New Tracers: rules in Europe Stefano Fanti Arturo Chiti

EUROPEAN LEGISLATION ON PHARMACEUTICALS The European process of regulatory harmonization in the pharmaceutical industry began in 1965 with the adoption of Directive 65/65/EEC, with the ultimate objective to ensure the quality of scientific assessments preceding the marketing of medicinal products and to allow quick access of innovative medicines to market. With regard to pharmaceuticals, the legislation shall govern the aspects related to the protection of public health and the free movement of goods (marketing authorization, clinical trials, pharmacovigilance, etc...). The European Union does not rule aspects such as price and reimbursement, covered by the national laws regulating the health policy of Member States, but it requires demonstration of quality, safety and efficacy for all medicines, also for diagnostic medicines as if they were to obtain a certain expected effect: a diagnosis (which of course is instead the result of converging laboratory data and clinical information) Lucignani and De Cristoforo, EANM

The Rules governing medicinal products in the European Union EUROPEAN LEGISLATION ON PHARMACEUTICALS The Rules governing medicinal products in the European Union The core of the European pharmaceutical legislative framework is contained in The Rules governing medicinal products in the European Union, published by the European Commission to regulate the sector of medicinal products for human and veterinary use. The body of legislation in the pharmaceutical sector is compiled in Volume 1 - EU pharmaceutical legislation for medicinal products for human use Volume 5 - EU pharmaceutical legislation for medicinal products for veterinary use The basic legislation is supported by a series of guidelines that are also published in the volumes of "The rules governing medicinal products in the European Union": Lucignani and De Cristoforo, EANM

Radiopharmaceuticals preparation and use in Europe INDUSTRIALLY PRODUCED AND MARKETED Ready-to-use licensed RPh RPh prepared just before use in the nuclear medicine department using licensed labelling kits and eluate of a licensed 99mTc generator EXTEMPORANEOUS PRODUCTION Magistral Preparations Officinal Preparations INVESTIGATIONAL PRODUCTS Under provision of different European directives Clinical trials (EU Directive) Lucignani and De Cristoforo, EANM

Radiopharmaceuticals preparation and use in Europe Marketing of a radiopharmaceutical is subject to the authorization of the medicinal products, based on what is required by Title III and IV of the Community Code, which expressly requires that Regulatory Agencies grant marketing authorization after evaluation of quality, safety and efficacy and that industrial production of any product be in accordance with GMP Directive 2001/83/EC does not require the MA for radiopharmaceuticals (final product administered to patient) prepared according to the manufacturer's instructions, by persons or establishments and health-care services authorized to use such medicines and provided that the radiopharmaceutical is prepared from generators, kits or precursor radiopharmaceuticals duly authorized (art. 7). Lucignani and De Cristoforo, EANM

MAGISTRAL PREPARATIONS EXTEMPORANEOUS PRODUCTION OF PET RP IS REGULATED BY BINDING GUIDELINES AND EUROPEAN PHARMACOPOEA MAGISTRAL PREPARATIONS Medicinal product prepared in the (radio)pharmacy in accordance with a prescription issued by a health care professional for a specific patient or on a request by a medicinal institution OFFICINAL PREPARATIONS Medicinal product prepared in the (radio)pharmacy in accordance with the Pharmacopoeia monographs (European pharmacopoeia or national pharmacopoeias in force in EU Member States) Lucignani and De Cristoforo, EANM

PET RP ARE EXCLUDED FROM THE SCOPE OF THE EU LEGISLATION DIRECTIVE 2001/83/EC AND ARE REGULATED BY NATIONAL LAWS The majority of PET RP for clinical practice or for experimental use is usually prepared just before use in healthcare facilities for logistic reasons The preparation of radiopharmaceuticals as formula magistralis and formula officinalis, not covered under the Directive 2001/83/EC, is under the responsibility of individual Member States legislation. Lucignani and De Cristoforo, EANM

FOR NON INDUSTRIAL PRODUCTS THE ACHIEVEMENT OF UNIFORMITY OF LAWS AND HARMONIZATION ACROSS MEMBER STATES IS STILL ONLY PARTIALLY ACHIEVED The reasons for lack of uniformity, and difficulties to overcome it, are diverse: Lack of regulations EXCEPT in the form of guidelines Different areas of competence of the various Directorates of the European Commission The different regulatory “power” of the decisions adopted at the European level Issues relating to radiation protection are not regulated by the European Commission but by Euratom. (specific of RP) The differences in the adoption of Directives and enforcement of Directives in Member States Lucignani and De Cristoforo, EANM

Lucignani and De Cristoforo, EANM GREAT NATIONAL DIFFERENCES HAVE BEEN IDENTIFIED IN THESE POINTS - 2012 Q1: Under which conditions can radiopharmaceuticals be administered if they have no marketing authorization and are prepared locally? Regulatory core Country Regulation reference / Guideline Remarks Based on individual patient prescription (“magistral”) Austria Arzneimittelgesetz Magistral preparation only strictly related to pharmacy practice, practically handled outside pharmacy Based on a Pharmacopeia Monograph (“officinal”) Italy   Also for “Experimental” Radiopharmaceuticals Other regulation Germany: For diagnostic application <20/week AmRadV Only based on Marketing authorization or Clinical Trial authorization France No magistral preparation of radiopharmaceuticals allowed Spain Magistral/officinal approach not allowed for parenteral preparations The Netherlands Marketing authorization required for PET radiopharmaceuticals (since 2011) Lucignani and De Cristoforo, EANM

Lucignani and De Cristoforo, EANM GREAT NATIONAL DIFFERENCES HAVE BEEN IDENTIFIED IN THESE POINTS - 2012 GREAT NATIONAL DIFFERENCES HAVE BEEN IDENTIFIED IN THESE POINTS - 2012 Q2: Who can be responsible for local preparation of radiopharmaceuticals without marketing authorization Regulatory core Country Regulation reference / Guideline Remarks Responsible physician Germany   Austria Radiopharmacist France Belgium Pharmacist / hospital pharmacy The Netherlands Supervision of Hospital Pharmacist Specifically authorized institution / QP UK “Special” Licence QP required for (most) PET centers particularly for Clinical Trials Lucignani and De Cristoforo, EANM

Not explicitly specified GREAT NATIONAL DIFFERENCES HAVE BEEN IDENTIFIED IN THESE POINTS - 2012 GREAT NATIONAL DIFFERENCES HAVE BEEN IDENTIFIED IN THESE POINTS - 2012 Q3: Under which conditions can radiopharmaceuticals be prepared locally Full GMP Germany AmRadV Since Mid 2011 Special recommendations in ZLG Memoire 07120801   UK “Special” GMP Italy Monograph in Pharmacopeia Switzerland Guideline of National Society Not explicitly specified Austria Lucignani and De Cristoforo, EANM Lucignani and De Cristoforo, EANM

I. Peñuelas SNMMI’15 Penuelas, SNM 2015 Penuelas, SNMMI 2015

Main changes introduced by Regulation 536/2014 I. Peñuelas SNMMI’15 Repeals Directive 2001/20 (the Clinical Trial Directive) Being a Regulation, it ensures that the rules for conducting clinical trials are identical throughout the EU A straightforward authorisation procedure allowing for: a fast and thorough assessment of the application by all Member States concerned resulting in one single assessment outcome. Simplified reporting procedures researchers no longer have to submit largely identical information to various bodies and Member States. The possibility for the Commission to conduct controls in EU countries and third countries to make sure the rules are being properly supervised and enforced Penuelas, SNM 2015

Penuelas, SNM 2015 Penuelas, SNMMI 2015

Entry into force and applicability I. Peñuelas SNMMI’15 Regulation entered into force on 16 June 2014 It WILL NOT be applicable at least until 28 May 2016 It will ONLY be APPLICABLE as from six months after “EU portal” is approved The Regulation shall be binding in its entirety and directly applicable in all Member States Penuelas, SNM 2015 Penuelas, SNMMI 2015

EANM Position Statement on Radiopharmaceutical Production for Clinical Trials Radiopharmaceuticals are classified as medicinal products and their production, indications and use are regulated accordingly. In European countries, the European Commission has issued European directives setting normative standards on this subject, while the European Medicines Agency (EMA) is in charge of the review and approval of marketing authorisation applications. In every single EU member state there is also national legislation on medicinal products that refers to the EU directives and in some instances to regulations issued by the national competent authorities. Despite their shared references to the relevant EU directives, national regulations are not exactly equivalent to each other.

EANM Position Statement on Radiopharmaceutical Production for Clinical Trials With the intention of overcoming the general negative effects that derived from the old Directive 2001/20 concerning clinical trials, on 27 May 2014 the European Commission issued a new regulation (No. 536/2014). Since a “regulation” of the EU is to be adopted as national law without any changes, it is more stringent than a “directive”, which requires transposition into the national body of laws. Within this new clinical trial regulation, there are three relevant points regarding the preparation of radiopharmaceuticals for clinical trials:

EANM Position Statement on Radiopharmaceutical Production for Clinical Trials Authorisation is no longer needed for the manufacture of diagnostic investigational radiopharmaceuticals for use in hospitals taking part in the same clinical trial based in the same EU member state. GMP production according to EudraLex 4 is no longer required for diagnostic radiopharmaceuticals even in the case of investigational medicinal products (IMPs), but can still be imposed by local (national) regulations. Simplified labelling of the primary packaging is allowed, solving the issue of the need to provide too much information on the primary packaging label. The regulation is applicable only to diagnostic IMPs and non-IMPs; therapeutic IMPs and non-IMPs are excluded.

EANM Position Statement on Radiopharmaceutical Production for Clinical Trials On the basis of a recent survey conducted by the EANM in various European countries (Spain, Italy, United Kingdom, France, Germany, the Netherlands, Belgium), it can be concluded that there are still differences between countries regarding the requirement for GMP.

GMP requirements for radiopharmaceutical production for clinical trials in Europe     IMP No IMP Diagnostic Therapy Profit No profit Public Private Spain Yes Italy No n/a UK France Germany The Netherlands Belgium

EANM Position Statement on Radiopharmaceutical Production for Clinical Trials Nuclear medicine departments are involved in clinical trials on both diagnostic and therapeutic radiopharmaceuticals, and there is an emerging and growing demand for new radiopharmaceuticals. This is particularly true for radiopharmaceuticals with short half-lives that are suitable for use with positron emission tomography scanners. However, the fact that not all clinical centres in Europe are qualified for GMP preparation seriously limits the use of such radiopharmaceuticals. Correct implementation of Regulation 536/2014 could partially overcome this hurdle, at least for diagnostic radiopharmaceuticals to be employed in clinical trials.

PET radiopharmaceuticals in clinical use, 2017 11C-acetate European Pharmacopeia 11C-choline Draft European Pharmacopeia 18F-fluoromethilcholine Marketing authorization 18F-fluciclovine 68Ga-PSMA European Pharmacopeia in preparation

PET radiopharmaceuticals in 2017