Falsified medicinal products Good afternoon everybody I’m going to talk today about the European directive of ... Chaïma MRIZAK Regulatory seminar 15th of November 2017

Outline Definition: Falsified medicines Scope of the problem EU laws on falsified medicines: Directive 2011/62/EU Role of the European Medicines Agency

Introduction Difficult to guess at first sight

1. What are falsified medicines? « Falsified medicines are fake medicines that pass themselves off as real, authorised medicines. » Those products usually contain sub-standard or falsified ingredients or no ingredients or ingredients, including active substances, in the wrong dosage be deliberately and fraudulently mislabelled with respect to their identity or source; have fake packaging

2. Scope of the problem Recent years: medicines were the leading counterfeit products seized by European customs, ahead of counterfeit cigarettes (Pharmaceutical Security Institute “2011 situation report”) Alarming increase of falsified medicinal products in the Union (identity, history or source) Falsified medicines: do not pass through the usual evaluation of quality, safety and efficacy .. Particular threat to human health Lack of trust of the patient in the legal supply chain. *There is .... Detected.... In relation to their... *....that is required for the EU authorisation procedure *This poses a particular .... At best not effective at all At worst very harmful . and may lead to a lack of trust.... There are many estimates of the scope and scale of the market in SSFFC medical products but little validated evidence to underpin those estimate No countries remain untouched by this issue — from North America and Europe through to Sub Saharan Africa, South East Asia, and Latin America

2. Scope of the problem Until recently: in wealthy countries  expensive 'lifestyle' medicines (hormones, steroids and antihistamines) In developing countries  life-threatening treatments ( malaria, tuberculosis and HIV / AIDS) Phenomenon on the increase: expensive medicines ++ (anticancer medicines), high demand (antivirals) Until recently, the most frequently falsified medicines in wealthy countries were expensive 'lifestyle' medicines, such as In developing countries, they have included medicines used to treat life-threatening conditions such as malaria, tuberculosis and HIV / AIDS. The phenomenon of falsified medicines is on the increase, with more and more medicines now being falsified. These include expensive medicines, such as anticancer medicines, and medicines in high demand, such as antivirals.

Falsified cancer medicine Bevacizumab (unknown origin) The falsified product closely matches the appearance of the real medicine, but tests indicate that it contains starch and acetone instead of active ingredient. The fakes were trafficked on a complex supply chain, through Turkey, Switzerland, and Denmark to US, in part by a Canadian firm and its offshore affiliates => The extent of harm to patients is unknown. Substandard heart medicine More than 125 people died in Pakistan of bone marrow suppression after a public cardiology pharmacy provided generic isosorbide-5- mononitrate tablets adulterated with a toxic overdose of pyrimethamine, an antimalarial drug. Result of a manufacturing error, although police allege that company, officials learnt of the error and sold the medicine anyway. If the allegation proves true, the medicine would be reclassified as falsified. BMJ | 24 NOVEMBER 2012 | VOLUME 345 No countries remain untouched by this issue Examples of dangerously compromised medicines in 2011-12 Once the problem was discovered, MSF followed-up about 3000 patients with proper medicines and counselling.

No countries remain untouched by this issue

3. EU laws on falsified medicines Directive 2001/83/EC of the European Parliament and of the Council lays down the rules for, inter alia, manufacturing, importing, placing on the market, and the wholesale distribution of medicinal products in the Union as well as rules relating to active substances. Directive 2001/83/EC should be amended in order to respond to this increasing threat.  EC: Directive 2011/62/EU of the european parliament and of the council of 8 june 2011 In May 2011, the European Council adopted a new Directive aimed at guaranteeing a high level of protection for public health against falsified medicinal products

Directive 2011/62/EU The Directive came into force on 21 July 2011. Member States had to start applying its measures in January 2013. This Directive aims to prevent falsified medicines entering the legal supply chain and reaching patients. It introduces harmonised safety and strengthened control measures across Europe by applying new measures By means of harmonized measures of controls and security at the borders and within the European Union, the Directive will make it possible to facilitate detection of falsified medicinal products, improve the quality of verifications and controls of the chain of production and distribution in order, in the end, to avoid introduction of falsified products into the legal chain of medicines. It also includes new requirements to be met by online pharmacies, and this in order to counter the illegal sale of medicines through the Internet.

First Definition ! Falsified medicines Counterfeit medicines fake medicines that are designed to mimic real medicines medicines that do not comply with intellectual- property rights or that infringe trademark law Licit medicines containing unintentional defects of quality attributable to errors of manufacturing or distribution FIRST DEFINITION OF FALSIFIED MEDICINAL PRODUCT Directive 2011/62/EU provides a first definition of falsified medicinal product and distinguishes clearly between the following: A definition of ‘falsified medicinal product’ should be introduced in order to clearly distinguish falsified medicinal products from other illegal medicinal products, as well as from products infringing intellectual property rights. The notion of falsified medicinal product is thus released from intellectual property in order to focus on the false medicine and its dangers for public health First Definition !

1. AFFIXING OF SECURITY AND TRACEABILITY DEVICES Verify authenticity and identification of individual boxes of medicines Verify whether the outer packaging has been violated The Directive provides for affixing devices for security and inviolability On 9 February 2016, the European Commission published a delegated regulation (Commission Delegated Regulation (EU) 2016/161): safety features to be placed on the packaging of most human medicines: a unique identifier (a 2-dimension barcode) and an anti-tampering device. The annexes of the regulation: list of medicines subject to the new requirement Application: no later than 9 February 2019 In order to verify the authenticity and identification of individual boxes of medicines and to verify whether the outer packaging has been violated, the Directive provides for affixing devices for security and inviolability. The obligation to affix these security devices on the packaging applies to all medicines delivered on prescription, barring exceptions (in cases in which evaluation makes it possible to demonstrate the innocuousness of the product in question Marketing authorisation holders must place these on the packaging of most prescription medicines and certain non-prescription medicines EMA and the European Commission have prepared an implementation plan, including regulatory requirements and timelines, to guide applicants and marketing authorisation holders of centrally authorised medicines in meeting the requirements:

2. IMPROVED CONTROL OF THE DISTRIBUTION CHAIN New requirements for improving the distribution chain New player: the broker who takes part in transactions but without entering into physical contact with the medicines. Directive: new responsibilities for wholesalers , definition of brokering activities as well as new responsibilities for brokers Agency: revision of good-distribution-practice guideline (2013/C 68/01) => specific provisions for brokering activities The EudraGMDP database now also includes information on good distribution practice (GDP). The Directive lays down rticle 111(6) of Directive 2001/83/EC and article 80(6) of Directive 2001/82/EC

3. NEW REQUIREMENTS CONCERNING RAW MATERIALS AND EXCIPIENTS Upgrading the requirements on verifications applicable to the manufacturers of medicines  guaranteeing their authenticity and quality From July 2013, all active substances manufactured outside the EU and imported into the EU have had to be accompanied by a written confirmation from the regulatory authority of the exporting country. The Directive provides for improving the quality of the supply, manufacturing and distribution of raw materials. The new provisions for verifying quality, which also concern operators outside the European Union, apply to active substances as well as to excipients. These measures are aimed at guaranteeing their authenticity and quality: Upgrading the requirements on verifications applicable to the manufacturers of medicines: manufacturers are required to ensure: that European manufacturers, importers or distributors of the active substances used are registered with the competent authority of the member State in which they are established; that, through audits, the active substances used have been manufactured and distributed in keeping with the good manufacturing and distribution practices. Exporting countries with an 'equivalent' regulatory framework will not need to issue these written confirmations. The European Commission, together with the Agency and Member States, is assessing the regulatory frameworks of countries applying for 'equivalent' status

Statements isued /manufacturing site /active substance NEW REQUIREMENTS CONCERNING RAW MATERIALS AND EXCIPIENTS Statements isued /manufacturing site /active substance ensure that standards of good manufacurting practice (GMP) equivalent to those in force in the EU are upheld. Regular controls, repeated and unexpected inspections during which certificates of good practices for active substances can be issued The Directive provides for improving the quality of the supply, manufacturing and distribution of raw materials. The new provisions for verifying quality, which also concern operators outside the European Union, apply to active substances as well as to excipients. These measures are aimed at guaranteeing their authenticity and quality: Upgrading the requirements on verifications applicable to the manufacturers of medicines: manufacturers are required to ensure: that European manufacturers, importers or distributors of the active substances used are registered with the competent authority of the member State in which they are established; that, through audits, the active substances used have been manufactured and distributed in keeping with the good manufacturing and distribution practices. Exporting countries with an 'equivalent' regulatory framework will not need to issue these written confirmations. The European Commission, together with the Agency and Member States, is assessing the regulatory frameworks of countries applying for 'equivalent' status

4. CONTROL AND HARMONISATION OF THE SALE OF MEDICINES ONLINE at any given moment, over 400 criminal websites with a .eu suffix, are online, targeting and selling falsified medicines into the EU Falsified medicines may reach the public in this way The Directive includes the minimal conditions to be met by online pharmacies to be authorized so as to engage in distance selling Counter the illegal sale of medicines to the public through the Internet The illegal sale of medicinal products to the public via the Internet is an important threat to public health as falsified medicinal products may reach the public in this way. In order to Benefiting from authorization or approval to deliver medicines to the public, including from afar, in application of the national legislation of the country in which the natural person or the legal entity is established; Notifying information on the online pharmacy to the competent authorities of the member State (address of the Internet site, name and permanent address of the place of business from which the medicines are supplied, etc.); Conformity of the medicines with the national legislation of the Member State to which they are destined; Specifying on the Internet site the contact data of the competent authority; Adding a hypertext link to the website of the Member State New requirements to be met by online pharmacies, and this in order to counter the illegal sale of medicines through the Internet

Since July 2014: Obligatory logo that will appear on the websites of legally operating online pharmacies and approved retailers in the EU. Link to the national regulatory authority websites, where all legally operating online pharmacies and approved retailers in their respective countries will be listed.  Member States: conduct campaigns to raise awareness of the logo and the dangers of falsified medicines . The Directive has introduced an Clicking on the logo will Common EU logo for online pharmacies/retailers The logo consists of three elements: 1 The pictogram(white cross with four green lines) 2 The national flag 3 The textual part hese objects should always be used together as one unit and may not be used separately. # The logo has to be regarded as an unchangeable symbol. It is not allowed to add any text, symbol, logos or other elements in the logo area.

Fight the Fakes is a campaign that aims to raise awareness about the dangers of fake medicines. The campaign gives a voice to those who have been personally impacted and shares the stories of those working to put a stop to this threat to public health. www.fightthefakes.org

4. Role of the EMA Cooperation+ EC + Member States Implement the Directive 2011/62/EU European Directorate for the Quality of Medicines and Healthcare (EDQM) and the World Health Organization's International Medical Products Anti-Counterfeiting Taskforce (IMPACT). The Heads of Medicines Agencies have identified falsified medicines as being a key issue facing the European regulatory network for the five years to 2015. enforcement of this legislation is the competency of Member States But: coordination between the national and international bodies involved in fighting falsified medicines is necessary The Agency is working closely with the European Commission and the EU Member States to They have stressed that

Role of the EMA A strategy for the Heads of Medicines Agencies, 2011-15 The Agency is also cooperating with international anti-counterfeiting trade agreements and other criminal-law instruments: the Council of Europe's Medicrime convention The Organisation for Economic Co-operation and Development (OECD) project on counterfeiting and piracy

Penalties for Falsifying Medicine « Effective, proportionate and dissuasive penalties » Penalties appropriate to a crime which puts public health at risk *Additional penalties and fines may be associated with specific infractions

And this does not of course take into account the human cost ! Conclusion The Falsified Medicines Directive will not stop this crimes What it will do – through the identification of medicines at the pack level, stricter regulation and stiffer penalties – => Traditional supply chain more secure => less attractive to the criminal. Identifying financial impact of falsified medicines across the EU: extremely difficult. *Peter Pitts (et al) : by 2010 the global trade in falsified medicines would reach $75bn. And this does not of course take into account the human cost ! EMA: working closely with its partners on the implementation of these law  Making progress but a long road to travel However, it would be foolhardy to believe that the criminal will move on to another sector. across the EU (let alone the globe) International criminal gangs do not file their annual returns Identifying accurately

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