), and search for information only for switches that we considered borderline. For example, we have considered the oral single-dose famciclovir likely to enhance patient adherence over five-times-daily application of aciclovir cream without seeking evidence.

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Table 1: Criteria for classifying innovative switch

FDA priority review examples20 Our innovative switch examples

1. Evidence of increased effectiveness in 1. Expected substantially increased treatment, prevention, or diagnosis of effectiveness in treatment, prevention, or disease; diagnosis of disease;

2. Elimination or substantial reduction of a 2. Expected elimination or substantial treatment-limiting drug reaction; reduction of a treatment-limiting drug reaction including interaction; 3. Documented enhancement of patient compliance; or 3. Expected substantial enhancement of patient adherence 4. Evidence of safety and effectiveness in a new subpopulation 4. Important advance for a significantly-sized subpopulation

Points 3 and 4 exclude formulation changes that are not usually switch issues, such as a gluten-free or a modified-release formulation. It also excludes combinations of medicines already available individually without prescription. It may include a substantially different route of administration that overcomes an important barrier for a significant-sized subpopulation.

Once a switch was classified as innovative for an individual country, we looked tothe international non-prescription markets in developed countries to determine whether it could be considered a ‘first-in-world innovative switch’.

RESULTS

The two countries have largely harmonised in scheduling, with most discrepancies resolved in the late 1990s or early 2000s. However, NZ has more recently switched medicines that Australia has not: sumatriptan (and two other triptans), oseltamivir, calcipotriol, and an oral vaccine for travellers’ diarrhoea and cholera. Sumatriptan and oseltamivir were rejected as switches by Australia at multiple meetings, and by the end of 2011, the ACMS had not yet considered either calcipotriol or the oral vaccine. Likewise, NZ has continued to reject switch of inhaled short-acting beta-agonist relievers for asthma21,22, which were reclassified across Australia in 1985, and in New South Wales earlier23.

SWITCHES IN AUSTRALIA AND NZ

In the past decade, both countries have switched many medicines. Approved switches (Table 2) were analysed for their ‘innovation’ (examples in Table 3), with all switches considered ‘innovative’ listed in Table 4. Australia progressed in innovative switches in 2000-2005, including tranexamic acid for menorrhagia (which was never launched and reverted to

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Table 2: Approved Switches in Australia and New Zealand (2000-2011)

Year of Committee Decision/ Australia New Zealand Recommendation 2000 Tranexamic acid Desloratadine Alclometasone dermal Oxiconazole vaginal Flurbiprofen lozenges* Etofenamate dermal* Felbinac dermal* Triamcinolone nasal Fluticasone nasal* Azelastine nasal* Acetylcysteine* 2001 Bifonazole scalp Levonorgestrel (emergency Desloratadine contraceptive pill) Triamcinolone nasal Levocetirizine 2002 Clobetasone dermal 2003 Levonorgestrel (emergency Sodium picosulphate‡ contraceptive pill) Oral fluconazole 150mg Drometrizole trisiloxane (sunscreen) 2004 Orlistat 120mg Oral fluconazole 150mg Ocular ketotifen Orlistat 120mg 2005 Pantoprazole 20mg† Alclometasone dermal Oxiconazole dermal* Clobetasone dermal 2006 Ibuprofen 400mg Sumatriptan 50mg Ocular ketotifen Oseltamivir Ocular azelastine Long-acting paracetamol Mepyramine dermal* Ibuprofen 400mg Oxiconazole vaginal Butaconazole vaginal Oral clemastine* Levocetirizine 2007 Paracetamol + caffeine* Ocular azelastine Butaconazole vaginal 2008 Omeprazole 10mg 2009 Guaiphenesin slow-release Pantoprazole 20mg Rabeprazole 10mg Oral famciclovir 3 x 500mg Guaiphenesin slow-release Ocular chloramphenicol Zolmitriptan 5mg nasal spray Lansoprazole 15mg Omeprazole 20mg 2010 Ocular chloramphenicol Calcipotriol dermal Omeprazole 10mg Rizatriptan 5mg wafers Lansoprazole 15mg 2011 Oral famciclovir 3 x 500mg Vibrio cholera and enterotoxigenic Escherichia coli vaccine *Non-prescription in NZ prior to 2000 †NDPSC decision in 2005 but reclassification delayed several years at sponsor’s request ‡Upscheduled to prescription one year prior under TTH, then reversed

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prescription in 2007 under TTHi,24), and moderate potency dermal corticosteroids, and culminating in the first-in-world switch of orlistat (for weight loss) in 200425 (Table 4). However, progress then slowed, with only two innovative switches in the past six years, one of which (chloramphenicol) was the result of TTH rather than being sponsor-driven. Mometasone, a potent dermal corticosteroid nearly reclassified before an about-turn in 200724. In contrast, NZ started slowly and gained momentum from 2004. NZ appeared conservative in the early 2000s, rejecting dermal moderate-potency corticosteroids, and up-scheduling some medicines from pharmacist-only to prescription, including cholestyramine and oxybutynin. From 2004 the committee appeared to become more progressive, including first-in-world switches of oseltamivir26, single-dose oral famciclovir27 and dermal calcipotriol28, as well as other innovative switches including sumatriptan, moderate-potency corticosteroids, proton pump inhibitors and oral fluconazole.

Table 3: Application of the Innovation Criteria (Examples)

Medicine Decision Rationale

Chloramphenicol eye Innovative Although ocular sulfacetamide was already non-prescription, it is drops considered “rarely of much value” and allergy can be problematic16.

Zolmitriptan nasal Innovative Although a me-too after sumatriptan tablets, it provides non- spray oral treatment and therefore efficacy for the sub-population of migraineurs who vomit16.

Oral fluconazole Innovative Although no more effective than vaginal treatments, oral fluconazole has important benefits for a subpopulation of sufferers of vaginal candidiasis: those with local irritation from the vaginal product; those menstruating; those using latex condoms or diaphragms; and/or those wanting to initiate treatment immediately (vaginal treatments are recommended for use at night)16,30.

Oral famciclovir Innovative Compliance for a single tablet dose should be higher than a cream used multiple times daily.

Alclometasone Innovative Moderate-potency corticosteroids are higher potency than dermal hydrocortisone16 already available without prescription.

Paracetamol plus Not innovative A non-prescription low-dose opioid (codeine) and paracetamol 3mg morphine combination already exists. Although theoretically a subpopulation in which codeine metabolism varies16 could provide an advantage for morphine, the benefits of low dose opioids ‘have not been substantiated’31, thus increased effectiveness of treatment cannot be expected.

Ibuprofen 400mg Not innovative Similar dosing to the ibuprofen 200mg tablets already available.

Acetylcysteine Not innovative Nutritional and mucolytic with no clear benefits over other mucolytics16.

iTTH intends harmonisation to the least restrictive schedule, but up-scheduling also occurs for safety or other reasons. NZ was not prepared to reclassify tranexamic acid without a sponsor providing packaging with appropriate warnings so would not harmonise. When no sponsor interest was apparent in Australia either, up-scheduling occurred.

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Table 4: Innovative Switches in Australia and NZ

Year of Committee Decision/ Australia New Zealand Recommendation 2000 Tranexamic acid* Alclometasone dermal 2001 Levonorgestrel (emergency contraceptive pill)

2002

2003 Levonorgestrel (emergency contraceptive pill) Oral fluconazole 2004 Orlistat Oral fluconazole Orlistat 2005 Pantoprazole Alclometasone dermal 2006 Sumatriptan Oseltamivir 2007

2008 Omeprazole 2009 Oral famciclovir Ocular chloramphenicol† Zolmitriptan 2010 Ocular chloramphenicol† Calcipotriol 2011 Oral famciclovir Vibrio cholera and enterotoxigenic Escherichia coli vaccine *Reverted to Prescription Medicine in 2007 †Ocular chloramphenicol switched in NZ following committee review without an application, then in Australia under TTH, not application

The minutes show multiple factors that may have supported NZ’s progress: committee member turnover, committee proactivity, non-sponsors driving the switch, and exemption to prescription (explained below). In 2004, half of the six-member committee changed32. Since then, the MCC has proactively suggested potential candidates for switching on multiple occasions29,33, and drove the chloramphenicol switch in the absence of sponsor application34-36. The medicines regulator drove switches in the early 1990s, and the emergency contraceptive switch in 200137. The two switches in 2010 and 2011 followed application by PharmacyBrands Ltd (PBL)33,38, a pharmacy retail group representing about one-third of NZ community pharmacies, most of which remain independently owned39. PBL does not sponsor these products, and therefore we consider these ‘third-party switches’.

Exemption to prescription appears on multiple occasions in MCC minutes (Table 5), for two reasons. Firstly, the exemption has allowed availability under limited circumstances which

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have not fitted the pharmacist-only category, such as the time of year and other rules with oseltamivir, and the accreditation for pharmacists and nurses with levonorgestrel. It has been commonly used for other health professionals, such as allowing optometrists to supply40. Secondly, the exemption has allowed a medicine to remain in international packaging. A third- party switch (such as with calcipotriol and the oral vaccine) means specific OTC packaging may not be possible, particularly in the small NZ market28.

Table 5: Examples of Exemption to Prescription

Medicine Conditions for exemption when first reclassified

Emergency contraceptive pill Accredited pharmacists and nurses*22

Oseltamivir When sold by a registered pharmacist between the months of May to September inclusive for the treatment of seasonal influenza to a consumer 12 years of age or more presenting in a pharmacy with early symptoms of influenza*41

Calcipotriol ≤50mcg/g or 50mcg/mL, in packs ≤30g or 30mL supplied by a pharmacist to an adult with mild to moderate psoriasis previously diagnosed by a doctor42

Vibrio cholera and enterotoxigenic In the form of an oral liquid containing Vibrio cholerae when Escherichia coli vaccine sold in a pharmacy by a registered pharmacist43

*Changes have since occurred with the emergency contraceptive pill and oseltamivir

While both countries have been innovative, a number of switch considerations have failed (Table 6). Although the ACMS (and formerly the NDPSC) in Australia have rejected a number of medicines, it has not rejected many switches that other countries have accepted. Sumatriptan stands as the only rejected switch attempt in Australia involving a medicine recently switched in multiple markets44-46. The MCC in NZ has outright rejected only two medicines: fluocortolone with cinchocaine and ocular fusidic acid (Table 6). Non-response by sponsors to committee requests or suggestions contributed to other failed switches in NZ.

Despite some innovative switches in Australasia, some medicines (both innovative and non- innovative) that have been reclassified in the UK remain prescription-only in both Australia and NZ (Table 7). In the period studied, of the seven innovative switches in the UK, five (azithromycin, simvastatin, mebeverine, domperidone, and tamsulosin) were not submitted in Australia, and four (azithromycin, mebeverine, tranexamic acid and tamsulosin) were not submitted in NZ, but tranexamic acid was considered under TTH. Had the sponsors provided requested information, domperidone, simvastatin and tranexamic acid might have switched in NZ (and tranexamic acid could have remained switched in Australia), suggesting loss of sponsor interest. Sumatriptan was rejected in Australia despite triptans being reclassified elsewhere. The meeting records showed that as soon as one committee concern was resolved another would arise, including concerns about rare events that could also be inappropriately treated with non-prescription analgesics. For example, the committee expressed a ‘much greater concern’ about potential pain relief from sumatriptan in subarachnoid haemorrhage or meningitis than about the overuse of sumatriptan, a well-established issue47,48. Eventually the

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committee concluded that no public need existed because an emergency supply could already be provided under Australian law24. The five non-innovative switches from the UK were not applied for in Australasia, suggesting little market attraction for sponsors, and given they were not innovative, consumers could access similar medicines.

Table 6: Non-approved Switch Considerations in Australia and New Zealand, 2000-2011*

Medicine Use Latest Year Reason for Non-approval Considered Australia

Dermal neomycin/ Skin infections 2004 Resistance concerns polymyxin B/bacitracin Paracetamol with low Pain 2006 Lack of evidence about abuse dose opioids potential Sumatriptan Migraine 2007 No public need Dermal mometasone Inflammatory skin 2007 NDPSC agreed to reclassify then conditions decided against reclassification, wanting experience with moderate potency corticosteroids first Aspirin with caffeine, Pain 2007 Considered under TTH, decided to paracetamol or up-schedule to prescription in NZ salicylamide instead Paracetamol with 3mg Pain 2007 Concern about addiction and other morphine concerns Oseltamivir Influenza 2008 Diagnosis, resistance uncertainties, cannot collect data if switched Loperamide liquid Diarrhoea 2009 Concern it may be used in children Vitamin D in high doses Vitamin D deficiency 2009 Inability for OTC diagnosis, need blood tests, medical management Montelukast Seasonal allergic rhinitis 2009 Risk versus benefit inadequate Orphenadrine with Pain 2011 Half-life mismatch, toxicity paracetamol concerns

New Zealand

Fluocortolone with Haemorrhoids 2001 No need for increased potency of cinchocaine (rectal) corticosteroid Salbutamol and Asthma 2005 Sought more information, which terbutaline (inhaled) was not forthcoming Simvastatin Prevention of heart 2005 Sought more information, which attacks and strokes was not forthcoming Domperidone Epigastric fullness 2006 Sought more information, which was not forthcoming Tranexamic acid Menorrhagia 2006 No sponsor interest, no OTC labelling Ocular fusidic acid Eye infections 2007 Resistance concerns

*Excludes rejected switches that were later accepted

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Continuing the comparison with the UK, Australia has had only one innovative switch in the past 12 years (famciclovir), which has not been replicated (as at June 2012) in the UK. Tranexamic acid was reclassified in Australia in 2000 but reverted in 2007 following TTH and lack of sponsor interest. Thus, Australia appears less progressive than the UK in this area.

Table 7: Medicines Switched in the UK,* But Not Switched in Australia or NZ

Submitted for Submitted Medicine Indication switch in NZ for switch in Comment since 2000? Australia since 2000? Innovative switches

Azithromycin Chlamydia trachomatis Not submitted Not submitted Highlighted by MCC as potential reclassification candidate, 2008 Mebeverine Irritable bowel Not submitted Not submitted Highlighted by MCC as potential reclassification candidate, 2008 Tamsulosin Benign prostatic Not submitted Not submitted hypertrophy Domperidone Various including Submitted 2005, Not submitted Highlighted by MCC as potential bloating, relief of 2006 reclassification candidate, 2008 nausea and vomiting Simvastatin Prevention of Submitted 2004, Not submitted In 2005, the MCC wanted cardiovascular disease 2005 information on handling of liver function tests (in datasheet) but no company response Sumatriptan Migraine Submitted 2006 Submitted, Highlighted by MCC as potential considered four reclassification candidate in times 200521 Pharmacist Only 2005-2007 Medicine in NZ, Prescription Medicine in Australia Tranexamic acid Menorrhagia Considered Reclassified No sponsor interest under TTH in 2000 then 2006 reversed 2007 under TTH

Non-innovative switches

Acrivastine Antihistamine Not submitted Not submitted Others available

Fenticonazole Vaginal candidiasis Not submitted Not submitted Others available Griseofulvin Fungal skin infection Not submitted Not submitted Others available topical

Hydroxyzine Allergies Not submitted Not submitted Others available Nedocromil Allergic conjunctivitis Not submitted Not submitted Others available eye drops

* Based on the MHRA’s consolidated list of medicines reclassified since April 200219

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NZ compares more favourably than Australia with the UK in progressing switch (table 7). While azithromycin, simvastatin, tamsulosin and tranexamic acid have not switched in NZ, sumatriptan has. Additionally, NZ has approved switches for calcipotriol, famciclovir, oseltamivir, and a travellers’ diarrhoea and cholera vaccine which have not been reclassified in the UK.

DISCUSSION

We found that Australia was more progressive in medicine switches than NZ from 2000 to 2003, but since then NZ has become more progressive, while Australia has had fewer innovative switches. Monitoring and comparing ‘progressiveness’ between specific countries can inform reclassification elsewhere, and can highlight to pharmaceutical companies useful test markets for reclassification.

Although Australia appeared to Gilbert et al. more advanced in non-prescription availability of medicines than the UK in 20038 and to the USGAO as advanced as the UK in 20079, we found more innovative reclassifications in the UK than Australia in the period studied. The UK has clearly become a world-leader with a number of innovative switches that were first- in-world (such as simvastatin14, tamsulosin49 and azithromycin), while Australia had only one first-in-world innovative switch in this time period. In this paper we reviewed switches for their innovation over a set period and comparatively analysed innovative switches in Australia, NZ, and the UK as world leader. This approach has been more informative for measuring progressiveness in switch and consumer access to medicines than the count of the WSMI tables. However, we note that our approach is more time-consuming, and requires access to appropriate records, which may not be readily available.

We have raised doubts about the findings of Gilbert et al., that NZ was more advanced than five other countries in 20038. However, NZ does currently have multiple innovative switched medicines that the UK does not, and since 2003 has had several first-in-world innovative switches. Hence, it appears that NZ could currently be considered one of the most progressive countries in switch in the world. Like the UK with azithromycin and tamsulosin, NZ has also innovated with antimicrobials (such as oseltamivir), and chronic conditions, including a collaborative care approach with calcipotriol requiring a doctor’s diagnosis and advice to the doctor of the non-prescription supply38. Non-sponsors driving switch applications appear to have enabled switches in NZ. Uniquely this has included a pharmacy-retail group, and their first switch has been published as a case study28. PBL has recently applied to switch influenza vaccinations and trimethoprim (both mandating special training and special criteria for supply), with both reclassifications gazetted in July 201250. Where switches are not driven by sponsors, an opportunity may exist for others to drive the applications.

We have demonstrated how receptivity to switches can change over time, for example dermal corticosteroids in both countries, and variation in the number of innovative medicines being reclassified at different periods in each country, when committee constitutions and factors considered in deciding reclassification have remained the same (until the NDPSC evolved

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to the ACMS in Australia in 2010). We have also seen the two countries differ in outcome for reclassification decisions, for example with sumatriptan, asthma reliever inhalers, and oseltamivir. These factors suggest variability in decision-making, which is the subject of further investigation by our team.

Given the first-in-world reclassifications in NZ (and Australia), yet the absence of switch of some medicines (often because of no application) that had been switched in the UK, both enablers and barriers to switch appear to be operating in these markets. One barrier may be the low sales of some switched medicines in the UK, such as simvastatin14, which may make companies reluctant to drive similar applications elsewhere. Another barrier may be Australian advertising restrictions. Companies can only advertise Pharmacist Only Medicines that are on an approved list3. Our review of the minutes show no new Pharmacist Only Medicines have been approved for advertising since 2007, which may deter companies in proposing new switches. We have further research underway to understand barriers and enablers to switch in both countries.

Aronson suggested a new intermediate category (pharmacist-only) to assist reclassification in the UK51, and Gilbert et al. suggested that the pharmacist-only category may make more medicines available without prescription8. We found that switches have been reasonably progressive in Australia and are currently more so in NZ, but it is difficult to determine to what degree a pharmacist-only classification explains this finding. Despite having a Pharmacist Only Medicines category, Australia rejected reclassifying sumatriptan, while the UK and Germany (countries with pharmacy-only but not pharmacist-only availability) switched sumatriptan and naratriptan, respectively45. This suggests pharmacist-only availability may not always enable switch and that lack of this category may not automatically inhibit switch. However, minutes from NZ suggest that restricting availability to pharmacists (through the Pharmacist Only Medicine category or exemption to prescription) offers reassurance for the MCC, for example with oseltamivir21 and calcipotriol38. Given the differences between Australia and NZ in decisions despite the pharmacist-only category (Appendix 2), and particularly given that one country has been progressive at one stage and the other has been progressive at another stage, other factors appear involved. Further research is required to identify whether the pharmacist- only category is enabling.

Reclassifications have benefits and 10,52risks . We have outlined the reclassifications and commented on the apparent changes in the committees in becoming more or less progressive or conservative. We have not judged the appropriateness of the switches that have taken place as this is outside of the scope of this project. Reclassification reversals have occurred internationally for safety reasons, for example with terfenadine52. In NZ, mupirocin53 and clindamycin54 were up-scheduled from pharmacist-only to prescription medicine over a decade ago following resistance concerns. While safety is paramount in the reclassification process, research should be undertaken after most first-in-world innovative reclassifications to monitor safety and appropriateness of the reclassification in the ‘real world’. Where two countries differ in their decision, as for inhaled short-acting beta agonists, sumatriptan and oseltamivir

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between Australia and NZ, further research is required to ascertain whether or not concerns that prevented reclassification in one country were borne out when reclassified elsewhere. Such research would need to take account of contextual differences between the systems. Recent research suggests some concerns that prevented reclassification of oseltamivir in Australia did not come to fruition on reclassification in NZ55.

STRENGTHS AND LIMITATIONS

We used switch decisions in NZ and Australia from meeting records to consider the current progressiveness of both countries. These records are authentic, and as meeting records are usually signed off by attendees, and the lead author attended 13 of the meetings involved, these records are considered to be reasonably accurate. However, the records are extensive, comprising an estimated 6000-7000 pages, and included some obscure medicine switches because of TTH. It was sometimes unclear (in early brief minutes in Australia) as to whether the medicines were switches or not. In Australia, meeting records also include poisons and veterinary medicines. It is possible, therefore, that a small number of switches of little-used medicines were missed; however, innovative switches were unlikely to be missed due to the lead author’s involvement in this area. We also used dates of decisions from minutes rather than seeking confirmation of gazettal. Thus our dates may not reflect actual implementation.

We used multiple people to ascertain the innovativeness or not of switches, rather than one person’s perspective. There was agreement amongst the four pharmacists in this context with respect to application of the ‘innovation’ criteria and final decisions as to which switches were considered progressive. It is possible that a different group of people would argue one or two of the borderline cases differently, but this would have little effect on our findings. We were unable to find an appropriate measure that did not involve a judgement of some kind; even first-in-class involves a judgement sometimes as we showed in the introduction.

We relied on the Medicines and Healthcare products Regulatory Agency ‘List C Consolidated list of substances which are present in authorised products which have been reclassified since 1 April 2002’ for the UK. This includes medicines such as mebeverine which reclassified in 199810, suggesting that this list includes some pre-2002 switches, and before our cut-off of 2000 (used for Australia and NZ). This list was satisfactory for our purposes of ascertaining if relatively recent innovative switches in the UK had not switched in Australasia.

To supplement the innovative switches, we have also considered whether the countries examined have had first-in-world innovative switches, but some of this information is not readily available, so we have used examples rather than an exhaustive list. Further research comparing first-in-world innovative switches for multiple countries alongside a list of innovative switches would provide useful information on progressiveness of countries.

We compared NZ and Australia with each other, and with the UK, which has been regarded as the most progressive country in switch10. Further comparisons would be useful to determine the progressiveness of these countries compared to other more reticent, developed countries, and this is the subject of our ongoing research.

©SELFCARE 2012 Accepted for publication 30 July 2012 101 INNOVATIONS FROM ‘DOWN-UNDER’

Unfortunately, lack of transparency and greater use of discussion at the regulator level in other countries13,56 limits the opportunity to compare switch rejections internationally.

CONCLUSION

Currently, NZ can be considered an innovator in medicines reclassification, with similar numbers of innovative switches and first-in-world switches as the UK. Australia demonstrated some progressiveness in the early 2000s, but recently has lagged behind NZ and the UK, despite having a pharmacist-only medicines category. Our framework for determining ‘innovation’ or ‘progressiveness’ in switches has potential to be applied longitudinally and in comparisons between other countries, pending availability of data.

Statement of Interests: Natalie Gauld has contracted to Pharmacybrands Ltd, and Pharmacy Retailing NZ Ltd in reclassification, and has received research funding from Roche Products NZ Ltd and NZ Pharmacy Education and Research Foundation. She was a member of the Medicines Classification Committee from 2004-2009. She has no other conflicts of interest relevant to the paper submitted. All other authors have no conflicts to declare.

There was no funding for this part of the research.

Contributions of the authors: Natalie Gauld planned the research in conjunction with the other authors, downloaded and analysed documents, developed the method for ‘innovative switches’, reported the findings, and wrote the first draft and revision of the paper. Associate Professor Stephen Buetow was involved in most aspects of the research including writing the paper. Dr Linda Bryant was involved primarily in the planning stage and method for innovative switches, and contributed to the paper. Dr Fiona Kelly and Associate Professor Lynne Emmerton contributed to the method for innovative switches, reporting and writing the paper.

Correspondence to: Natalie Gauld, Department of General Practice, School of Population Health, University of Auckland, Private Bag 92019, Auckland, New Zealand. Telephone +64 9 923 9340 or +64 21 336 685, Fax +64 9 373 7624. Email: [email protected].

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Appendix 1 Process of Reclassification and Committee Composition

In both countries, any organisation or person can apply to reclassify a medicine, but the application needs to supply specified information4,57,58. The Therapeutic Goods Administration (TGA) and Medsafe sites publish advance notice of scheduling considerations and meeting records for ACMS and MCC meetings, respectively, allowing public consultation and objections or post-meeting comments. The MCC agenda provides a link to the main application for reclassification (excluding confidential information, appendices and references). Scheduling considerations usually include an independent evaluator report in Australia. These are usually provided to the applicant for the reclassification in advance of the meetings for comment, but are not available publicly. Although Medsafe has provided reports on reclassifications in the past, this has been rare in recent years. Public submissions on reclassifications are welcomed in both countries.

The NDPSC included representatives of States and two Territories and the Commonwealth (jurisdictional members), the TGA, and various experts and representatives from pharmacy, industry and consumer representatives, and two representatives from NZ (including one from Medsafe)3,59. The TGA representative (usually the Principal Medical Advisor) was the Chair. Decisions required support of the majority of the jurisdictional members, a process that has been criticised and since removed with the change to the ACMS60.

The ACMS (since mid-2010), has an independent Chair (neither from the TGA nor States or Territories), and currently has 15 members including nine representatives of States and Territories and the Commonwealth, and up to six other people with expertise in one or more of the required fields, including community pharmacy, medical practice, consumer health, industry and clinical pharmacology5. The ACMS makes a recommendation on medicine classification and permitting advertising for pharmacist-only medicines, and the Secretary of the Department of Health and Aging (or Delegate) makes the final decision.

The MCC comprises six members: two nominees from the Ministry of Health, (including the Chair); two Pharmaceutical Society of NZ nominees; and two NZ Medical Association nominee4. The committee provides recommendations on classification matters, with the Minister of Health’s Delegate making the final decision.

Appendix 2 Classification Considerations in Australia and NZ

Australian Considerations

ACMS

The Therapeutic Goods Act 1989 (dated 28 March 2012) requires the following matters to be taken into account in reclassification (where relevant)58:

a. the risks and benefits of the use of a substance;

b. the purposes for which a substance is to be used and the extent of use of a substance;

c. the toxicity of a substance;

d. the dosage, formulation, labelling, packaging and presentation of a substance;

e. the potential for abuse of a substance;

f. any other matters that the Secretary considers necessary to protect public health.

NDPSC

The NDPSC took into account the following, where relevant, (based on an earlier Therapeutic Goods Act 1989 dated 4 March 2005)59:

a. the toxicity and safety of a substance;

b. the risks and benefits associated with the use of a substance;

c. the potential hazards associated with the use of a substance;

d. the extent and patterns of use of a substance;

e. the dosage and formulation of a substance;

f. the need for access to a substance, taking into account its toxicity compared with other substances available for a similar purpose;

g. the potential for abuse of a substance;

h. the purposes for which a substance is to be used;

i. any other matters that the Committee considers necessary to protect public health, including the risks (whether imminent or long-term) of death, illness or injury resulting from its use; and may take into account the labelling, packaging and presentation of a substance.

NZ Considerations

The MCC takes the following into account in reclassifying medicines4:

• Consumer convenience: Accessibility of the medicine and suitability for self-treatment. Accessibility includes time and location factors. Conditions suitable for self-treatment are usually minor and self-limiting

• Potency: The ability of a medicine to produce a wanted pharmacological effect

• Current availability: The availability of products with a similar therapeutic purpose

• Therapeutic index

• Toxicity: The potential of a substance to produce adverse preclinical and clinical effects. Adverse clinical effects will be assessed by frequency and severity

• Abuse potential

• Inappropriate use: Factors relevant to the minor ailment or symptom for which the medicine is indicated, including the suitability of the condition for self-monitoring and the likelihood of misdiagnosis

• Precautions: Factors relevant to the medicine under consideration such as contraindications, side-effects and interactions with other medicines

• Communal harm: The possibility of community harm resulting from wider use of the medicine in question, e.g. the development of antibiotic resistance in bacteria