JUNE 2002 JUNE

T RANSLATED FROM LA REVUE P RESCRIRE Reorienting European Policy

Background for human use are changed to suit the best interests of industry. European regulations on medicinal Its overriding objective is to make the products, adopted during the 1960s and European market even more permissive, 1970s, have had a major positive impact with permanent marketing authorisations in European Member States. In particular, granted more rapidly and more easily, they have obliged national policy-makers with no need to show therapeutic to create effective drug control and moni- advance; no regular postmarketing reap- toring infrastructures designed to improve praisal of the risk-benefit ratio; no care quality and , and explanation of EMEA decisions; no com- also to stimulate healthy competition parative assessments on which to fix among drug manufacturers. prices more reasonably; and direct-to- The European Medicines Evaluation consumer advertising of prescription-only Agency (EMEA) was created in response drugs under the guise of "information". to the call for greater European integra- We are publishing a series of documents Contents tion. More resources and more indepen- and reviews on current European phar- dence were expected to bring greater maceutical policy, aimed at helping indi- •Background ...... 1 transparency and harmonisation. vidual citizens and policy-makers to reach •A call to national and European policy-makers ...... 2-3 But, discreetly, by a thousand cuts, well-founded conclusions. EMEA has been driven away from its pri- Among these papers you’ll find a •Editorial: A free hand ...... 4 mary mission as a safeguard of European detailed description of the European • citizens’ health. The pharmaceutical Medicines Evaluation Agency (EMEA) is now decided at the European level ...... 5-7 industry now has its foot firmly in the website, notably underlining its fake door. •European pharmaceutical transparency. policy is turning its back Strangely, EMEA is part of the We offer a description of the instru- on public health ...... 8-10 Enterprise Directorate General rather than ments and institutions of European •An industry-serving the Health and Consumer Protection pharmaceutical policy, and a review of the pharmaceutical policy .....11-13 Directorate of the European Commission. current activity of EMEA, the cornerstone •Towards a medicines policy It now receives most of its funds directly of the system. We identify a number of that supports basic public from the drug companies. The administra- strong points and institutions that should health needs ...... 14-15 tive open door known as the mutual be maintained, but we also identify strate- •Internet ...... 16-20 recognition procedure has been institu- - Drugs agencies have a duty to gies that are being used to drive the inform tionalised and a shroud of secrecy has system away from its primary objective: - EMEA: fake transparency descended. The European pharmacovigi- public health. - FDA: an example of transparency lance system has not fully materialised, We also report on the proposals of - FDA MedWatch and most of the data obtained in this field Directive and Regulation of the European President: Jacques Juillard have remained in a black box. Commission Enterprise Directorate (on Ever more pressing, the pharmaceutical behalf of a pharmaceutical lobby group), Address: Prescrire International lobby, supported (and sometimes preced- and the positions of various patient and BP 459 – ed) by the Enterprise Directorate, has consumer organisations and professional (F) 75527 Paris Cedex 11 been making strenuous efforts to ensure bodies. E-mail: [email protected] Website: www.prescrire.org that the European Directive on medicines ©PI

P RESCRIRE I NTERNATIONAL - E UROPEAN M EDICINES P OLICY • 1 A CALL TO NATIONAL AND EUROPEAN POLICY-MAKERS Putting european drugs policy back on tracks

It is vital to restore European pharmaceutical policy to its rightful public health context, for the individual and collective benefit of European citizens, by restoring independence and transparency throughout the system. If the is to remain dynamic and efficient in the long term, it must be actively re-directed towards true public health needs and therapeutic advance, both in Europe and throughout the world. We call on members of the European Parliament, ministers of the Council of Europe, and European Commissioners to reconsider the policies outlined in the draft Directive and Regulation on medicinal drugs prepared by the European Commission’s Enterprise Directorate. In the interests of public health, we call them to adopt new priorities.

Our demands are the following: Free access to scientific data. Drug-related matters must not be an exception to the obligation of transparency in national and Public health before industry. being a cor- European institutions. Indeed, this information is required to nerstone of any , national and European regulatory ensure optimal use of drug prescribed to European citizens. bodies charged with authorising new drugs and postmarketing It is also a moral duty to render public the results of clinical surveillance must be directly accountable to national and EU research in which thousands of citizens volunteer to participate. health authorities. Thus, Thus, • National and European medicines agencies must be re- • European Union health ministers, and not industry organised to ensure that the public and health profession- ministers, must, in conjunction with the European als have access to detailed and referenced reports of the Parliament, decide European pharmaceutical policy and scientific information on which their decisions are based, all relevant Directives and Regulations; whether positive or negative. This must apply not only to • The European Medicines Evaluation Agency (EMEA) national, centralised and mutual recognition procedures, must become part of the Health and Consumer Protection but also to postmarketing data (, com- Directorate General instead of the Enterprise Directorate parative studies of drug benefits, drug errors, etc.). General. Universal and strict centralised procedure. The mea- Financial independence. Given the massive economic sures taken since 1995 to harmonise and concentrate resources stakes, it is essential that the structures and personnel charged through the creation of the European Medicines Evaluation with drug registration and control be financially independent Agency (EMEA) and the European centralised marketing autho- from pharmaceutical companies. risation procedure must be continued and amplified. Thus, Thus, • The budgets of EC Member States and of the European • The mutual recognition procedure must be phased out Union itself must rapidly be increased to cover the full oper- as rapidly as possible, in favour of an efficient and trans- ating costs of national and European medicines agencies; parent centralised procedure for all drugs intended to be • Fees paid by drug companies for marketing applications marketed in more than one European Union Member must be attributed to Member State and EU coffers, and State; not directly to the medicines agencies concerned, in order • The European Medicines Evaluation Agency budget to avoid conflicts of interest; must be considerably increased, so that this cornerstone • These fees must be re-adjusted in such a way as to of European pharmaceutical policy has the means to ful- encourage manufacturers to choose the European cen- fil its responsibilities in terms of expertise, independence, tralised marketing procedure for products they wish to transparency and surveillance; sell throughout the European Union; • The time allocated to examine marketing applications • All conflicts of interest of agency personnel and out- (both national and European) must not be systematically side experts must be declared regularly, accessible on shortened. Agencies must have the time necessary for the Internet, and be taken into account in practice. thorough critical assessment of these applications, with

2 • P RESCRIRE I NTERNATIONAL - E UROPEAN M EDICINES P OLICY the overriding aim of protecting patients. This time should only be shortened in strictly defined situations involving Reference documents serious diseases for which no treatment is available; • Periodic re-examination of marketing authorisations, both national and European, must be strengthened and The following documents are essential for a thorough understan- actually applied. This re-assessment must focus not only ding of the current debate on European medicines policy. on efficacy and , but also on the overall value of individual drugs in light of new data and new thera- • “The ISDB Declaration on Therapeutic Advance in the Use of peutic options (drug and non drug). Medicines” Paris, 15-16 November 2001. The Declaration puts patients’ needs at the forefront, and separates real advance from Quality information for rational use. Rational drug use, mere “innovation”. especially the prevention of side effects and errors, Available in several languages on the ISDB website: www.isdbweb.org requires that citizens and health professionals be adequately informed. • “Helsinki Declaration: Ethical Principles for Medical Research Thus, Involving Human Subjects” World Medical Association 2000 edition. • National and European authorities must take all the News treatments must be assessed in comparison with reference necessary measures to ensure that European citizens and options (whenever available) rather than against placebo. health professionals have access to reliable information. Available on the ISDB website: www.isdbweb.org That means information independent of drug companies, well documented and referenced, comparative, and • “Uppsala Declaration: Statement of The International Working designed in transparent manner, on diseases and available group on Transparency and Accountability in Drug Regulation” treatments, together with preventive, diagnostic and (1996), by Health Action International and Dag Hammarskjöld screening tools, and their correct use; Swedish Foundation, Uppsala, 11-14 September 1996. How to tack- • International nonproprietary names rather than trade le obstacles to transparency and public control of official measures names must be adopted as the main identifiers involving medicines. throughout the European Union, by regulators, patients Available on the ISDB website: www.isdbweb.org and health professionals; • Drug companies must be strongly encouraged to • “Erice Declaration: On Communicating Drug Safety Information” improve the information in patient leaflets and on drug (1997), by (among other parties) the Uppsala Monitoring Centre on packaging; adverse drug reactions, under the aegis of the World Health • Drug advertising must be tightly regulated in all Organisation (WHO). What regulatory authorities should do to Member States: advertisements for non prescription drugs carry out their mission in terms of information to professionals and must be approved before their release; direct-to-consumer the public? advertising of prescription-only drugs must be banned; Available on the ISDB website: www.isdbweb.org advertisements targeting health professionals must be controlled retrospectively; and effective sanctions must be • “Penser et prescrire en DCI: une bonne pratique professionnelle” applied rapidly to all offenders. (la revue Prescrire n° 209);“Les médicaments génériques”. Prescribing and dispensing medicines under international nonproprietary names Transparency in drug cost. Drugs can serve a public-health (INN) or generic names is a first step towards rational use of drugs. oriented policy only if they are universally accessible and if their Available in French only, on request. prices are compatible with health budgets. Thus, in order to deal with the current spectacular • “Prix des médicaments remboursables: quelle logique ?” la revue increase in drug prices, Prescrire n° 222 and 233. • National and European policy-makers must undertake Available in French only, on request. strict studies of drug production costs, and particularly the true cost of biomedical research and development; • The European Union, and its individual Member States, must create adequately funded bodies capable of sponsor- ing, co-ordinating and stimulating clinical research aimed at answering the numerous questions that are left pend- ing by industry-sponsored studies; • They must also create institutional structures designed to provide patients, health professionals, organisations paying for medicines with clear, synthetic, referenced, up- to-date comparative drug information on which to base rational choices among available therapeutic options.

Several years of sustained effort are required. ©PI

P RESCRIRE I NTERNATIONAL - E UROPEAN M EDICINES P OLICY • 3 Translated from Rev Prescr June 2002; 22 (229): 401

A free hand

In this supplement we review the performance of the European Medicines Evaluation Agency (EMEA), and the European drugs policy. Time is pressing, as draft Directive and Regulation will be submitted for adoption by the European Parliament and the Council. These drafts are prepared and sponsored by Enterprise Directorate of the European Commission, on which EMEA has so far depended. We believe, like many other independent observers, that EMEA’s performance is not that good. And things may get even worse over the next seven years if the current drafts, which are supported by a pow- erful industrial lobby, are adopted. Some hold that the European community is a technocratic juggernaut that disregards its own citizens' interests and stifles national vitality. We believe this is far from the truth. On the contrary, harmonisa- tion is an effective way of optimising scientific and human resources, and European institutions are not ill-designed and sclerotic, but open to public influence. Editorial The real problem is one of public apathy: who, apart from drug com- panies, is monitoring, and trying to influence, European pharmaceu- tical policy? So it is hardly surprising that this policy is increasingly industry- oriented, or that EMEA has been linked to Enterprise Directorate General (and not Health and Consumer Protection Directorate General), and receives most of its funds from industry (like most national medicines agencies). Medicines are now seen as simple goods serving the European economy, rather than as a cornerstone of citizens’ health. A "free market" policy that disregards public health regulations will be detrimental to European citizens. This trend is not inevitable. It is not too late to act. We can, and must, demand that change serves the public interest first and foremost. The pharmaceutical industry must not be given a free hand to ride roughshod over the rest of society. ©PI

4 • P RESCRIRE I NTERNATIONAL - E UROPEAN M EDICINES P OLICY Translated from Rev Prescr June 2002; 22 (229): 461-463 REORIENTING EUROPEAN MEDICINES POLICY

National marketing authorisation is granted by a national medicines agency, on the basis of an application file, after approval by the national licensing authorities. This form of authorisation is only valid in the country in which it is granted; European centralised marketing au- thorisation is granted by the European Commission, after examination of the file by the European Medicines Evaluation Agency (EMEA) and taking into account the opinion of the European Commission for Proprietary Medicinal Products (CPMP). This marketing authorisa- tion is valid in all EC Member States; Marketing authorisation by mutual recognition (also known as the decen- tralised procedure) is granted by national medicines agencies through recognition of marketing authorisa- tion initially granted by another Member State. This latter Member State is known as the Reference Member State (a), because it builds up the assessment report that is sub- mitted for recognition by other Member States. EMEA is kept informed of the procedure by the company, but the CPMP is only con- sulted when arbitration is required between Member States.

• EMEA (European Medicines Evaluation Agency). Created by a European Regulation in 1993, and in Pharmaceutical policy is now operation since 1995, EMEA is based in London. It co-ordinates the scien- decided at the European level tific resources provided by the differ- ent Member States for assessing and monitoring human and veterinary or about a decade now, phar- required to understand the new legal drugs. maceutical policy has been framework of the countries in which EMEA has no deciding power, but Fdecided and organised mainly we live and work. offers an “opinion” to other at the European level, within a con- First, a short glossary. text of international harmonisation. a- “Rapporteur country”, now called “Reference Some national responsibilities per- • Marketing authorisation. Member State”, i.e. the country which initially granted sist, but they are almost all governed Marketing authorisation allows a marketing authorisation within the mutual recogni- tion procedure should not be confused with “rappor- by rules that apply throughout the drug company to sell a proprietary teurs” and “co-rapporteurs”, who are CPMP members European Union. (industrially manufactured) drug. working within the framework of the centralised pro- Europe currently has three types of cedure. The latter are responsible for analysing drug A firm grasp of the functioning of assessment files on behalf of their CPMP colleagues. European institutions is therefore marketing authorisation: They act as members of a European expert Committee, not on behalf of their countries of origin.

P RESCRIRE I NTERNATIONAL - E UROPEAN M EDICINES P OLICY • 5 Distribution of roles within the European Union

• European Council: impetus and community treaties and decisions are Further information direction of general policies. Each enacted. It employs about 20 000 staff. European Communities. “Annuaire interinsti- Member State is represented by the head tutionnel – Qui fait quoi dans l’Union of government (or head of state) and min- • Advisory committees. The Européenne?” Office des publications offi- Economic and Social Committee, which cielles des Communautés européennes, ister for foreign affairs. Luxembourg 2002. Besides general informa- comprises three groups (employers, tion on EU institutions, this directory contains • European Parliament: shared leg- workers and miscellaneous activities), lists of all Members of Parliament and of the different institutions. All this information can islative power and budgetary power. has a consultative role. For example, it also be accessed via the Europa server of the The European Parliament has legislative organised a consultation on the drug reg- European Parliament (see below). power (in conjunction with the European ulation now undergoing discussion. The • Sauron JL “L’application du droit de l’Union Council), budgetary power and control Committee of the Regions, created with européenne en France” La Documentation power. It is composed of members of the the aim of bringing European institutions Française Collection Réflexe Europe, Paris European Parliament, who are elected by closer to the citizen and comprising local 2000: 135 pages. European citizens for 5-year terms of and regional representatives, also has a • The ABC of Community Law “Borchardt office. This is the only EC institution that consultative role. KD”– Fifth edition. European Communities 2000; European Commission, Directorate - meets and debates in public. General for Education and Culture - • Directives and Regulations. The Publications Unit, rue de la Loi - Wetstraat • European Council: shared legisla- scope of Directives and Regulations is 200, B-1049 Brussels (available in all EC lan- tive power. The Council (of ministers) of defined by article 249 of the European guages). Treaty: the European Union is also a legislative Website: body (in conjunction with the European « In order to carry out their task and in -European Parliament accordance with the provisions of this Treaty, http://www.europarl.eu.int (mostly in all EC Parliament). It includes one ministerial rep- languages). resentative from each Member State, and the European Parliament acting jointly with -European Union online its composition can vary according to the the Council, the Council and the Commission http://www.europa.eu.int/inst-fr.htm (mostly in all EC languages). issue in hand. Drug related matters can be shall make regulations and issue directives, discussed by ministers of health or indus- take decisions, make recommendations or try according to the decisions taken. deliver opinions. A regulation shall have general application. • European Commission: sole leg- It shall be binding in its entirety and directly islative initiative. The European applicable in all Member States. Commission is the only EC institution A directive shall be binding, as to the result with the right to propose new legislation. to be achieved, upon each Member State to It prepares legislation, in principle in keep- which it is addressed, but shall leave to the ing with the large directions laid down by national authorities the choice of form and the Council of the European Union. The methods. draft Directive and Regulation now being A decision shall be binding in its entirety discussed were prepared by the Enterprise upon those to whom it is addressed. Directorate General of the European Recommendations and opinions shall have Commission.The European Commission is no binding force. » also the European Community’s executive ©PI body, responsible for ensuring that

European institutions (mainly the • CPMP (Committee for Pro- groups on efficacy, safety, pharma- European Commission, which grants prietary Medicinal Products). covigilance, biotechnics, blood- or refuses marketing authorisation, The CPMP is one of EMEA’s consul- derived medicinal products, and and Member States for pharma- tative committees. The CPMP cur- phytotherapy, among others. In covigilance matters). rently comprises two experts from addition to EMEA, another commit- EMEA has a number of consulta- each Member State, chosen for their tee is now responsible for giving tive committees (mainly the CPMP) experience in drug assessment and opinions on orphan drugs and expert groups composed of appointed for a renewable period of (Committee for Orphan Medicinal members seconded by the different three years. These experts are scien- Products). Member States. tific experts, not political representa- In 2001, EMEA employed 208 tives of their countries of origin. • EPAR (European Public Asses- salaried staff (2002 estimate: 251), and The role of the CPMP is to offer an sment Report). EPARs are EMEA its budget was 65 866 000 euros (2002 opinion on drugs intended for publications on drugs that have been estimate: 70 547 000 euros), 69% of human use, through the centralised authorised through the centralised which came from taxes and fees paid procedure. It also arbitrates in procedure. They are supposed to by companies to have their marketing disputes over mutual recognition. reflect the assessment file submitted application files examined (1). The CPMP is assisted by working by the manufacturer, its analysis by

6 • P RESCRIRE I NTERNATIONAL - E UROPEAN M EDICINES P OLICY the CPMP, and the reasons underly- prescription (these elements are not evaluation will be reduced to ing the CPMP’s opinion. In fact, yet fully harmonised within the EU). the lowest common denomina- these brief documents have been tor. expurgated of all data considered • European marketing authori- Health professionals and patient confidential from a commercial or sation number. When a product is organisations have made virtually industrial point of view, and are granted European marketing autho- no contribution to this process, approved by the manufacturers con- risation through the centralised pro- which should be monitored closely cerned before being released to the cedure, the marketing authorisation (by consulting the website of a major public. number (which can be found, for medicines agency such as EMEA) EPARS relate only to marketing example, on the packaging or in the and opposed when necessary. authorisations granted through the SPC) is composed of the following ©PI centralised procedure. No assess- elements: ment report is available on products -the letters “EU”, for European 1- The European Agency for the Evaluation of that are refused marketing authori- Union; Medicinal Products “Work Programme 2002” 18 December 2001: 62 pages (“Annex 1 – sation. Similarly, none of the numer- -the number “1” or “2”, according to EMEA establishment plan 2000-2002” pages ous decisions taken through the whether the drug is designed for 42-43; “Annex 2 – EMEA budget summaries mutual recognition procedure give human use (“1”) or veterinary use 2000-2002” page 44). rise to EPARs. (“2”); -two figures corresponding to the • SPC (Summary of Product year of initial authorisation (95 for Characteristics). Attached to the 1995, etc.); marketing authorisation, these -three figures corresponding to an “identity cards” recap the state of identification number given to each knowledge on a drug when market- drug; ing authorisation is granted, and are -three figures for each product in the revised after each five-yearly re- range, corresponding to to its formu- appraisal of the assessment file. lation, dose strength and package Drafted by the manufacturers, contents. SPCs are submitted along with the For example, EU/1/97/031/044 marketing application. They are corresponds to the human drug finalised when marketing authorisa- NeoRecormon°, in injectable form, tion is granted, and are translated 6 000 IU per syringe, sold in boxes of (European marketing authorisation 6 syringes, and authorised in 1997 only) into the different languages of through the European centralised the European Union. procedure. The SPC is written according to a standard layout. Further information • ICH (International Confe- can be added throughout the life- rence on Harmonisation for time of a drug, such as warnings on technical requirements of regis- side effects that were not identified tration of pharmaceuticals for during the initial assessment phase. human use). The ICH process was The SPC contains the information launched in 1990, driven by the reg- that companies must mention on all ulatory authorities and pharmaceuti- advertising aimed at health profes- cal industries of the United States, sionals (such as brochures, adverts, Europe and Japan. Further information Key information on European pharmaceutical and monographs in a datasheet com- The aim is to harmonise marketing regulation can be obtained from the following pendium). authorisation procedures by adopt- sources: Another annex to the marketing ing common recommendations for • History of the construction of European drug authorisation (now called Annex III) drug evaluation and similar adminis- legislation: Campion G “Clefs pour l’Europe du sums up the information contained trative procedures. médicament” Éditions de Santé, Paris 1996: in the SPC in plain language. This Through international conferences 251 pages. annex forms the basis for compulso- held every two years, and especially • Current EC drug regulations; definitions, concepts, and list of current texts: Brunet P ry information in the patient leaflet. the work of a 14-member committee “Dictionnary of the main reference terms – supported by industrial and adminis- Pharmaceutical law in the European Union” • Blue box. This is the informa- trative experts, ICH has seen more Éditions de Santé, Paris 1999: 236 pages. tion box, surrounded by a blue line than a hundred common recom- • Marketing authorisation procedures in theo- that figures on the packaging of mendations adopted by pharmaceu- ry and practice: “La réglementation des médicaments dans l’Union Européenne – preparations approved through the tical firms and medicines agencies Volume 2A. Avis aux demandeurs – Médica- centralised procedure. It carries This rapid harmonisation is wel- ments à usage humain” Office des publications information specific to Member come because it saves time and officielles des Communautés européennes States where the product is market- money (for example, fewer redun- 1998: 175 pages. ed. This includes the drug’s legal sta- dant clinical trials and animal stud- • Current European texts (Directives and Regulations) and proposed amendments to tus (e.g. classificaton of controlled ies). However, there is also a risk that these texts: European Union website substance) and any restrictions on its international requirements for drug http://europa.eu.int/eur-lex

P RESCRIRE I NTERNATIONAL - E UROPEAN M EDICINES P OLICY • 7 Translated from Rev Prescr June 2002; 22 (229): 464-466 European pharmaceutical policy is turning its back on public health

t is on the basis of its practical These documents, which include and analysis of the European regula- impact at the Member-State and about ten pages of useful scientific tory system published by two British Ipan-European levels that current data, were supposed to be written by researchers provides food for European pharmaceutical policy EMEA then released to the public thought during the run-up to the should be judged. and updated regularly. submission of the draft Directive and Is the policy transparent? Is it part Independent European drug bul- Regulation for approval by the of a coherent overall public health letins belonging to ISDB (the Interna- European Parliament (e)(12). policy? Does it aim to strengthen the tional Society of Drug Bulletins) ini- John Abraham, a sociology profes- responsibilities and roles of the dif- tially praised this initiative, and pro- sor and head of the Centre for ferent players (patients, health pro- posed ways of further improving to Research in Health and Medicine at fessionals, regulators and manufac- the EMEA (9). the University of Sussex, and Graham turers)? Following the deteriorating quality Lewis, a consultant in international Readers of la revue Prescrire find of EPARs, the European ISDB group drug regulations, examined, between answers to these questions in each published a detailed study of nine 1994 and 1999, European bodies issue of the journal, and especially in consecutive EPARs (September 1996 handling medicines-related matters, our year-end reports. We have often to August 1997), which it then together with the role of individual criticised the French medicines extended to cover all EPARs pub- member states. authorities for their administrative lished in 1999 and 2000. These stud- Their work, funded principally by secrecy, the secrecy of postmarketing ies compared the information distrib- the British Council for Social and studies, and the weaknesses of their uted by EMEA and that collated by Economic Research, was based on drug pricing policy. ISDB members. The results were interviews with staff in about fifty At the European level, our readers very negative: the EPARs were not industrial organisations and adminis- will have noted that: harmonised, reliable or correctly trative bodies in European Member – centralised marketing authorisa- updated (10,11). States (especially Germany, the tion does not always mean therapeu- The Prescrire staff that analyses the United Kingdom and Sweden – tic advance (1-3); files of new drugs considers that countries with strong pharmaceuti- – the European Medicines Evaluation things have now got even worse. cal industries), and on the numerous Agency (EMEA) is financially depen- EMEA has no documentary resources published and unpublished docu- dent on fees paid by pharmaceutical independent of drug companies (c). ments they were able to gather. firms to balance its budget (a)(4); In many cases, analysis of EPARs sug- The authors first recall the econom- – EMEA, as illustrated by its website, gests that these documents are totally ic, sociological and political context in is lacking transparency towards citi- or mainly written by the firms them- which the European pharmaceutical zens and health professionals alike (5); selves, or edited by copying and past- system was build up. They then – current European regulations hin- ing from the firm's application (d). describe its functioning, illustrated by der effective price controls on drugs Too many EPARs are vague or even a number of examples. They con- at the member-state level (6,7). inconsistent. In addition, irregular We are not the only organisation publication of their updates on the to denounce the current inadequa- EMEA website means that their value cies of national and European mea- is highly uneven (5). a- In 2002, the industrial contribution to the EMEA EPAR are only released for drugs budget rose to 69.46% (ref 14) from 53% in 1998 (ref 4). sures driving pharmaceutical policy b- The transparency principle figures in the away from its initial objectives. Here authorised through the centralised Citizenship Chapter of the Charter, in articles 41 are three other examples. procedure, yet the bulk of products are (Right to a good administration) and 42 (Right of access to documents) (ref 8). A Regulation on access to approved through the totally secretive documents, adopted in 2001, came into effect on 3 and increasingly popular mutual December 2001, and provides for application of the ISDB: minimal agencies recognition procedure, which gives transparency principle (ref 15). c- It must be stressed that EMEA is not the only med- rise to no usable centralised informa- icines agency in this position. For example, the French At its creation, EMEA undertook tion. Hardly any national agencies agency for health product safety does not have solid to guarantee transparency, in the make public the results of their evalu- industry-independent documentary resources that it same way as all other European can use systematically to analyse both the literature ation, even when they operate as rap- (including independent journals) and the conclusions institutions, in line with the spirit of porteur (the Netherlands recently of other drugs agencies worldwide. the Charter of Fundamental Rights introduced a few exceptions). d- According to EMEA internal procedures, EPARs of the European Union (b)(8). are sent to the firms concerned, for their opinion, before publication. We recommend that EMEA states EMEA made systematic publication how and by whom EPARs are actually written, and of public assessment reports (EPARs) Worrisome results of an inde- who gives the pass for press. on drugs authorised through the pendent survey e- A 243-page textbook with more than 400 refer- ences reports the results of this work, and represents a centralised procedure the corner- major source of information on European drugs poli- stone of its communication policy. The results of a 5-year follow up cy (ref 12).

8 • P RESCRIRE I NTERNATIONAL - E UROPEAN M EDICINES P OLICY Quoted from: The Lancet – Volume 358, Number 9275 – 07 July 2001 This point is made in several guidelines, including the E10 document CPMP members’ standpoint of the International Conference for Harmonisation last year, that medicines should be tested against comparative EMEA under DG health way to develop a drug, to decide on drugs rather than placebos. These guide- control. “EMEA is located in an indus- approval of that drug, and, in appeal lines generated a strong reaction from the trial institution of the European cases, to decide on approval for a second European Federation of Pharmaceutical Commission (initially called Directorate time. Scientific advice should not be a sys- Industries and Associations, which stated General [DG] III, now called DG tematic activity, and should be given that for legal, scientific, and public-health Enterprise) despite the fact that its mis- more on the CPMP's initiative than at reasons "quality, safety, and efficacy must sion is "to promote the protection of the request of companies. If the CPMP remain the only criteria to assess the appli- human health … and of consumers of were to give a negative opinion on a cations for marketing autorisation (…)". medicinal products". Public health drug, it should not be able to change its Few therapeutic areas and indications should be the fundamental concern of opinion on the same dossier within a exist, besides rare diseases, for which EMEA because it is the final outcome of mere 120 days. Appeals should only be there is no treatment; in these cases only improved availability of medicines (…). possible for serious reasons, such as delib- must placebo be used rather than an If public health issues were paramount, erate misuse of information in the dossier. active comparative drug (…)”. EMEA approval of new drugs would The appeal should be judged by an inde- Drug cost overlooked. “Despite depend on their benefit to patients, and pendent group of experts who come from regular appeals to take economic aspects would be granted only for well defined outside the CPMP. into consideration and contain health- indications after extensive research (…)”. Assessment of the dossiers could also be care costs, the CPMP works in an ideal For a financially independent improved. One of the two CPMP rappor- world in which there are no financial EMEA. “Financial support for EMEA teurs is normally suggested by the compa- limits on new drugs (…)”. comes from two sources: a European ny. This situation is difficult to condone. SPCs are not comparative. Community grant, and the fees EMEA A company would be unlikely to select its “However, in these summaries, drugs are charges industry for the assessment of rapporteur from CPMP members who described as if they were the only ones on dossiers and other services. EMEA is forced are thought to be critical (…). In addi- the market; comparisons should be made to compete with national agencies for these tion, a report by an independent expert is with other drugs with a similar mecha- fees, because – apart from biotechnology a required part of the dossier.3 In prac- nism of action that are available for the products – industry can apply to these tice, these "neutral" experts tend to extol same indications (…). Distribution of the agencies via the decentralised procedure, the virtues of the new drug rather than summary among should be and hope to obtain approval with greater give a balanced view of its pros and cons. done by national authorities (…)”. ease than through the EMEA. To elimi- A summary of the dossier prepared by the Lack of Transparency. “Informa- nate this conflict, all applications for the company would be a less hypocritical doc- tion on withdrawn applications is confiden- European market should be made to one ument (…). tial, and no data are made public. Public agency, the EMEA. Industry can stop the procedure several health interests would be served by publica- EMEA should be allowed to do its own times, for several months if required, but tion of such data. Therefore, either no with- research (or to contract research out to the CPMP must follow a rigid schedule. drawal should be allowed after prelimi- third parties) to confirm or disprove data The CPMP should be allowed equal flex- nary assessment, or the essential character- reported by industry. EMEA should also ibility in the timing of the assessment istics of any drug whose application has be equipped to deal with pharmacovigi- process”. been withdrawn should be reported (…). lance, to review drug use, and to make Comparative assessments are If a drug is not approved or rejected active investigations rather than relying lacking. “European Union legislation unanimously, the minority view is lost on spontaneous reports and secondhand repeatedly states that drugs should be along the route to making the commit- data. assessed for their quality, efficacy, and tee's opinion on the drug public. Reports Europe should acknowledge the need safety. However, this statement has been of all views in all documents, including for the EMEA to take on these new roles, interpreted and acted on as if each drug the summary of product characteristics and supply the substantial investment were to be made available in a therapeu- and the EPAR (European Public that they would require. EMEA is still tic vacuum. Industry has determined that Assessment Report) would enable people much smaller than the US Food and once quality is acceptable, efficacy is sug- to make up their own minds. Although Drug Administration, although it covers gested even if not shown, and safety rais- votes are needed to reach a decision at the almost double the population of its es no serious concerns – any drug should regulatory level, the majority decision transatlantic cousin. If the European be allowed on the market. The apparent does not necessarily represent the truth”. Community's grant were adequate, fees aim of industry is to produce a European Mutual recognition too lax. paid to EMEA by industry would be a catalogue from which physicians, or even “The decentralised system seems to con- small proportion of its income, and allow in some cases patients, can select which tribute more to the free movement of phar- the agency to be free and independent”. medicine to use, and national health ser- maceutical products in the European Experts must be independent, vices can select drugs to be reimbursed. Union than to patients' interests (…)”. not judge and jury. “It is unusual However, if there is no way of making Re-assessment of authorisations for the same organisation and especially valid comparisons between products, is needed. “Public health interests would the same individuals--ie, CPMP mem- how can physicians or patients make be better served by an updated analysis bers--to advise industry about the best informed choices? of the drug's benefit-risk profile (…)”.

P RESCRIRE I NTERNATIONAL - E UROPEAN M EDICINES P OLICY • 9 Following of page 8 cluded that the ten- increased, with the aim of unifying the 1- Prescrire Rédaction "Nouveaux médicaments dency to produce and to authorise approval, monitoring, and policies on à AMM européenne: cotation Prescrire en ever more drugs, increasingly rapidly, medicinal products, including pharma- 1999" Rev Prescr 2000; 20 (202): 60. 2- Prescrire Editorial Staff "EU centralised pro- was overshadowing public health covigilance and review of drug cedure does not mean a drug is innovative" considerations. use. The institutional location Prescr Int 2001; 10 (52): 53. 3- Prescrire Editorial Staff "Our judgements on They also analysed how medicines of EMEA should be changed so it reports products approved through the centralised pro- agencies compete with one another in to the directorate of public health, not cedure in 2001" Prescr Int 2002; 11(58): 60. a context of still inadequate harmoni- industry. Approval of new drugs must 4- Prescrire Editorial Staff "Funding of Medicines agencies" Prescr Int 2000; 9 (46): 34. sation, and noted that they are involve comparative assessments. More 5- see pages 17-19 of this issue. financed mainly by the pharmaceuti- criticism is needed in the approval of new 6- Prescrire Editorial Staff "The real beneficia- ries of European drug policy" Prescr Int 2002; cal industry, with the sole exception of drugs. To defend patients’ interests, com- 11(58): 34. the German agency which, at the time panies cannot be allowed to release drugs 7- Prescrire Editorial Board "Prix des médica- of the survey, received "only" 40% of with the sole aim of obtaining a slice of ments remboursables: quelle logique? Deuxième partie - Prix proportionnels à l’inno- its funds from industry. Like EMEA, the market. The increasing power of the vation: principe raisonnable, maigres résultats" national agencies mainly live off the pharmaceutical industry requires an Rev Prescr 2001; 21 (223): 859-863. 8- Charter of Fundamental Rights of the European taxes and fees paid by companies seek- equally strong counterpart to ensure that Union (2000/C 364/01) 18 December 2000: ing marketing authorisations. drugs continue to be beneficial to patients, 22 pages. The two researchers also recalled and are not just a profitable business.” 9- Bardelay D "ISDB Euro-group relations with EMEA" ISDB Newsletter 1999: 13 (1): 4-5. the dangers inherent in the lack of 10- International Society for Drug Bulletins independence of many scientific "ISDB assessment of nine European Public Conclusion: urgent reform is experts involved in the drug evalua- Assessment Reports published by the European necessary Medicines Evaluation Agency (EMEA)" tion process. Finally, and above all, 26 June 1988: 12 pages. they described a total lack of trans- 11- ISDB European Group "The failings of the Seven years have passed since the European Medicines Evaluation Agency" ISDB parency in the drug regulation, and creation of EMEA and effective Newsletter 2001: 15 (1): 11-13. the authorities' failure to explain 12- Abraham J and Lewis G "Regulating medi- implementation of European phar- their decisions. cines in Europe - Competition, expertise and maceutical policy. It is time to draw public health" Routledge, London & New York The impact of these trends on 2000: 243 pages. lessons from this experience. European countries with smaller 13- Garattini S and Bertele V "Adjusting EMEA, depending on DG Europe’s drug regulation to public health pharmaceutical industries is only Enterprise, cannot properly serve needs" Lancet 2001; 358: 64-67. briefly mentioned. A continuation of 14- EMEA "Work programme 2002 - Annex 2 - European public health interests. On this survey would be welcome dur- EMEA budget summaries 2000-2002" the contrary, it behaves mainly as an 18 December 2001: 44. ing this period of European expan- 15- "Règlement (CE) n°1049/2001 du administrative service for the phar- sion. Parlement européen et du Conseil du 30 mai maceutical industry. 2001 relatif à l’accès du public aux documents du Parlement européen, du Conseil et de European institutions have started la Commission" [Editor's note: also applies to Severe criticism by CPMP to revise the Directive and Regulation all agencies created by these institutions] experts calling for regulations on medicines. The Council of Europe Journal Officiel des Communautés européennes, 31 May 2001: L145/43 - L145/48. adapted to public health has repeatedly stated that pharmaceu- requirements tical policy must be part of a welfare protection system at the service of Silvio Garattini, a director of the patients; that rational drug use must Italian Mario Negri Institute, a clini- be promoted; and that new cal pharmacology research centre offering patients real advance must be with universally recognised exper- developed. tise, especially in the cardiovascular The draft modifications proposed field, is a CPMP member. Together by DG Enterprise would only worsen with Vittorio Bertele, another expert the pro-industry of the current at the Mario Negri lnstitute who is policy in the short term. They dis- also a CPMP expert, he published in agree with the Council of Europe's the Lancet, in July 2001, a detailed guidelines, and carry major risks, analysis of the weaknesses of the both for patients and, in the long European medicines system, and run, for the European pharmaceuti- proposed a series of amendments cal industry itself, by facilitating the (13). The inset on page 9 contains marketing of drugs that provide no parts of their analysis. tangible therapeutic advance. The two experts concluded that ©PI “centralisation of at least one part of the marketing authorisations at the EMEA is satisfactory, and should be gradually

10 • P RESCRIRE I NTERNATIONAL - E UROPEAN M EDICINES P OLICY An industry-serving pharmaceutical policy

he framework texts of dimension be taken into account landscape, such as globalisation. DG European drug policy have more effectively by the relevant Enterprise considers that current reg- Tundergone multiple amend- European institutions (2). ulations are unsuitable, and that they ments over the last four decades. risk isolating Europe and weakening Directive 65/65/EEC (1965) laid the The European Commission its pharmaceutical industry (5). groundwork for the definition of empowers " Enterprise Directo- rate General " (DG Enterprise). medicinal products and for the princi- Double language ple of marketing authorisation, which The European Commission, via DG Enterprise – on which EMEA is is now obligatory for all pharmaceuti- Some of the main objectives stated dependent – has drawn up a draft cal preparations (i.e. industrially pre- in the Memorandum are mutually reform of European drug regulations. pared drugs). Similarly, Directives incompatible: [Note that the Commission is the only 75/318/EEC and 75/319/EEC defined « – to provide a high level of health pro- European body able to initiate such the foundations for analytical assess- tection for the people of Europe and changes (see pages 6).] The two draft ment of the pharmacological, toxico- tighter surveillance of the market; texts, on drugs for human use (one logical and clinical properties of new – to complete the internal market in phar- Directive and one Regulation), have drugs prior to their market release. maceutical products taking account of been in the discussion stage since The current versions of these the implications of globalisation and to 2001, with a view to their adoption texts are Directive 2001/83/EC establish a regulatory and legislative by the European Parliament and the (26 November 2001) and Regulation framework that favours the competitive- Council of Europe in late 2002 (3,4). 2309/93 (22 July 1993). ness of the European pharmaceuticals These draft texts are accompanied industry sector; by two particularly interesting docu- – to meet the challenges of the future The Council of Europe's desire ments – a Memorandum clarifying enlargement of the European Union; to protect public health has the rationale behind the texts (5), – to rationalise and simplify the system as not been respected and a document on likely impact of far as possible, thus improving its overall the proposed modifications on the consistency and visibility, and the trans- The creation of the European Medi- drugs industry (6). cines Evaluation Agency (EMEA) in parency of procedures and decision making» (5). 1995, and its early marketing autho- DG Enterprise has chosen its The Memorandum then sum- risation and pharmacovigilance acti- camp. The impression given by the marises each of the points on which vities, were important steps in the Memorandum is that DG Enterprise DG Enterprise proposes modifica- implementation of European legisla- has simply ignored the numerous tions. It is highly instructive to com- tion on medicinal products. Seven criticisms that have arisen from both pare what is said on each of these years on, it is time for the European within and without EC institutions. points in the Memorandum (5); in authorities to draw lessons from this The same applies to key guidelines the document on the impact on the experience and to adapt current reg- of the Council of Europe. This impres- proposed modifications on the phar- ulations accordingly. The Council of sion is confirmed when one reads the maceutical industry (6); and in the Europe's position on this need for document on the industrial impact of proposed Directive and Regulation change was developed at the Lisbon the proposed changes, and also the that is shortly to be submitted to the Conference on medicines and public draft Directive and Regulation (3-6). European Parliament and Council of health in April 2000 (1). For example, DG Enterprise seems Ministers for approval. Taking into account current trends to base its opinion of the EMEA's in the pharmaceutical market, the first five years of operation only on Council underlined the need to iden- an audit done in 2000, at the Easier marketing authorisa- tify drugs with real added therapeu- Commission's request, by Cameron- tion. The Memorandum states that tic value, to scrutinise drug costs in Mc Kenna and Andersen Consulting. the quality of the scientific debate order to ensure more rational use, The Memorandum refers to com- (on marketing application files) and to develop drug information ments made by the interested parties must be maintained when Europe resources that are independent of (Member States, drug companies, expands to 20, 25 or 28 Member the pharmaceutical industry. pharmaceutical industry organisa- States (5). It briefly mentions the The Council considered it vital to tions, and pharmacist importance given by the Council of identify drugs bringing real thera- organisations, and patient and con- Europe to the identification of drugs peutic advance, not only to protect sumer groups) (5), but it fails to that have substantial added thera- the consumer, but also to promote a mention the documents in which peutic value relative to existing healthy pharmaceutical industry (1). these parties' opinions are expressed. options, but states that regulations These objectives were restated at It also mentions none of the docu- are not the appropriate way of the Ghent conference on health in ments critical of EMEA that we achieving this aim. Europe in December 2001, towards examined on pages 8-10. The document on the industrial the end of the Belgian presidency of The Memorandum underlines DG impact of the proposed changes the European Union. It was also rec- Enterprise' wish to take into account states that firms will be able to obtain ommended that the public health ongoing changes in the industrial marketing authorisation more

P RESCRIRE I NTERNATIONAL - E UROPEAN M EDICINES P OLICY • 11 Dangers of the mutual recognition procedure

Marketing authorisation by mutual base their decision to grant marketing Lack of harmonisation in decisions recognition (also known as the decen- authorisation are not made public (with and expertise. In the mutual recognition tralised procedure) is granted by national occasional exceptions (a)). procedure, the criteria on which decisions medicines agencies on the basis of initial True, this secrecy is shared by almost all are based are not standardised, and the approval by another Member State. This national marketing authorisations in level of scientific expertise varies from one “Reference Member State”, establishes an Europe, but the mutual recognition proce- national agency to another, as do the inde- assessment report that is then submitted dure is its most blatant illustration. pendence and critical capacities of nation- for “recognition” by the other EU coun- al experts. Companies are naturally quick tries. The European Medicines Evaluation A “marketplace” for marketing to exploit these differences in their own Agency (EMEA) is kept informed by the authorisation. Most national medicines best interests. firm, and the Commission for Proprietary agencies are funded, totally or mainly, by Medicinal Products (CPMP) is only called the fees paid by drug companies to have When a drug is intended for sale in on to arbitrate if one or more Member their marketing applications examined (b) more than one Member State, European States refuse to recognise the initial mar- (3). It is therefore crucial, for their financial health would be best served by the keting authorisation. existence, that these agencies are appreci- removal of the mutual recognition proce- ated by their clients, i.e. firms, who might dure, after a short transition period, in A “transient” procedure that per- otherwise opt for the centralised proce- favour of a reinforced, efficient and trans- sists. This procedure was initially under- dure. parent centralised procedure. stood to be transient, pending full opera- Needless to say, drug companies are only ©PI tion of the centralised procedure (for a too pleased to see national agencies com- description of this procedure, see page 5). peting with one another for their custom. a- For the moment, only the Netherlands have Yet the mutual recognition procedure has made tentative steps towards transparency in this area. Representatives of the Swedish agency have developed over the years, and, little by lit- Down-grading of requirements. suggested publishing assessment reports, but noth- tle, become institutionalised under the Firms will naturally choose those agencies ing has yet come of this project. French law makes it impetus of some national medicines agen- which have the least stringent require- obligatory to publish such reports (art. L.5311-1 of the Code of the public Health), but is not imple- cies and drug companies. And the draft ments and/or which examine applications mented. Directive of DG Enterprise proposes, at most rapidly (the two are not always but b- In a 1999 survey, only the German agency received more than half its funds from the public length, to maintain manufacturers’ right to often linked). budget; industry funding nevertheless amounted to use this procedure, and even to facilitate it. National agencies compete on the basis 40% of its budget (ref 2). There follows a list of fundamental of their “flexibility”, as specialists say (in objections to the mutual recognition pro- fact, their pliability) (4). And each national 1- Garattini S and Bertele V “Adjusting cedure, which carries inherent risks for agency is linked to all the other national Europe’s drug regulation to public health needs” Lancet 2001; 358: 64-67. public and individual health (1,2). agencies within the framework of the 2- Abraham J and Lewis G “Regulating mutual recognition procedure: if a given Medicines in Europe – Competition, expertise A particularly secretive system. As agency voices too many objections, other and public health” Routledge London – New York, 2000: 243 pages. responsibility for marketing authorisation agencies may “seek revenge” when the 3- Prescrire Editorial Staff “Funding of medi- is diluted in the mutual recognition proce- country in question is rapporteur, making cines agencies” Prescr Int 2000; 9 (46): 34. dure, and as transparency is not obligato- it less attractive to its potential “cus- 4- Bouzy C and Abadie E “L’Europe du médicament” Rev Prat 2002; 52: 510-514. ry, the data on which national agencies tomers”.

rapidly; that suppression of five- the quality of the scientific debate ments would no longer be arbitrated yearly re-evaluations will save time (a)); by the CPMP, but by a small, and money; and that the mutual – that a fast-track procedure be cre- autonomous "facilitating" group rep- recognition procedure, whose flexi- ated for "innovative" drugs (the term resenting the Member States bility is appreciated by drug compa- "innovative" is not defined). In our involved in the dispute (3,4). nies, will be maintained (6). view such a procedure should be The proposed Directive and Regu- reserved for exceptional situations, Cheap, secretive pharmacovig- lation recommend: such as new drugs likely to bring ilance. The Memorandum speaks of – that the risk-benefit ratios of new major therapeutic advance in life- maintaining a high level of drug safe- drugs should continue to be assessed threatening diseases without ade- ty, and better management of phar- without any need for a comparison quate treatment; macovigilance crises (5). But the with existing reference treatments – that the current five-yearly re- document on the likely industrial (yet this makes it impossible to iden- evaluation of marketing authorisa- impact of the proposed changes tify drugs with real therapeutic tions be suppressed, and that the states that the proposed reinforce- added value); principle of permanent, once-and- ment of pharmacovigilance will not – that the period allowed to exam- for-all approval be adopted, whatev- cost firms money, as they already ine marketing applications (for both er the assessment procedure fol- have the necessary system (6). It is national and mutual recognition pro- lowed; hard to see exactly how pharma- cedures) be cut from 210 to 150 days – that the mutual recognition proce- covigilance would be reinforced. (this would be unlikely to improve dure be facilitated: most disagree- The proposed Directive and Regu-

12 • P RESCRIRE I NTERNATIONAL - E UROPEAN M EDICINES P OLICY lation in fact call for minimal level of transparency should be guar- a- 210 days may seem long. But when one changes in this area, mainly requir- anteed by the adoption of rules examines all the steps involved, the time actually ing firms to prepare pharmacovigi- ensuring public access to non confi- left for thorough study of a marketing application is in no way excessive. For example, in the centralised lance reports on their products every dential information (4). Somewhat procedure, rapporteurs have no more than 70 days to 3 years instead of 5 years at present vague terms for a draft regulation. prepare their report. (b)(3,4). Note that the creation b- Currently, PSURs (periodic safety update reports) must be submitted to the relevant authorities (nation- of a European pharmacovigilance al or European) by the marketing licence holder every database presently touted as a major six months during the first two years, then once a Industry first year for three years and every five years thereafter. advance by DG Enterprise and by the These reports are supposed to comprise data on sales pharmaceutical industry, has been volume, the numbers of prescriptions and of patients In short, although the Memoran- one of EMEA's tasks since 1995: it is exposed to the drug, and adverse events known to the dum, which precedes the proposed firm. The reports must, in principle, be accompanied therefore nothing new. In addition, Directive and Regulation, hints at by the results of trials conducted to complete the safe- this database is not accessible yet to ty assessment. In practice, it is impossible to know public health (5), the proposals them- what PSURs actually contain because they are not health professionals or patients. selves are mainly designed to publicly available, at either the national or the European level. strengthen the short-term competi- Generic drug development c- The G10 is composed of 13 members: two members tiveness of pharmaceutical compa- of the European Commission (DG Enterprise and the hindered. The Memorandum claims nies (3,4). The annex on the likely DG Health and Consumer Protection), five ministers, it will be easier to market generics three representatives of manufacturers' organisa- industrial impact of the proposals (5). But the document on the indus- tions, the president of GlaxoSmithKline Europe (the confirms this impression, as it reas- leading European pharmaceutical group), one repre- trial impact of the proposed changes sures firms that the proposed texts sentative of mutuality health insurers, and one states that harmonisation of data patient representative (ref 7,8). will have only a limited impact on protection periods will delay requests their activity (6). for "light" marketing authorisation Similarly, the conclusions of the procedures by generics manufac- G10 – an informal group with strong turers (6). industry representation, convened The proposed Directive and by the European Commission to Regulation in fact recommend a examine the draft proposals – con- lengthening of data protection firms that the pharmaceutical indus- periods, which is an obstacle to the try welcomes the proposed changes marketing of generics (3). with open arms (c)(7). It is hardly surprising that some Direct-to-consumer advertise- organisations of health professionals, ment facilitated. The Memorandum patients, consumers, together with is very clear on this point, recom- organisations paying for medicines, mending a pilot phase during which are extremely worried about the three drug classes will be able to be impact of these proposed measures advertised directly to the public (5). on European public health. They On this point, which has been hotly have drawn up in many European 1- 2281st Council meeting – Health "Follow debated in recent months, the pro- up to the Lisbon-Conference on medicinal countries joint counter-proposals posal in the Directive is less explicit products and public health – Conclusions" aimed at preserving the initial spirit Luxembourg 29 June 2000: 8-9. than that in the Memorandum, using of European regulations, namely 2- Mossialos E et al "The influence of EU law on the word "information" instead of the social character of health care systems in strict assessment of new drugs, active the European Union – Report submitted to the "advertising". But as the relevant pro- pharmacovigilance, tight controls on Belgian Presidency of the European Union – posals are found in the section of the Final version" Brussels 19 November 2001: drug promotion, and a transparent Directive devoted to advertising, it is 60-80. pharmaceutical policy dedicated to 3- "Proposal for a Directive of the European clear they are not referring to inde- public health (see page 14). Parliament and of the Council amending pendent information (3). Directive 2001/83/EC on the Community code ©PI relating to medicinal products for human use (Text with EEA relevance)" 2001/0253 (COD): Transparency of procedures and 87-119. decisions: half-promises. Greater 4- "Proposal for a Regulation of the European Parliament and of the Council laying down transparency of procedures and deci- Community procedures for the authorization sions is announced in the Memo- and supervision of medicinal products for human and veterinary use and establishing a randum (5) but is not even men- European Agency for the Evaluation of tioned in the document on the Medicinal Products (Text with EEA relevance)" industrial impact of the proposed 2001/0252 (COD): 14-57. 5- "Explanatory memorandum" preceding texts changes (6). 2001/0253 (COD) and 2001/0252 (COD): 77-86. In contrast, transparency is men- 6- "Impact assessment form. Impact of the pro- posal on businesses, particularly on small and tioned in the proposed Regulation, medium-sized enterprises (SMEs)" 68-75 which state that expurgated assess- (Directive) and 126-133 (Regulation). ment reports on drugs authorised via 7- Albanese V "Compétitivité industrielle en Europe. Le G10 émet 14 recommandations" the centralised procedure should be Pharmaceutiques 2002; 96: 36-39. published (but this is already the case 8- European Commission “High level group on innovation and provision of medicines. Recom- with EPARs, of uneven quality: see mendations for action” G10 Medicines -Report - page 8); and that an appropriate 07 May 2002: 30 pages.

P RESCRIRE I NTERNATIONAL - E UROPEAN M EDICINES P OLICY • 13 Towards a medicines policy that supports basic public health needs

fter carefully scrutinising the Norway, the Netherlands, Portugal access to balanced, comparative, relevant, DG Enterprise' complex draft and Spain), addressed members of the up-to-date, accurate and unbiased infor- Amodifications of the Directive European Parliament who will vote, mation on pharmaceuticals and non- and Regulation on medicinal prod- in late 2002, on the proposed changes pharmaceutical treatments but only DG ucts (see pages 11-13), various organ- to the European Directive on medici- Enterprise defended their proposal (to isations and high-ranking persons nal products (3). advertise prescription medicines). throughout the European Union The letter lists current problems • No one claims responsibility for the have launched a counter- and laments the fact that EMEA cur- commission’s proposal. No one could say operation. Here are some examples. rently serves the interests of the who exactly is driving this proposal. DG pharmaceutical industry rather than Enterprise said that this proposal was European public health. They espe- based on expectations expressed by patient Independent journals cially denounce: groups but it could not name a single – the fact that EMEA depends on patient group supporting this proposal. The International Society of Drug of the Enterprise Directorate of the The director of the European Federa- Bulletins (ISDB (a)), has intervened European Commission rather than tion of Pharmaceutical Industries and in many European institutions (b). the Health and Consumer Protection Associations (EFPIA) claimed that they ISDB stressed the specific role of Directorate; have no position on DTCA and represen- the different players of the health – EMEA funding by the pharmaceu- tatives from AstraZeneca, Novartis and care system in the field of drug infor- tical industry to the tune of 70%; Merck Sharp & Dohme, who attended, mation. In particular ISDB: – EMEA secrecy regarding its goals, offered no comment. 1- calls for the development of inde- data, and some of its decisions, It became clear that some national pendent information sources on whereas the Charter of Fundamental health policy makers (such as the Dutch therapeutics; Rights of the European Union and Ministry of Health) reject DTCA but 2- denounces repeated major abuses European Regulation n°1049/2001 want to improve the quality and accessi- of drug advertising towards health (on access to documents) provide for bility of information about medicines professionals; greater transparency; (which does not require any change in 3- considers that these past abuses – the fact that marketing authorisa- legislation). automatically disqualify drug manu- tion is granted for many drugs that • There is evidence that direct-to-con- facturers from providing information are only equivalent, or simply "not sumer advertising of prescription to the public; inferior", to those already on the medicines threatens public health. 4- recommends the continued ban of market, for reasons that are not (…)» all direct-to-consumer advertising of made public; prescription drugs throughout the HAI and EPHA demand that the EU: – the short period that experts are « – Reject this proposal in its current form, European Union; given to prepare their opinion of 5- considers that drug manufacturers as it does not uphold the Community's applications, which are often difficult Treaty obligation to ensure a high level have already enough on their hands, to assess rapidly because of the lack with the need to improve their drug of public health in all of its activities as of comparative data, among other set out in article 152 of the EU Treaty. packaging and patient leaflets. (1). reasons. ISDB also denounces the negative Neither does it conform to the WHO's impact of accelerated marketing Ethical Criteria for Medicinal Drug authorisation procedures (shorter Consumers organisations Promotion as agreed on by all WHO mem- assessment periods, or unjustified ber states in 1988. use of accelerated procedures), as The non governmental organisa- – Vigorously enforce the present legisla- well as the continuation (instead of tions Health Action International tion with review, sanctions, and thorough the disappearance) of the complex (HAI (c)) and the European Public monitoring of promotion to health profes- and opaque mutual recognition pro- Health Alliance, a group of European sionals and the general public. cedure, and the intention to suppress non governmental bodies (EPHA – Develop a robust consumer informa- the current 5-yearly re-examination (d)), organised an international sym- tion and education strategy to ensure of marketing applications, which is posium on direct-to-consumer adver- that people receive and can use quality, poorly enforced at present (2). tising of prescription drugs (Brussels, objective information on medicines. 10 January 2002) (4). Specifically, HAI and EPHA issued a joint state- – Improve the quality of patient infor- CPMP members ment. Here are a few extracts : mation leaflets to make them more read- er-friendly, comprehensive, and under- In an open letter dated 25 February « This meeting clarified a number of standable. 2002, nine expert members of the points: – Encourage the provision of indepen- Committee for Proprietary Medicinal • People want objective information dent and comparative information Products (CPMP) belonging to seven on prescription medicines. Everyone about medicines for health professionals countries (Finland, Iceland, ltaly, emphatically agreed that the public needs and the public. Furthermore, promote

14 • P RESCRIRE I NTERNATIONAL - E UROPEAN M EDICINES P OLICY regular independent testing of the effec- tions in the light of new pharmacovigi- considerable effort has already tiveness of medicine information in edu- lance data is essential to guarantee been made to harmonise the regu- cating and informing professionals and patient safety and rational use. lation of medicines in Europe. But much the public. It’s also important to re-assess the com- remains to be done in the field of phar- (…) » parative benefits of different drugs in the macovigilance at the European and inter- light of new international data so that national levels, and also to improve mar- patients can always be prescribed the keting authorisation procedures. While Medicines in Europe Forum most effective treatment. (…) the centralised procedure has a good per- formance in terms of harmonisation, the The aim of the Medicines in Europe • Drug safety cannot be ensured if mutual recognition procedure is still Forum, created in March 2002 in pharmacovigilance is passive and Paris, is to provide information to all chaotic, and its quality is highly variable. secretive (see articles 101-107 of the those concerned by European phar- In addition the mutual recognition proce- proposed directive). EMEA already col- maceutical policy, and to propose dure is not trustworthy because it is total- lates spontaneous notifications of adverse amendments to the draft Directive ly opaque. (…) ». drug reactions, but what purpose do the © PI and Regulation of the European data serve if those most directly concerned Commission (e). – health professionals and patients – Here are some of the reasons don't have access to them? The database a- Created in 1986, the International Society of Drug underlying its creation (5). of adverse drug reactions must be accessi- Bulletins (ISDB) is an international network of drug bulletins that are independent from the pharmaceu- ble on request, and so must pharmacovig- «• Medicines are not mere consumer tical industry. Its web address is www.isdbweb.org ilance reports. (…) b- Its representatives participated in the Conference goods. Above all the European Medicines on European Integration and Health Care Systems: a Medicines are used by people who are Challenge for Social Policy, organised by the Belgian Evaluation Agency must create an inde- presidency of the European Union (Ghent, 7-8 either sick or have risk factors for a par- pendent and proactive pharmacovigilance December 2001, (ref.1)), and also in the consultation ticular disease. All medicines, whether by the European Economic and Social Committee on system. It must be given the means to con- used therapeutically or preventively, "What are the consequences of the EU commission's duct prospective surveys, in collaboration proposals on the health of EU citizens, and especially have potential adverse events. In addi- with the agencies of EU member states on drug safety?” (Brussels, 6 March 2002), (ref.2). tion, the medicines market is captive: c- Health Action International (HAI) is a network of and those of other countries. (…) some 150 consumer groups and bodies focusing on patients take drugs when required, not health and development in over 70 countries. Its web by choice; they are not mere consumers. address is www.haiweb.org For these reasons, approvals of new • Three principles must be reinforced. d- European Public Health Alliance (EPHA) repre- (…) Three principles need to be reinforced sents more than 80 organisations and non govern- medicines must be thoroughly assessed; mental organisations involved in health matters. known and potential side effects must be in all sections of the proposed directive and www.epha.org actively monitored; and health profes- regulation if European citizens are to be e- The Medicines in Europe Forum, created in Paris given every public health guarantee: in March 2002, groups together family organisations, sionals and citizens must have access to consumer groups, patient groups, mutual insurance thorough and reliable information on – The principle of transparency. (…) systems, and health professional organisations. E-mail: [email protected] the medicines they may be called on to Secrecy now prevailing at the European prescribe, dispense or use. (…) Medicines Evaluation Agency and in most national agencies is an obstacle to • Reducing the time for assessing a rational drug use. Transparency must be marketing application from 210 to improved if patients and health profes- 150 days (see article 17 of the pro- sionals are to regain confidence in this key posed directive) means the quality of organisation, and if these interested par- assessment cannot be guaranteed. It ties are to join force for improving ratio- takes time to evaluate pharmaceutical, nal drug use. toxicological and clinical data on new Real patient representation in the drugs, and the process cannot be acceler- EMEA (articles 58, 50.3 and 51.1 of the ated without compromising on quality. proposed regulation) Representatives of patients must be 1- Bardelay D - European Group of the The experience of experts working with International Society of Drug Bulletins national agencies or with the European allowed to participate actively in all "Information for consumers" European integra- EMEA consultative bodies. tion and health care systems: a challenge for Medicines Evaluation Agency shows that social policy" Ghent 7-8 December 2001: 8 it is already difficult to comply with the Article 58 must provide for balanced pages. representation of patients and drugs com- 2- International Society of Drug Bulletins current period of 210 days. (…) "About the proposals of the EU Commission The accelerated procedure should be panies on the EMEA Management (COM 2001-404 Final) regarding drug reserved for exceptional circumstances, board, as well as transparent procedures approvals and pharmacovigilance" European, for selecting these representatives. Economic and Social Committee, Brussels 6 such as medicines likely to offer a signifi- March 2002: 8 pages. cant benefit for patients who have no alter- – The principle of independence. 3- Group of 9 experts of the Committee of (…) The proposed directive and regula- Proprietary Medicinal Products "Dear Members native treatment. (…) of the European Parlement – Proposed amend- tion must restore key guarantees of inde- ments to the EU pharmaceutical legislation" • Given the rate at which new scien- pendence. Community funding of the Milan 25 February 2002: 2 pages. EMEA must be increased substantially to 4- Health Action International – European tific knowledge now accumulates, Public Health Alliance "Joint Statement on the medicines must be re-assessed regu- reinforce its independence and to provide proposed relaxation of the EU Ban on direct to it with the means required for its role and consumer advertising of prescription medicines" larly (contrary to article 24 of the 28 January 2002: 3 pages. proposed directive). responsibilities to be fulfilled. 5- Medicines in Europe Forum "Platform" Re-assessment of adverse drug reac- – The principle of harmonisation. A March 2002.

P RESCRIRE I NTERNATIONAL - E UROPEAN M EDICINES P OLICY • 15 Translated from Rev Prescr June 2001; 21 (218): 464 DRUGS AGENCIES HAVE A DUTY TO INFORM

ational drugs agencies must In particular, all information posted on guarantee the transparency of drugs agency websites must be regularly N their decisions, and have a duty updated, and dates on which information to inform not only political authorities is posted must be clearly stated. and the pharmaceutical industry, but also What matters most, however, is whether health professionals and citizens (1). these sites provide clear answers to legiti- The most appropriate medium through mate questions on national drugs policies. which to convey this information to the The criteria we used to evaluate drugs public is now the internet: costs are min- agency websites are listed on page 10. They imised; daily updates can be made; and may not be comprehensive, but they rep- decision-making can be traced. resent the bottom line. The quality of drugs agencies’ websites We regularly assess websites of regula- reflects the quality of their work, and their tory agencies and other important web- willingness and capacity to inform and sites in our French edition. thereby fulfil their public health mission. First impressions of websites are usually based on their user-friendliness, 1- “Statement of the International Working Group on Transparency and Accountabiblity in Drug i.e. accessibility, rapidity, compatibility Regulation” Uppsala, 11-14 September 1996. with popular browsers and software, Available on the ISDB website : www.isdbweb.org and layout.

Prescrire’s criteria for assessing drugs agency websites

1- Organisation of the agency tions of recorded meetings). –Reports of spontaneous notifications by –Organisational flow chart: positions and –Register of ongoing and completed prescribers and pharmacovigilance studies contact details of managerial personnel; clinical trials. Comparative assessment of –List of pharmacovigilance and pharma- lists of experts; conflicts of interest. drug cost-effectiveness: work of ad hoc codependence centres, etc. –Calendar of meetings, with precise min- commissions; access to all reports made –Downloadable notification forms for utes, and whether or not meetings are by these commissions, to evaluations of reporting adverse effects (for drugs, open to the public. « services rendered » relative to other medical devices, herbal products, etc.). –Detailed annual activity reports. available products, and the reports on –Board of Directors’ reports; financial which they are based. controllers’ reports; etc. –Clinical guidelines; calen- 5- Consumption, Usage, Pricing –Budgets. dars; etc. –Data on consumption. –Data on usage: non compliance, depen- dence, off-licence indications, prescrip- 2- Regulatory matters 4- Pharmacovigilance tions not observing the SPC. –All regulatory texts defining the role –Pharmacovigilance decisions, and the –Market withdrawals, stock shortages. and objectives of the agency, its commis- data on which they are based: alerts, –Regularly updated details of price of sions and its task forces. warnings, packaging modifications, drug reimbursed by the public health –All decisions and recommendations batch withdrawals (industrial prob- insurance system. signed by the directors. lems), circulars (to manufacturers, –Lists of generics, drugs with special sta- pharmacovigilance centres, health pro- tus, controlled drugs (opioids), blood- fessionals, etc.), market withdrawals 6- Other products derived products, etc. and suspensions of marketing authori- Drugs agencies’ responsibilities are rarely –List of banned advertisements, with the sation. limited to proprietary medicinal products: reasons for prohibition. –Changes to SPCs relating to adverse their websites must also, depending on effects, interactions, pregnancy, warn- regulations and the missions of the dif- ings, restricted indications, dose regi- ferent institutions, include: 3- Assessment reports mens, overdose, special clinical settings. –extemporaneous preparations made in –Summaries of Product Characteristics –Reports of completed pharmacovigi- community or hospital ; (SPC), including information for profes- lance surveys. –medicinal plants; sionals, patient information leaflets and –Reports of commission meetings on –blood-derived products; pack labelling, with precise details of any pharmacovigilance, pharmacodepen- –medical devices; wording changes. dence, drug interactions, pregnancy and –dietary products. –Assessment reports submitted in sup- breast-feeding, etc. ©PI port of applications for marketing autho- –Drugs subject to special monitoring (list risation (with dates of drafting and sub- of ongoing surveys, lists of monitored mission, clearly mentioning updates (a)). a- For instance the European Public Assessment Reports drugs). (EPARs) of the European Agency, and Drug Reviews of –Reports of discussions by commissions –Pharmacovigilance bulletins (national the US Food and Drug Administration. No such reports and specialised task forces (or transcrip- and regional pharmacovigilance centres). exist in France.

16 • P RESCRIRE I NTERNATIONAL - E UROPEAN M EDICINES P OLICY Translated from Rev Prescr June 2002; 22 (228): 386-388 EMEA: fake transparency

http://www.emea.eu.int summary of product characteristics (SPC) tralised procedure are posted online, but and modules 3 to the leaflet. Modules 6, only as abstracts. EPARs rarely provide 7 and 8, which deal with the scientific references of the published clinical trials he European Medicines Evaluation discussion, the different evaluation steps on which EMEA scientific discussions are TAgency (EMEA) is responsible for and any postmarketing assessments, are based. assessment of the quality, efficacy and only available in English. Revised texts are posted online, but safety of human and veterinary drugs Pre-licensing opinions. On 1 April they are not dated and the changes are within the European Community. 2001, as a result of lobbying by citizens not highlighted. EMEA's chief missions are the following: and professionals, EMEA agreed to Minimal pharmacovigilance data. –co-ordination of drug assessment publish summaries of the opinions EMEA is responsible for pharmacovigi- (European centralised marketing autho- reached by the Committee for Proprie- lance of all drugs used in the 15 member risation procedure) and scientific arbitra- tary Medicinal Products (CPMP) on ini- states of the European Community, yet tion of disputes arising from mutual tial marketing applications for human hardly any pharmacovigilance data are recognition of national marketing autho- medicines. These " summaries of opin- available on its website. risation (European decentralised proce- ion " are placed online on the day the In 2001 EMEA posted only seven prod- dure); opinion is reached, whether it is posi- uct safety warnings concerning drugs – co-ordination of European pharma- tive or negative, and can be down- already marketed in Europe (Product safe- covigilance; loaded from http://www.emea.eu.int ty announcement), and four withdrawals – co-ordination of drugs industry inspec- /htms/human/opinion/opinion.htm). of marketing authorisation. tion activities, especially verification of Once marketing authorisation has been Neither the pharmacovigilance issues Good Manufacturing Practices, Good granted (or refused) by the European discussed by EMEA nor reports of meet- Laboratory Practices and the Good Commission, the summary is deleted ings on adverse drug reactions are Clinical Practices. from the EMEA website and replaced released to the public. EMEA also offers scientific advice on the by the European public assessment EMEA does not offer health profession- conduct of preclinical and clinical trials. report (EPAR) compiled by the CPMP als the possibility to receive e-mail alerts or During its first six years of activity, EMEA (for a description of this procedure, go notifications of centralised withdrawals or appraised 339 centralised marketing to http://www.emea.eu.int/pdfs/human suspensions; this information can only be applications for human pharmaceutical /opinion/163501en.pdf). obtained by clicking the red "Product preparations, approving 194 of them. Yearly EMEA activity reports are also alert" button on the website's homepage. During the same period, EMEA regis- posted online at http://www.emea.eu.int EMEA does not provide download- tered 1399 applications made through /htms/general/direct/ar.htm the mutual recognition procedure and able side effect notification forms. The arbitrated in 10 disputes. Finally, the website simply gives the name, telephone Agency examined 5 240 proposed modi- Purely cosmetic transparency number and e-mail address of the person fications of licensing terms. to contact (00 44 20 7418 85 92, No detailed reports of CPMP meetings [email protected]). are available. The EPARs and CPMP Other pharmacovigilance data are scat- Strengths opinion summaries posted on the web tered among the different pages of the only represent the tip of the administra- website or are embedded within assess- The EMEA website provides two useful tive iceberg. ment documents. For example, the categories of document. EMEA position statement on the risk of Secrecy of the mutual recognition venous thrombosis linked to "third-gen- European Public Assessment procedure. Assessment reports relating eration" oral contraceptives is located in Reports (EPAR). EPARs on drugs to mutual recognition procedures, which the Press-Orientated Information pages. approved through the centralised proce- are by far the most numerous, are not Changes to EPARs that are made in dure are made public, together with any published on the EMEA website. response to new pharmacovigilance data subsequent revisions (section: Human Approximately 2 500 drugs that were are not identified as such: to obtain this Medicines; subsection: Product informa- approved through the decentralised pro- information the visitor must consult each tion\Authorized products: http://www. cedure (either before mutual recognition, revised EPAR, one by one, comparing emea.eu.int/htms/human/epar/epar.htm). or post-marketing modifications of each revised paragraph in the different EPARs are based on published clinical licensing terms) are listed on another site versions. trials but also mention a number of (European Product Index, http://mri.meda- EMEA is not currently responsible for unpublished trials. gencies.com/prodidx/), but only the pub- medical devices and materials. Initially, EPARs were published as a lic assessment report for one of these single document and only in English, and drugs is available at this address. some of the older EPARs are still only The EMEA website has no hypertext A labyrinth available in this language. EPARs cur- links to assessment reports or summaries rently comprise eight independent sec- of product characteristics generated by "User-unfriendly" is the term that best tions ("modules"). The choice of this lay- the 15 member states' proper mecha- describes the EMEA website. Users' com- out is not explained. Modules 1, 3, 4 and nisms. puters must be capable of handling the 5 are almost always translated into 11 Java programming language. According to languages, and module 2 is occasionally No references, vague dating. EPARs EMEA, Windows users can only visit the translated. Module 4 corresponds to the for drugs authorised through the cen- site properly if they have Internet

P RESCRIRE I NTERNATIONAL - E UROPEAN M EDICINES P OLICY • 17 Explorer version 5 or Netscape Site created in 1995 stresses the importance of making public all Navigator version 4.7 or later. MacIntosh information likely to affect the health of European users must be equipped with Netscape Editor(s). The European Medicines Evaluation citizens. Navigator version 4.7: all Internet Agency (EMEA), created on 1 January 1995, has The EMEA website only represents the tip of an its offices in London. EMEA is a "community Explorer versions for Mac give poor information iceberg, as it only contains docu- agency", i.e. a permanent European public body. results. Other flaws are the use of hierar- ments and information that EMEA has decided to It is attached to the European Commission chical pull-down menus and tiny charac- make public, in concert with the respective drug Enterprise Directorate General (DG Enterprise). companies. ters, and the fact that only the top of each EMEA, legally represented by its chief executive page appears on-screen. The result of this "" is an inad- officer, has a management board composed of 34 equately clear editorial policy and a confusing members (two representatives per Member State, transparency policy. Explanatory paragraphs scat- two representatives of the European Parliament, Navigation tips tered around the EMEA website describe the and two representatives of the European types of documents and data that the Agency has Committees). Although bulky, the site map provided decided to make available to European citizens EMEA has three scientific commissions that are and health professionals, but the reasons under- on the homepage is nicely done: it gives responsible for preparing opinions on questions a good idea of the site layout and pro- lying these choices are rarely given. Some docu- relating to the assessment of human and veteri- ments state that transparency is a major concern vides direct links to the different pages. nary drugs. for EMEA (see, for example, the report of the News. The "Just Published" page pro- The Committee for Proprietary Medicinal Products workshop entitled "A clear step forward: vides a list of all new documents posted (CPMP), is composed of 30 members (two per Transparency at the EMEA" available at Member State), and meets monthly. Another com- on the site; it is updated daily and pre- http://www.emea.eu.int/htms/general/manage/ mittee gives opinions on orphan drugs only sented in reverse chronological order ar.htm). The External Catalogue of EMEA (Committee for Orphan Medicinal Products, or Documents (http://194.81.125.53/EMEAApps (http://www.emea.eu.int/whatsnewp.ht COMP). m). Users wanting to keep themselves /dbCat/OraExternalCatalogue.htm), which has its The CVMP, or Committee for Veterinary Medicinal own search engine and contains all the docu- informed of EMEA news should book- Products, is charged with assessing drugs for mark this page. ments generated by EMEA since 1 December veterinary drugs. 2000, categorises documents according to their The website of DG Enterprise (unit F2, The EMEA organigram (undated) is available, and degree of confidentiality, as P (public document), European Commission) – the interface a list of CPMP members can be obtained at Rt (document under temporary embargo, clear between EMEA and the European http://www.emea.eu.int/htms/aboutus/cpmp.htm title), Ct (confidential, clear title), R (temporary Commission – provides rapid access to The visitor seeking regulatory texts defining the embargo, masked title) and C (confidential, European regulatory and pharmaceutical role and objectives of the agency and its commit- masked title). Thus, the 109 drug assessment information. tees is directed to Eudralex, on the reports produced by EMEA in 2001 all have "Pharmaceuticals" website of DG Enterprise, at masked titles ("Assessment Report of a Product") Drugs register. The Pharmaceuticals http://dg3.eudra.org/F2/eudralex/index.htm. site map (http://dg3.eudra.org/F2/sitemap. and all are classified confidential (C). So much An overview of European drug legislation and the for EMEA transparency: all the full versions of sci- htm) can be used to access the EC human respective roles of the different institutions entific assessments, including those for autho- drugs register (drugs marketed through (Commission, DG Enterprise, EMEA, etc.) can be rised drugs, remain confidential. Furthermore, the centralised procedure only) and the downloaded from http://pharmacos.eudra.org European Public Assessment Reports (EPARs) – orphan drugs register ("Register" page). /F2/pharmacos/docs/b rochure/pharmaeu.pdf summaries of the full scientific reports drawn up The former register can be searched either Finally, users should know that the EMEA website in concert with the company concerned – are not in alphabetical order of proprietary names, is only one of six EC sites on medicinal products routinely given Public Document status (P): a large or by chronological order (but not by ther- in Europe. All these sites can be accessed via the number are under temporary embargo with apeutic class or international non propri- Eudra portal at http://eudraportal.eudra.org. masked titles (R), and some are classified confi- etary name). In both cases, all the drugs dential (C). Somewhat paradoxical for a "public" are listed on a single page. Clicking a name Funding. In 1999, 2000 and 2001, EMEA funding report! Manufacturers even have the right to with- (blue hypertext link) leads to the SPC and broke down approximately as follows: 25% from draw their application files just before the CPMP the patient information leaflet, in the lan- a European Community grant, 70% from industry gives its opinion: in this case the results of the sci- guage of one's choice. fees, and 5% from "other sources" (2001 EMEA entific assessment remain confidential (more than report, downloadable from http://www.emea.eu.int/ 50 files have withdrawn before the CPMP opinion Search index. The internal search htms/general/direct/ar.htm). since 1995). index on the EMEA website offers two Companies must pay 200 000 euros to have their The full version of the CPMP opinion on a given search modes (“EMEA new Web” and/or marketing authorisation applications evaluated by drug – on which the European Commission bases “EMEA Web”). The old EMEA server EMEA, plus 20 000 euros for each supplementary its final decision to grant or not to grant market- (EMEA web), whose internet address dose strength and/or formulation, and 5 000 ing authorisation – also remains confidential. Only was closed in February 2001, still con- euros for each supplementary formulation or dose summary opinions is released to the public, and tains some EPARs that have not been strength. only for initial marketing applications (CPMP opin- transferred to the new site. Note that the EMEA scientific opinions cost companies from 30 ions on subsequent revisions are not routinely two search options can be selected simul- 000 to 60 000 euros according to the number of made public). taneously. expert categories involved. Furthermore, when a drug is authorised on the basis of a majority opinion within the CPMP, the Advertising. None. scientific arguments of the dissenting minority are never made public. Fate of users' personal data. No personal data One would expect confidentiality to apply only to are requested. industrial manufacturing processes, yet many preclinical and clinical data are also shrouded in Editorial policy. The EMEA code of conduct secrecy. (http://www.emea.eu.int/pdfs/general/admin/Con EMEA rarely states its reasons for granting tem- duct/3767499FR.pdf) stresses that all work done porary or permanent confidentiality status to cer- by the agency is highly confidential. The manage- tain documents produced by its commissions. ment board, committee members and experts undertake, in writing, to exercise total lifetime dis- Update policy. Some EPAR sections ("modules") cretion. However, the same code of conduct

18 • P RESCRIRE I NTERNATIONAL - E UROPEAN M EDICINES P OLICY are regularly updated; this is notably the case of Translated from Rev Prescr October 2001; 21 (221): 705-706 module 8, which describes measures taken once a proprietary drug has been released onto the European market. The file describing each autho- FDA: an example of transparency rised drug states which modules have been revised and indicates the number (but not the http://www.fda.gov materials, including public alerts, are date) of the last revision. The nature of revisions gathered together under the heading is only rarely stated in the relevant texts: there is he Food and Drug Administration Postmarket issues. The CDRH home page no introductory note, and no special labelling (i.e. T(FDA) evaluates the risks and bene- can be found at http://www.fda.gov/cdrh/ italics, boldface, highlighting or underlining) that fits of health products (drugs, medical index.html would help the reader to identify the changes in a devices, screening tests, etc.) and moni- – Medwatch (see inset page 20) is a gen- revised document. tors the safety of foodstuffs and some eral FDA department responsible for Last, but not least, the space provided (at the bot- consumer products that carry a potential pharmacovigilance and materials surveil- tom of each EPAR module) for the date of the last health risk (portable phones, microwave lance; the home page can be found at update is systematically empty. The European http://www.fda.gov/medwatch/index.html public is being abused… ovens, etc.). The FDA website is well designed and – Center for and Applied Author(s). More than 3 000 European experts are currently provides online access to some Nutrition (CFSAN) is charged with seconded to EMEA by the fifteen member states 140 000 administrative or technical doc- monitoring the safety of foodstuffs con- to prepare the scientific assessments on which uments. sumed by the American population the EMEA's two scientific committees base their Each main FDA department has its (with the exception of meat, poultry and opinions. own subsite on the FDA server. eggs). The prevention of foodborne ill- The names of these European experts, classi- Strong points. The home page makes nesses is thus one of its main responsibil- fied by country, are available online at it easy to access the information sought, ities. CFSAN is also responsible for the http://www.emea.eu.int/pdfs/aboutus/Experts with separate internal links to pages for: safety of food additives and dietary sup- Co.pdf. Their fields of expertise and declared – consumers, patients, health profes- plements, milk formulas and other foods conflicts of interest are not mentioned, but "can sionals, manufacturers, journalists, used for human therapeutics, and cos- be provided on request". women, elderly people and children metics. The CFSAN home page can be Information last verified on 7 March 2002 (Information for); found at http://vm.cfsan.fda.gov ©PI – publications (Reference room); Limitations. The FDA has the legal – news (FDA news); obligation to make available on its web- – product types (Products FDA regu- site the information it holds. The limita- lates); tions of the website reflect those of the – clinical trials, commissions, surveil- FDA itself. lance, etc. (FDA activities); In brief. The web page entitled FDA – FDA contact pages: to report a prob- Manuals and Publications provides easy lem, request a public document, etc. (Let access to all the documentation present us hear from you). on the site. The different types of docu- Departments with their own subsites ment are classified and can be accessed include: via a short list of key words given in – Center for Drug Assessment and alphabetical order. Each FDA depart- Research (CDER), which is responsible ment also offers a specific list of its online for assessing new drugs in terms of man- documents. ufacturing quality, efficacy, safety and Three search modes are provided at information leaflets, and gives its opinion the bottom of the home page: a precise on whether a new product warrants plan of the site (Site map), an A to Z key marketing authorisation in the US. The word index (A-Z index) and an internal CDER home page can be found at search engine (Search). Information http://www.fda.gov/cder/index.html contained in the site’s database cannot be – Center for Biologics Assessment accessed using these three search modes: and Research (CBER) is responsible for each database must be searched individ- evaluating the efficacy and safety of ther- ually. apeutic products of microbiological, The home page for health profession- plant, animal or human origin, such as als (Health professionals) has links to all blood and blood products, vaccines, the FDA website pages likely to interest monoclonal antibodies, enzymes and them: this is a time-saver for the health interferons, genes, xenografts, allergens, professional who just wants to browse. etc. Laboratory tests for infectious agents The visitor seeking specific information are also dealt with by CBER. The home can use the advanced search mode page can be found at http://www.fda.gov (Advanced Search) to find all the pages /cber/index.html containing a string of closely related or – Center for Devices and Radiological unconnected words, and can choose to Health (CDRH) is responsible for assess- search the entire text or simply the titles ing the safety and efficacy of medical and/or keywords. A specific search can devices (prostheses and orthoses, blood be made for documents posted online glucose monitors, surgical robots, etc.), the previous day or week. The informa- and the safety of radiation-emitting tion contained in databases cannot be devices (microwave ovens, video screens, accessed in this way. The user is advised cellular phones, radiological equipment, to type words entirely in lowercase or etc.). American surveillance data on uppercase letters, and to place each

P RESCRIRE I NTERNATIONAL - E UROPEAN M EDICINES P OLICY • 19 word inside quotation marks to opti- mise the search (click on Search tips for MedWatch more details). The FDA safety information and adverse event reporting program Users can subscribe to various mailing lists (FDA News Digest, FDA Consumer, MedWatch “What’s new”, etc.). Links to http://www.fda.gov/medwatch/index.html are archived by date and in alphabetical order. these services are found at the bottom of The standard adverse effect form can be down- the home page (Subscribe to FDA’s E- MedWatch is the name of the FDA’s safety infor- loaded. Health professionals and members of mail lists). mation and adverse event reporting program for the public can notify adverse effects online. drugs, biological products, medical devices and The MedWatch site encourages comments dietary supplements sold on the US market. and questions on product documents and reports, and provides an online form for this purpose. Strong points. Pharmacovigilance alerts and One section provides a list of product or batch Site created in 1995 new warnings on adverse effects are readily acces- withdrawals, each accompanied by the reason. Publisher(s). US Food and Drug Administration. sible. Most involve manufacturing problems (inap- Funding is stated. The site is financed by FDA, The Safety Information section provides phar- propriate packaging, failure to respect good man- whose provisional budget for 2002 is macovigilance alerts and explanatory documents ufacturing practices, etc.), illegal copies – which $ 1 414 391 000 (approximately 40% from the (letters, reports, etc.). It has five subsections, are relatively frequent in the United States (iden- public coffers and 60% from industry dues). entitled biological products, dietary supplements, tifiers are provided), batch withdrawals of blood- drugs, medical devices, and “miscellaneous”. derived medicinal products (identification of a Advertising. None. A brief summary of pharmacovigilance data risk factor in a donor, such as an infection, ongo- ing drug therapy, an underlying health disorder; Fate of users’ personal details. FDA states that it appears on screen, with hypertext links to detailed and labeling errors, etc.), and lack of conformi- never communicates to third parties any person- documents, circulars addressed to health pro- ty of medical devices. al information volunteered, such as e-mail fessionals, reports, etc. Alerts are archived by addresses, which must be given to subscribe to year and in alphabetical order. Weak points. MedWatch only covers drugs FDA mailing lists, or personal details required to All modifications to summaries of product marketed in the United States. A drug marketed notify surveillance problems. characteristics (SPC) for drugs marketed in the US are published online. These modifications cover elsewhere may also be available in the United Update policy. New documents are posted online all the different sections of the SPC, i.e. adverse States but may have a different brand name, indi- each day. Documents published on the FDA web- effects, precautions for use, warnings, con- cation or dose strength. site are updated regularly and modifications can traindications, indications, dosage and mode of be posted daily. administration, and interactions, as well as clin- Short-cuts. The What’s New page shows the ical pharmacology, oncogenicity, etc. The new last two weeks’ alerts. Automatic e-mail alerts Author(s). The FDA employs 9 000 people, text is marked clearly in bold, underlined char- can be received by subscribing to the MedWatch including chemists, microbiologists, clinicians, acters. A hypertext link is provided if the text con- mailing list. veterinarians, lawyers, biomedical engineers, taining the data that led to the modifications is health inspectors, pharmacy inspectors, etc., and available on the FDA website. SPC modifications © PI also has a number of advisory committees com- prising experts in the various areas the FDA cov- ers. The authors of online documents may be agency employees or outside experts. Information last verified on 19 August 2001 © PI

20 • P RESCRIRE I NTERNATIONAL - E UROPEAN M EDICINES P OLICY