Succeeding in Switzerland's regulatory environment for pharma

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Nov 10, 2012 - Swissmedic's requirements for marketing authorisation ..... a Swiss-based consultancy with a UK affiliate
Focus on Switzerland

Succeeding in Switzerland’s regulatory environment for pharma – similarities and differences compared with the EU Shayesteh Fürst-Ladani highlights critical differences between the Swiss and EU regulatory systems that drug manufacturers should be aware of and discusses how Swissmedic plans to shorten its review timelines. Article 13 procedure

Swissmedic’s requirements for marketing authorisation application (MAA) dossiers are similar to those of the EMA. Nonetheless, sponsors that are unfamiliar with the Swiss regulatory system may face some unexpected challenges. It is thus important for companies that are not located in the country to familiarise themselves with the country-specific requirements. In contrast to the EU (centralised procedure), where a legal entity located in the European Economic Area (EU member states plus Iceland, Liechtenstein and Norway) can act as an MAA applicant, in Switzerland applicants must hold an additional establishment licence from Swissmedic in order to file an MAA.

Article 13 TPA/Articles 5a-5d VAM (referred to below as Article 13) allows Swissmedic to expedite reviews for medicines that have already been authorised by regulators (reference authorities) in countries with a “comparable control system”. The procedure was introduced to minimise delays to market entry and allow Swissmedic to allocate its resources more effectively in a targeted, riskbased manner5-7. This applies to MAAs for all drugs including orphan drugs, with some exceptions. Swissmedic reserves the right to accept or reject an application under Article 13. The countries recognised by the Swiss agency as having comparable control systems (reference countries) are Australia, Canada, EEA member states, Japan, New Zealand, Singapore and the US. European authorisation can be based on the centralised, mutual recognition and decentralised procedures, or on national authorisations. Swissmedic’s use of the reference authority’s evaluation as the basis for its own decision can potentially reduce the usual 330-day target processing time for MAA evaluation by one-third. Furthermore, the fees payable for individual cases can also be reduced by one-third. Approvals that have been obtained in a reference country can be considered in Swiss applications for: • known active substances/generics (Art 5b VAM); • new active substances (NAS) and extended indications (Art 5c VAM); and • parallel submissions to Swissmedic and the EMA for marketing authorisation/ modifications (Art 5d VAM). Notably, oncology products are not eligible for consideration under Article 13 and must follow the normal full evaluation procedure by Swissmedic or the fast-track authorisation procedure (described below) if applicable. Furthermore, applications that obtained approval by the reference authority via fast-track status decisions are not eligible for Article 13 review. In general, the MAA submitted for evaluation according to Article 13 should be the same as that authorised by the reference authority. However, in certain circumstances, the product may have minor differences from that in the reference country. If this is the case, the applicant must justify those differences and

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Swissmedic intends to introduce a new advanced registration procedure next year

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This requires setting up a quality management system (QMS) that has to be inspected and approved by Swissmedic, which takes on average six months. During this time, the pharmaceutical company cannot file an MAA. In order to save time, the company can use the support of local organisations holding the required licences. These organisations can act as an applicant, file the MAA with Swissmedic and provide support to establish the QMS in parallel. Once the pharmaceutical company has obtained the Swissmedic establishment licence, the rights can be transferred from the local organisation to the pharmaceutical company. Since a number of Swiss regulatory pathways may be similar but are not identical to those of the centralised procedure in the EU (see Table 1), companies should avoid making assumptions about Switzerland’s regulatory landscape based on their experience in the EU. For example, three regulatory pathways that are intended to provide opportunities and incentives for applicants in Switzerland are: Article 13 of the Therapeutic Products Act (TPA)/Article 5a-5d Medicinal Products Ordinance (VAM); the fast-track procedure; and the simplified procedure.

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Switzerland is a leading force in the European pharmaceutical industry and a key strategic market in which to develop and launch new products. It accounts for nearly 16% of the €27.4 billion annual R&D investment by the pharmaceutical industry in Europe and is home to more than 460 licensed pharmaceutical manufacturers1,2. There are various reasons why international companies ranging from the large players to a growing number of small and medium-sized biotech enterprises have chosen to base their European or global headquarters in Switzerland. The country’s competitive strengths include the presence of leading scientific research institutions, a robust collaboration between the academic and business sectors, and a high R&D expenditure. These are among the qualities that ensure that much of the research is translated into marketable products3. Approval of medicinal products by Switzerland’s agency for therapeutic products, Swissmedic, is especially important for Swissheadquartered companies because many nonEuropean countries require authorisation in the country of origin (ie the place where the company is headquartered) as a prerequisite for local registration. Because of Switzerland’s status in the European pharmaceutical arena, however, it may be easy to forget that the country has its own regulatory framework which is distinct from that of the EU. Companies need to acknowledge this in order to succeed in the Swiss market. This article illustrates some of the differences between Swiss and EU regulations and examines certain country-specific regulatory pathways in Switzerland such as the fast-track procedure. These were, in fact, topics of discussion at the Swissmedic International Regulatory Symposium held on 20-21 September 2012 in Interlaken, Switzerland, to mark the agency’s 10th anniversary4. Swissmedic presented the results of a study suggesting that authorisation of medicines in Switzerland may lag behind the European Medicines Agency even though Swissmedic has already improved its efficiency by using certain regulatory routes. This lag even appears to be the case for treatments of illnesses with a high unmet need; it does not bode well for Swiss patients with rare or lifethreatening diseases. © Informa UK Ltd 2012

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Focus on Switzerland Table 1. Key differences between the EU and the Swiss regulatory systems EU (centralised procedure)

Switzerland

MAA filing

A registered company in the EEA is sufficient for MAA filing.

Companies must be located in Switzerland and also have an establishment licence from Swissmedic.

Recognition of authorisations in other countries

The European Medicines Agency always performs a complete assessment, irrespective of whether the medicinal product is already authorised in other major markets such as the US, Japan, etc.

Under certain conditions, Swissmedic will consider a foreign regulator’s assessment for an application when the drug is approved in countries with comparable regulatory systems, ie Australia, Canada, EEA member states, Japan, New Zealand, Singapore, US (the so-called Article 13 procedure). However, Swissmedic will perform its own assessment of the MAA. If Swissmedic agrees to review an MAA under the Article 13 procedure, the assessment time and fees may be reduced by one-third.

Fast-track (accelerated) procedure

An accelerated assessment procedure exists with a 150-day maximum time limit (versus the standard 210-day limit) for an opinion by the EMA’s CHMP.

A fast-track procedure exists with a 140-day maximum time limit (versus the standard 330-day limit), for a higher fee.

Orphan drug legislation

Specific orphan drug legislation (Regulation (EC) No 141/2000) has existed since 2000. Incentives for development of orphan drugs include 10-years market exclusivity, protocol assistance (scientific advice) and fee reductions. Companies can submit a common application for orphan medicinal product designation to both the EMA and the US Food and Drug Administration.

Orphan drugs are mentioned in the Swiss Therapeutic Products Act. However, no specific orphan drug legislation exists.

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Article 13, which may be subject to denial, even when such drugs have been authorised in the EU. This would be a cause for concern, as Swiss patients could be denied access to life-saving drugs that their neighbours can obtain. There are about nine products authorised in the EU as orphan drugs that at the time of writing were not approved by Swissmedic and only had orphan designation status in Switzerland8. As the Swiss agency does not publish information about filings, negative opinions, rejections or withdrawals of MAAs, the reasons behind this incongruity are not completely clear.

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provide supporting information in the appropriate sections of the dossier. The differences that are permitted include those relating to the place of manufacture of the finished product; batch release; quality control(s); and primary and secondary packaging. Additional country-specific documentation must be submitted depending on which reference authority is being named in the application. For example, if the application is based on an EU decision under the centralised procedure, additional documents must include the Day 80 assessment report, the Day 120 list of questions and the Day 180 list of outstanding issues, as well as other relevant documentation such as responses to questions. Companies that have already filed an MAA with Swissmedic under its national procedure can apply to switch to an evaluation under Article 13 after receiving a positive opinion in a reference country. It should be made clear that Swissmedic will make its own evaluation and conclusion on the MAA. One should not confuse this regulatory pathway with the EU’s mutual recognition procedure whereby concerned member states can save time and resources by recognising a marketing authorisation of the reference member state. Indeed, there have been cases where Swissmedic did not recognise the reference authority’s approval and followed another authority’s rejection of the MAA even when that regulator was not named as the reference authority. The same would also apply to orphan drug authorisations submitted under

Applications for orphan designation can be based on orphan status granted by a reference authority following a comparable regulatory system (particularly the EMA). Products with orphan status are eligible for review under Swissmedic’s simplified authorisation procedure with reduced fees. However, there are no incentives such as those in the EU.

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Fast-track procedure If Article 13 does not apply (eg for oncology medicinal products), companies seeking to benefit from faster review timelines in Switzerland can submit eligible MAAs for innovative medicinal products via the fasttrack procedure. This procedure was introduced to ensure that patients get early access to innovative medicines for life-threatening diseases. Certain conditions have to be met for the product to be eligible for this procedure9: • the product is a promising therapy for a severe, debilitating or life-threatening illness; • treatment with currently approved drugs are either absent or unsatisfactory; and • high unmet medical benefit is expected by using the new drug. Applications filed under the fast-track procedure can be for new active substances for human use, line extensions, new dosage www.scripregulatoryaffairs.com

forms or known active substances. The review can be carried out within 140 days. The fee for a fast-track application is higher than that for other applications. Swissmedic says this fasttrack mechanism is a “highly competitive” procedure10, although the process does have its limitations due to the strict eligibility criteria. In the EU, the accelerated procedure set out in Article 14(9) of Regulation (EC) No 726/2004 on the authorisation and supervision of medicines applies to MAAs for medicines that are “of major interest from the point of view of public health and, in particular, from the viewpoint of therapeutic innovation”11. The request needs to be substantiated; however, there is no single definition of what constitutes a major public health interest. This is decided on a case-by-case basis12. So far, this pathway is seldom used – between September 2011 and September 2012, seven requests for accelerated approval were submitted to the EMA’s Committee for Medicinal Products for Human Use (CHMP), of which two have been accepted13.

Simplified procedure There are various circumstances in which products may qualify for authorisation under Swissmedic’s simplified review procedure14. Eligible drugs include those with known active substances, complementary medicines or those prepared by a hospital pharmacy for the needs of the hospital. In addition, orphan drugs that are not approved in a comparable market and, therefore, are not eligible for review under © Informa UK Ltd 2012

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www.weforum.org/issues/global-competitiveness 4. Swissmedic International Regulatory Symposium, Interlaken, Switzerland, 20-21 September 2012, http://bit.ly/TxBY8Q 5. Swissmedic, Administrative Ordinance Instructions. Authorisation of medicinal products already authorised in foreign countries (Article 13, TPA), 22 June 2010, http://bit.ly/TB0neb 6. Bundesgesetz über Arzneimittel und Medizinprodukte (Heilmittelgesetz, HMG), Die Bundesbehörden der Schweizerischen Eidgenossenschaft (The Federal Authorities of the Swiss Confederation), 15 December 2000, www.admin.ch/ch/d/sr/c812_21.html 7. Verordnung über die Arzneimittel (Arzneimittelverordnung, VAM), Die Bundesbehörden der Schweizerischen Eidgenossenschaft (The Federal Authorities of the Swiss Confederation), 17 October 2001, www.admin.ch/ch/d/sr/c812_212_21.html 8. Swissmedic, Humanarzneimittel, http://bit.ly/R7RZWi 9. See Reference 7 10. Swissmedic, 2011 Annual Report, http://bit.ly/R7HbVY 11. Regulation (EC) No 726/2004 of 31 March 2004 on the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency (Text with EEA relevance), OJ, 30 April 2004, L 136, 1-33, http://bit.ly/ONHnM9 12. European Medicines Agency, Guideline on the Procedure for Accelerated Assessment Pursuant to Article 14(9) of Regulation (EC) No 726/2004, EMEA/419127/05, 17 July 2006, http://bit.ly/T2CniU 13. European Medicines Agency, CHMP: Committee meeting reports, September 2011-September 2012, http://bit.ly/T2Cqvi 14. Verordnung des Schweizerischen Heilmittelinstituts über die vereinfachte Zulassung von Arzneimitteln und die Zulassung von Arzneimitteln im Meldeverfahren (VAZV, 812.212.23), 22 June 2006, http://bit.ly/UeLX8B 15. Regulation (EC) No 141/2000 of 16 December 1999 on orphan medicinal products, OJ, 22 January 2000, L 18, 1-5, http://bit.ly/PFMy2n 16. See Reference 10 17. European Medicines Agency, Q&A: Orphan application guidance, http://bit.ly/RcjZqi 18. Swissmedic, Richtlinie Fristen Zulassungsgesuche, 20 June 2008, http://bit.ly/T2Cvz2 19. See Reference 10 20. Swissmedic, Partner authorities, http://bit.ly/Vc22HX 21. European Medicines Agency, MRA with Switzerland, 2002, http://bit.ly/T4BWsU 22. European Medicines Agency, Switzerland, http://bit.ly/S0fgHv 23. Swissinfo.ch, Drug agency aims for European agreement, 2009, http://bit.ly/RMo1I0

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A Swissmedic-sponsored study, presented at the Swissmedic International Regulatory Symposium in September, indicated that the agency can be quicker than the EMA when applying a fast-track procedure such as those mentioned above. For example, under the fast-track procedure, sponsors can potentially have their applications reviewed by Swissmedic within 140 days. This is positive news for Swissmedic and applicants alike. However, the Swiss agency acknowledges that its review timelines of an MAA under standard procedures can also be much longer than its targeted timelines of 330 days (though the law sets a 300-day limit) and those of its counterparts18. Notably, the initial conclusions of the study illustrated that around 25% of MAAs rejected by Swissmedic received approval by the EMA, regardless of the regulatory pathway used. This is particularly worrying for orphan drugs, which may be readily available to patients just across the border in the EU, but not to those in Switzerland. Swissmedic is committed to introducing new processes that will ensure early patient access to medicines. Its representative stated at the symposium that the agency plans to increase staff numbers in 2013 and aims to review 99% of applications within 330 days by 2014. In addition, the agency intends to introduce a new advanced registration procedure next year. This procedure should be used for innovative medicinal products that do not fulfil the criteria of the current fast-track

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Seeking greater efficiency

authorisation procedure19. Applications will be processed within reduced timelines but they will be subject to higher fees. Another area of note is the increasing collaboration between Swissmedic and foreign regulators. An important feature of such agreements has been the potential exchange of information for ongoing evaluations of marketing authorisations, thereby enabling collaborating agencies to gain insight into the basis for decisions taken by their international counterparts. In 2003, Swissmedic initiated such an arrangement with the US and similar arrangements are in place with Canada (2006), Australia (2006), Singapore (2008), New Zealand (2009) and Japan (2010)20. Although the Swiss regulatory system remains distinct from that of the EU, there is an established co-operation between Swissmedic and the EMA21. One of the more recent collaborations has involved the two agencies agreeing to exchange confidential information about the authorisation and safety of medicines used in the context of the 2009 (H1N1) influenza pandemic22. In 2009, the Swiss health minister expressed concerns about delays in introducing new medicines in Switzerland. The concerns arose because of a three-week delay in making the swine flu vaccine Pandemrix available in Switzerland. Swissmedic was asked to start negotiations with the EMA in order to access the agency’s confidential data and speed up approvals23. The arrangement with the EMA was started in 2010, renewed for a year in 2011 and was recently extended again in 2012.

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Article 13, can seek authorisation under the simplified procedure. The applicant must prove that the medicinal product is used for the diagnosis, prevention or treatment of a rare, lifethreatening or chronically invalidating disease that affects a maximum of five people in 10,000 in Switzerland. This is in line with the EU orphan drug legislation (Regulation (EC) No 141/2000)15 where the disease must not affect more than five people in 10,000 in the EU. Notably, a product must receive an orphan drug designation before it can be authorised as an orphan drug. Whereas Swissmedic will often recognise an orphan drug’s status granted by a country or region16, the EMA does not recognise orphan status granted in other regions17. In the EU, orphan designation can only be granted by the European Commission once an application for designation has been endorsed by the EMA’s Committee for Orphan Medicinal Products. However, the EU has an agreement with the US whereby an applicant can submit a common application dossier for orphan designation in both countries.

Conclusions At its 10th anniversary symposium, Swissmedic presented its plans to shorten review timelines. To this end, it intends to introduce a new advanced registration procedure and engage more reviewers. Swissmedic will use these measures in addition to using its existing expedited pathways such as Article 13, the fast-track procedure and the simplified procedure. The combination of these efforts may strengthen pharmaceutical companies’ perception of Switzerland as a key market in their international plans, but it remains to be seen whether they will result in more – and faster – approvals. References 1. European Federation of Pharmaceutical Industries and Associations, The Pharmaceutical Industry in Figures – Edition 2011, http://bit.ly/RGV8ty 2. Swiss Federal Office of Public Health/World Health Organization, September 2011, Switzerland Pharmaceutical Country Profile, http://bit.ly/S7DqBO 3. World Economic Forum, The Global Competitiveness Report 2011–2012, www.scripregulatoryaffairs.com

Shayesteh Fürst-Ladani is managing director of SFL Regulatory Affairs & Scientific Communication Ltd, a Swiss-based consultancy with a UK affiliate that provides comprehensive regulatory, legal, public affairs and communication support to life sciences companies. Email: [email protected]. November 2012

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