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N°1004 LA REVUE

Translated from Rev Prescrire July-August 2004; 24 (252): 481. in Europe: the most important changes in the new legislation

As we digest the results of the European elec- But we must not drop our guard: patients, tions and the last-minute agreement on the health professionals,consumers,health insurers European Constitution, the drafting process of and concerned politicians still have to ensure that the new legislative framework on medicines for the “competent authorities” fulfil their new human use reminds us once again that European obligations and make the pharmaceutical citizens’ voices can and must be heard. industry respect the legal framework that For more than two years the pharmaceutical European society has chosen for it. majors and their lobbyists took it for granted that “Europe” is not some distant land,but is at the they could obtain made-to-measure legislation heart of many of the most important decisions supporting their own narrow financial that shape our society.And Europe is neither

ÉDITORIAL Action bears fruit

interests, with scant regard for inaccessible nor incomprehensible:we just have or for the economic survival of national health to roll up our sleeves and make sure that care systems. special interest groups are not given a free hand. What they failed to realise was that Euro- Finally, Europe is not “too technical”: each new pean citizens from all quarters, including this dossier implies important choices for society. Journal, its subscribers, the “Association Mieux Europe was founded on the notions of free Prescrire” and the diverse member organisa- trade and free circulation,and was bolstered by tions of the Medicines in Europe Forum would the successful introduction of a single currency. come together to scrutinise the draft texts, In future,“Europe” will be increasingly synony- explain the stakes, sound the alarm, make mous with welfare and public services, chief counter-proposals, meet with European among which is health care.Many battles remain, deputies, and lobby ministers. given the inevitable clashes between major What we achieved together was a major financial interests and basic human health needs? change of perspective: in the end, European We offer our congratulations to all those who legislators endorsed the view that medicines contributed to correcting the course of Euro- are not just another consumer good.The drafts pean legislation on medicinal products. And underwent major improvements, not least we stand shoulder to shoulder with all those ensuring greater transparency on the part of defending accessible, high-quality health care. medicines agencies. ©Prescrire International

PRESCRIRE INTERNATIONAL AUGUST 2004/VOLUME 13 N° 72 • PAGE 158-1 Ouvertures e UROPE Translated from Rev Prescrire July-August 2004; 24 (252): 542-548. Medicines in Europe: citizens’ successes

The new European legislative uropean harmonisation on medici- ed extracts on Prescrire website, www. framework for human medicines was nal products started in the 1960s, prescrire.org). A joint position was published on 30 April 2004, after a Ewith the founding Directive finally adopted by the Council of procedure lasting more than two 65/65/EC. It continued over subsequent Ministers on 3 June 2003 (8). years. years, notably with the creation of the In late 2003, deputies and ministers European Medicines Evaluation Agency again came under pressure, notably from The stakes were high, as the new in 1995 (1). the Enterprise Directorate-General and texts determine the level of After multiple additions and amend- industry representatives, to complete their guarantees offered to EU citizens on ments, two major texts, valid until 2003, work before the new member states joined marketing authorisation, risk set out the legislative framework for the Union. The last compromises, management and information on medicinal products: namely Directive adopted on 17 December 2003, were medicines. 2001/83/EC, instituting the community reached after hasty negotiations. code on medicines for human use Patients, consumers, health (grouping together the provisions of As a result, the final Directive and professionals and health insurance previous Directives); and Regulation Regulation, published in the Official organisations joined forces, notably 2309/93, establishing community Journal of the European Union on within the Medicines in Europe procedures and creating the European 30 April 2004 (10,11), differ substantial- Forum, to make their views heard Medicines Evaluation Agency (2,3). ly from the initial drafts. We list the most and to act as a counterweight to the The European Commission, which important changes affecting patients and powerful pharmaceutical lobby. initiates legislative changes, presented health care professionals, comparing two drafts: one to replace the 2001 the new text with the previous wording, The citizens’ lobby made several Directive, and one to replace the 1993 and pointing out the most negative pro- noteworthy gains, especially Regulation. The Enterprise Directorate- posals that were ultimately rejected (b). regarding medicines agencies’ General of the European Commission is transparency. But pharmaceutical responsible for matters relating to medic- majors, with support from the inal products. Its overriding aims were to Transparency of medicines agen- European Commission’s Enterprise make the European pharmaceutical cies: unprecedented obligations Directorate-General, succeeded in industry more competitive, and to ensure ensuring that the notion of “ added that the single European market contin- therapeutic value” will not be taken ued to function after EU expansion on The main change concerns transparency into account when considering 1 May 2004. The draft texts placed too obligations by medicines agencies, which whether or not to authorise new much stress on relaxing marketing was barely an issue in the previous texts. drugs, and that the “clinical data authorisation procedures and permitting protection period” will be even advertising, while largely overlooking National agencies: public access longer than before. public health concerns (1,4). to the agendas and reports of meet- ings, and to assessment reports. The EU citizens must remain The European Commission had to Directive now requires that “member mobilised to ensure that the texts are revise its work. The two new texts were states shall ensure that the competent author- effectively enacted in national adopted through the co-decision proce- ity (i.e. the national medicines agency) makes legislation and are strictly applied in dure, involving the European Parliament publicly accessible its rules of procedure and patients’ best interests.We must also and the Council of Ministers (a). This those of its committees, agendas for its meet- be on the lookout for the tricks that procedure took more than two years, ings and records of its meetings, accompa- the drug companies will inevitably from late 2001 to early 2004 (1,4-9). nied by decisions taken, details of votes and employ to preserve their financial At the first reading by the European explanations of votes, including minority interests. Parliament, in 2002, deputies adopted opinions” (D article 126b). It further stip- many amendments intended to place the ulates that the competent authorities accent on public health, despite strong will make marketing authorisation pressure from the industry lobby (6). “publicly accessible”, “without delay”, Some European health ministers subse- together with the assessment report Medicines in Europe : quently rejected a number of amend- and the underlying reason for their ments they thought might undermine the opinion provided separately for each the complete file is funding of national medicines agencies indication (D articles 21-3 and 21-4). available free in or the financial interests of their coun- tries’ drug companies. Others rallied to The European agency: public French and English defend patients’ interest, but the deter- access to all documents underlying on www.prescrire.org mined European Commission continued decisions. In the 2004 Regulation, to support the industrial sector (see select- almost all the articles concerning deci-

PAGE 158-2 • PRESCRIRE INTERNATIONAL AUGUST 2004/VOLUME 13 N° 72 sions made by the European Medicines staff (…) responsible for granti- Evaluation Agency and the documents ng marketing authorisation, underlying these decisions mention an rapporteurs and experts (…), have obligation to make these documents no financial or other interests in available to the public (see below for the details of each of the agency’s core tasks). which could affect their impar- In addition, article 73 of the 2004 tiality. These persons shall make Regulation stipulates that European an annual declaration of their Regulation 1049/2001 on public access financial interests” (D article to documents held by European insti- 126b). tutions now applies to the medicines The 2004 Regulation states agency. The agency is therefore required that the financial interests of to create a “register (…) to make available members of the management all documents that are publicly accessible board, committee members, (…)”, as is already the case for other insti- rapporteurs and European tutions. These registers were created to Medicines Evaluation Agency make documents easily accessible, even experts must be declared on when they are numerous and diverse. a yearly basis. The same In addition, article 80 of the 2004 Reg- article requires that declara- ulation states that the agency’s internal tions be made at each meet- rules and procedures must be made avail- ing of “specific interests which able to the public, both at the agency’s could be considered prejudicial headquarters and via the Internet. to their independence with respect to the items on the agenda. These Penalties to be made public. Accord- declarations shall be made ing to article 84 of the 2004 Regulation, available to the public” (R arti- the European Commission “shall publish cle 63-2). the names of the marketing authorisation holders (this applies only to the centralised More public funding for pharma- Drug evaluation: lip-service procedure) (…), and the amounts of and covigilance. In addition, the Directive to the notion of “added reasons for the financial penalties imposed” stipulates that “management of funds therapeutic value” when companies fail to follow the intended for activities connected with Regulation. , the operation of com- munication networks and market surveil- Previously, the only criteria that The Medicines in Europe Forum, lance shall be under the permanent control needed to be met before a drug could be among others, had demanded of the competent authorities in order to marketed were pharmaceutical quality, such measures. If citizens remain guarantee their independence” (D article efficacy and safety of use. Nothing has vigilant to ensure that these 102a); this does not, unfortunately, changed in this respect: no comparative measures are fully and durably imple- mean that the funds will necessarily clinical evaluation is required to deter- mented, medicines agencies’ notorious come from public sources. mine whether a new drug offers a real secrecy will be a thing of the past. The 2004 Regulation clarifies the therapeutic advance (added therapeutic funding of the pharmacovigilance value) relative to reference drug or non activities of the European agency: these drug treatments. Medicines agencies’ independ- activities “shall receive adequate public ence: minor progress funding commensurate with the tasks The need for comparisons is final- conferred” (i.e. from the community ly quoted. The 2004 Regulation states budget) (R article 67). that, on request of the Commission, the Currently, medicines agencies’ main The publicly accessible European European Medicines Evaluation Agency sources of funding are the fees paid medicines database (c), the creation of will be required to “collect any available directly to them by pharmaceutical firms, which is provided for in the 2004 information on methods that Member States’ notably for evaluating marketing appli- Regulation, must also be established, competent authorities use to determine cations (12). As the experts who work updated and managed by the agency, for these agencies are also often involved “independently of pharmaceutical companies” in assessing drugs on companies’ behalf, (R article 57-1-1). a- European ministers of industry could have been char- drug companies wield considerable ged with the file (medicinal products being the responsibi- influence over medicines agencies’ deci- These obligations may appear to lity o the Enterprise Directorate-General), but it was health sions (13). The previous Directive did not represent the strict minimum. ministers who actually participated in the co-decision pro- even mention conflicts of interest, while But at a time when drug cess. b- We specify each reference to articles of the new texts by an article of the previous Regulation only companies are funding more and either the letter D (for 2001 Directive, modified in 2004), mentioned this problem in passing. more public-sector activities, these or the letter R (for articles of the 2004 Regulation). obligations are a major victory for those c- This will be a new database, with only basic contents: Public declaration of financial seeking to ensure that medicines it will contain only the texts of patient leaflets, but will have the advantage of including, eventually, all drugs marke- interests. The 2004 Directive requires agencies are and remain independent. ted in Europe, whether authorised through national pro- member states to “ensure that members of cedures or the European centralised procedure.

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the added therapeutic value that any new obligatory only for biotech drugs. Nation- Keep watch on this medicinal products provide” (R article 60). al procedures were commonly used, timetable The end-use of this information is not followed increasingly by mutual recog- stated, but the existence of this measure nition among Member States — a loose- Directive 2004/27/EC, published on acknowledges that Member States are ly regulated and highly secretive proce- 30 April 2004 (1),makes a number of changes obliged to compensate for the insuffi- dure (4). Agencies had 210 days to to the previous Directive (2001/83/EC). It ciencies of marketing authorisation, by examine marketing applications, and will not be applicable in individual Member sorting out the new drugs. marketing authorisation had to be States until it has been transposed into The concept of added therapeutic value renewed every five years for a drug to national legislation,which must be done by also appears in an article of the 2004 remain on the market. All these points 30 October 2005 at the latest (article 3). Directive concerning data protection have been extensively modified. Regulation (EC) 726/2004, replacing Regu- (D article 10-1), and in the correspon- lation 2309/93, applies immediately, with- ding article of the Regulation: the extra European centralised procedure: out transposition, to all Member States. year of data protection will be granted obligatory for other types of sub- Nevertheless,some of its measures can be for “one or more new therapeutic indications stances. The field of application of the applied only when the 2004 Directive comes which, during the scientific evaluation prior centralised procedure has been extend- into effect (3). to their authorisation, are held to bring a ed. This application procedure is based Here are the application dates of the texts significant clinical benefit in comparison on an assessment of marketing applica- and their parts,and the corresponding meas- with existing ” (R article 14-11). tions by the European Committee for ures: Medicinal Products for Human Use • 20 May 2004: immediate application of Thus, the comparison of new (CHMP, previously CPMP), rather than the part of the 2004 Regulation relating to drugs with available reference by a national agency. From 20 Novem- the functioning of the European medicines treatments, long demanded by ber 2005, in addition to biotech drugs, agency; patient groups and health care it will also be obligatory for all new drug • 20 November 2004: the medicines professionals but rejected by pharma- substances intended for use in AIDS, agency’s management board must rule on ceutical firms, finally appears in the cancer, neurodegenerative disorders the application of European Regulation European regulation on medicinal and diabetes, and also to orphan drugs 1049/2001(on public access to documents) products. This comparison is not obliga- (d). And as of 20 May 2008, it will also to the agency; tory prior to marketing application, but become obligatory for drugs intended to • 30 October 2005: actual transposition at least a small step has been made in the treat autoimmune diseases and other of the 2004 Directive into national legisla- right direction. immunological disorders, and for antivi- tion by all Member States.This covers all ral drugs (R article 3-1 and annex). items dealing with the authorisation and Ethical clinical trials, wherever they monitoring of medicines at the national are done. The conduct of clinical trials Despite pressure in favour of the level; is not dealt with in the 2004 Directive or mutual recognition procedure, • 20 November 2005: application of the Regulation. Other specific texts focus on which companies consider more rest of the 2004 Regulation; in particular, clinical trials, notably Directive “flexible” and agencies consid- the centralised marketing procedure will 2001/20/EC on good clinical trials er more lucrative (at least the agencies become obligatory for four new therapeu- practice. Nevertheless, an important of the “reference Member States”), the tic classes; document has now been added to the centralised procedure is gradually • 20 May 2008: the centralised market- list that applicants must provide (for gaining ground. This had been another ing procedure will become obligatory for both national procedures and the demand of the Medicines in Europe two further therapeutic classes; European centralised procedure), name- Forum. • No later than 2014: the European ly “a statement to the effect that clinical Commission must publish a general report trials carried out outside the European National procedures: a little less on experience accumulated with the appli- Union meet the ethical requirements of secretive. Companies can still choose cation of the new procedures. Directive 2001/20/EC” (D article 8-i-b, the national marketing authorisation ©PI R article 6-1). procedure or the mutual recognition Thus, the principles of Directive procedure for all other medicines. But the 1- “Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2001/20/EC (which has still not been coordinating group responsible for 2004 amending Directive 2001/83/EC on the transposed into French law) must be examining questions relating to the Community code relating to medicinal followed, with respect to the protection mutual recognition procedure now has products for human use” Official Journal of the European Community 30 April 2004: L 136/34- of participants, ethics committee and a legal framework: the 2004 Directive L 136/57. adverse event reports, even when a drug defines the group and its composition, 2- “Regulation (EC) No 726/2004 of the intended for the European market is and stipulates that its rules of procedures European Parliament and of the Council of 31 March 2004 laying down Community tested outside the EU. must be made public (D article 27). In procedures for the authorisation and the 2004 Regulation, the opinion of the supervision of medicinal products for human CHMP will be requested “whenever there and veterinary use and establishing a European Medicines Agency” Official Journal of Marketing authorisation: is disagreement in the evaluation of medici- the European Community 30 April 2004: L the worst-case scenario avoided nal products through the mutual recognition 136/1-L 136/33. procedure”. This practice already existed, 3- The European agency for the evaluation of in principle, but the 2004 Regulation medicinal products “Press release - New pharmaceutical legislation enters into force on Up to now, the centralised European states “the opinion of the Committee shall be 20 May 2004” London 3 May 2004: 2 pages. marketing authorisation procedure was made publicly accessible” (R article 5-3).

PAGE 158-4 • PRESCRIRE INTERNATIONAL AUGUST 2004/VOLUME 13 N° 72 Provided medicines agencies are withdrawing their application, and the Drug access prior to marketing forced to implement the new agency must make this information authorisation: “compassionate use” transparency demands (see available to the public (R article 11). now officially recognised. An article above), this would permit more Similarly, if centralised European mar- of the 2004 Regulation introduces a new insight into exchanges between nation- keting authorisation is refused, the agency concept: that of “compassionate use”. It al agencies during mutual recognition of must make the underlying reasons avail- authorises access to drugs that are under a national marketing authorisation. able to the public (R article 12-3). review by the centralised authorisation procedure or undergoing clinical evalu- Maintenance of the 210-day Public release of conditions placed ation for “patients with a chronically or seri- period for examining marketing on marketing authorisation. Now, ously debilitating disease, or whose disease is applications. The 210-day period when marketing authorisation is considered to be life-threatening, and who currently permitted for examining granted with conditions (such as further cannot be treated satisfactorily by an autho- marketing applications will be kept for clinical trials, or specific pharmacovigi- rised medicinal product” (R article 83-2). both the centralised procedure and nation- lance studies), the relevant agency The CHMP opinion on these exceptional al procedures (D article 17; R article (national or European, depending on the cases must be made public (R article 6-3). This is another victory for EU procedure) must make them public, 83-6). Continuous access to medicinal citizens, because companies were seek- together with the deadlines. Continued products must be ensured between the ing a shorter period, and the European marketing authorisation will be subject moment when marketing authorisation Commission had proposed just 150 days to a yearly assessment of whether these is granted and the drug is effectively for national procedures. conditions have been met (D article 22; marketed, in order to avoid treatment For the centralised procedure, the R article 14-7). interruption (R article 83-8). 2004 Regulation provides for a shorter Publication of centralised marketing period of 150 days, but only if the drug authorisations in the Official Journal of the This is a first, in Europe, for is “of major interest from the point of view European Union must now, according to patients who have no effective of public health and in particular from the the 2004 Regulation, mention the inter- therapeutic alternatives, and is point of view of therapeutic innovation” and national non proprietary name (INN) of similar to the French system of if “the request is duly substantiated” the active substance (R article 13-2). This “temporary licence” (14). But the rele- (R article 14-9). was not previously mandatory. vant text does not cover drugs following national marketing authorisation proce- No less than 80 days for rapporteurs No “permanent” marketing dures, and does not satisfy all patient to analyse the scientific data. The authorisation: obligatory reassess- associations’ demands. For example, it 2004 Regulation guarantees, in the ment after 5 years. One constraint does not stipulate who can initiate the centralised procedure, that CHMP that companies would have liked to see request for compassionate use pro- rapporteurs will have the time necessary removed was the five-year renewal of grammes, or who will pay for them. to do their work thoroughly: “the dura- marketing authorisation. This was often tion of the analysis of the scientific data in the a simple administrative formality, but file (…) (within the overall 150- or 210- could also offer an opportunity to Better labelling and patient day period) must be at least 80 days, except re-assess the evidence. The Commis- information leaflets in cases where the rapporteur and co-rappor- sion had recommended that marketing teur declare that they have completed their work authorisation be granted for an unlim- before that time” (R article 6-3). ited period. However, the 2004 Direc- Drug labelling was already regulated, In case of arbitration during the mutu- tive and Regulation stipulate that but mainly with the aim of protecting al recognition procedure, the CHMP will “marketing authorisation shall be valid for companies and medicines agencies have up to 80 days to give its opinion five years”, and “may be renewed after five when adverse effects occurred. European (D article 32-1). years on the basis of a re-evaluation of the deputies proposed a number of amend- risk-benefit balance by the competent author- ments intended to make drug labelling Despite drug companies’ lobby- ity” (D article 24-2; R articles 14-1 and more informative for patients. Some of ing to have their products autho- 14-2). The new texts also provide for a these amendments were adopted, despite rised more rapidly, only the time second reassessment: “once renewed, the pressure by some quarters. allowed for certain administra- marketing authorisation shall be valid for tive tasks has been shortened. In princi- a unlimited period, unless the competent Greater use of the INN, and inscrip- ple, the scientific assessment should not authority decides, on justified grounds relat- tions in Braille. The outer pack and be botched because of unreasonably tight ing to pharmacovigilance, to proceed with primary packaging (bottle, blister, etc.) deadlines. one additional five-year renewal (…)” must now mention the international non (D article 24-3; R article 14-3). proprietary name (INN) “where the prod- Information to be provided on uct contains up to three active substances” withdrawals of marketing applica- This 5-year reassessment of the (D article 54-a), instead of only one tions and refusals of European risk-benefit balance has a strate- previously. Fixed-dose combinations centralised marketing authorisation. gic importance. Vigilance will be should be easier to identify, even if Until now, withdrawals of marketing required to ensure that medi- application often went unnoticed. Now, cines agencies do not make it a simple for drugs following the centralised administrative formality, but, on the d- In Europe, a can have orphan drug status if it is indicated for a disorder that affects less than 5 per 10 000 procedure, firms must inform the Euro- contrary, take consideration of all avail- EU inhabitants. See reference 22 for the Regulation specif- pean agency of their reasons for able data. ically dealing with these drugs.

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the texts do not stipulate a minimum for patient information on drugs at the Proposed amendments that called for print size for the INN. The outer packag- general meeting of the European Feder- boxes of new drugs to carry a statement ing will have to mention the INN, the ation of Pharmaceutical Industries meaning “newly authorised drug, please dose strength, the pharmaceutical form (EFPIA)(15). report any adverse effects” were fought and the trade name in Braille format Pharmaceutical majors are already by the Commission and were finally (D article 56a). gradually expanding their public “infor- rejected. mation” campaigns on certain conditions. Information leaflets to be tested by The most recent, on erectile dysfunction, Data analysis: sales figures too. Drug patient panels before marketing cholesterol, depression, osteoporosis, obe- companies must now provide medicines authorisation. The patient information sity and mycosis, are highly instructive: agencies, on request, with “all data leaflet “shall reflect the result of consultations companies are simply seeking to per- relating to the volume of sales (…) and (by the company) with target patient suade as many people as possible that they volumes of prescription”, along with other groups to ensure that it is legible, clear and have these disorders, and that they should information required to assess safety easy to use” (D article 59-2), and “the results ask their doctor for a prescription drug. profiles (D article 23a; R article 23c). of assessments carried out in cooperation In practice, the regulation is increas- with target patient groups shall also be ingly bypassed. Market withdrawal of products provided to the competent authority” when with negative risk-benefit balances. requesting a marketing authorisation The list of reasons for which a Member (D article 61-1). Pharmacovigilance: still too State may withdraw a drug from the secretive, and no extra market has been extended. The 2001 If patients and consumers are power for patients Directive mentioned the following vigilant to ensure that the Direc- reasons: wrong drug composition, tive is effectively applied, the harmfulness in normal conditions of use, information on the drugs they The 2004 Directive and Regulation do and lack of therapeutic activity. To these use will be simpler and clearer. not fundamentally modify the current has now been added “the risk-benefit pharmacovigilance system, but more balance is not favourable under the autho- precisely define collaboration among rised conditions of use” (D article 117-1-c). No direct-to-consumer advertis- Member States. Some advances have This is better than the wording “an ing of prescription drugs nonetheless been achieved. unacceptable level of risk” which was very nearly adopted. Funding: a small dose of inde- Although authorised in other coun- pendence. The funds necessary for Data distribution: minimal require- tries, “direct to consumer advertising” pharmacovigilance activities must be ments. The new texts imply that the (DTCA) is still forbidden in the European managed at the national level by the European drug surveillance network will Union, despite pressure from drug com- relevant authorities; at the European continue to collect data, but that patients panies and the European Commission, level, funding must come from the EU and health care professionals will have which had recommended authorising coffers (see above). virtually no access to them. advertising for the public, disguised as The 2004 Regulation simply states information (5). Few extra constraints on drug that the European agency will make Strong opposition from deputies and companies. Regarding the collection of public CMPH’s opinions on necessary most health ministers ensured that data on adverse effects, few extra demands measures in case of pharmacovigilance DTCA of prescription drugs remains on drug companies have been made, even problems (R article 22). The EU Com- forbidden in the EU. As before, this though the new texts are slightly more mission’s proposals did not include even “prohibition shall not apply to precise than before. Companies are still this small measure. Moreover, data on campaigns carried out by industry and required to provide periodic reports on “serious adverse reactions and other approved by the competent authorities of the adverse effects — every six months pharmacovigilance data (…) shall be made Member States” (D article 88). during the first two years, every year for publicly accessible, if relevant, after the next two years, then every three years evaluation” (R article 26). Beware “information” on some (previously every five years). These reports conditions. The Commission has been (Periodic Safety Update Reports (PSUR)) This latter wording is sufficiently asked to prepare “a report on current must now “include a scientific evaluation vague to prevent public access practice with regard to information provision (done by the company) of the risk-benefit to pharmacovigilance data. It is — particularly on the Internet — and its risks balance of the medicinal product” (D article therefore unlikely that the field and benefits to patients” (D article 88a). 104-6; R article 24-3). of pharmacovigilance will become According to the same article of the 2004 transparent any time soon. But at least Directive, the Commission will be able to Data collection: still no patient the authorities responsible for pharma- make proposals defining a drug infor- involvement. The recommendation covigilance will no longer be able to use mation policy. that patients be encouraged to report the lack of a regulatory framework as an suspected adverse effects directly was excuse for inaction. It is noteworthy that the EU rejected, mainly because health minis- commissioner responsible for ters feared their agencies would be Health and Consumer Protection swamped by the extra workload. Yet recently announced the devel- the usefulness of such patient reports is opment of a public-private partnership now widely recognised (16).

PAGE 158-6 • PRESCRIRE INTERNATIONAL AUGUST 2004/VOLUME 13 N° 72 Industrial protectionism: vague and complex to make it more Transposition of the Directive a victory for drug companies difficult for generics manufacturers to into national legislation, obtain marketing authorisation (D arti- and application cle 10-2, 3 and 4). In particular, it will be of the Regulation Drug companies employed all the more difficult to avoid conducting new means at their disposal to prolong the pre-clinical and clinical trials when the period during which their drugs are manufacturing process (especially when The pharmaceutical companies protected from generics (17). Prior to based on biotechnology) is only slightly have won a major victory for the 2004 Directive and Regulation, different from that used for the origina- protectionism, but advocates of protection of clinical trial data lasted tor product (20). patients’ interests won many 6 years in about half the 15 Member other battles. States, and 10 years in the others (includ- The money spent by pharma- The worst-case scenario has been ing France) (e,f)(18). ceutical majors to influence avoided, as there will be no indefinite deputies and ministers, and to marketing authorisation; no reduction in Delayed generic development. After spread malicious rumours on the period allotted to assess marketing two years of intense debate and infight- the potential risks of generic drugs, was applications; no direct-to-consumer ing between the powerful pharmaceuti- well invested. Welfare organisations and advertising of prescription drugs. cal majors and the less powerful mutual health insurers will soon feel the Major victories include unprecedent- generics manufacturers, clinical trial data economic pinch. ed obligations placed on the European protection in Europe was harmonised and national medicines agencies to be towards a longer period. The period is more transparent; the concept of added now 8 years, but generics will not be able Last but not least therapeutic value is now mentioned to be marketed for 10 years, whether the in several articles; information leaflets originator drug was authorised through must be tested by relevant patient groups, the national or the centralised procedure It is impossible to describe in detail all and the results must be included in (g) (D article 10-1; R article 14-11). the provisions of the 2004 Directive and marketing applications; patient repre- Regulation (h), but here are some other sentatives will be present on the man- A bonus for new indications. A noteworthy changes: agement board of the European Medi- further year of data protection can be – When a drug is not actually marketed, cines Evaluation Agency. granted if a new indication is authorised its marketing authorisation becomes void The new European legislative frame- during the first eight years, and if this after three years (D article 24-4; R arti- work for medicinal products is at the indication offers “a significant clinical cle 14-4); same time basically sound but fragile in benefit in comparison with existing therapies” – Holders of marketing authorisation are parts. Sound, because it is based on the (D article 10-1; R article 14-11). It will required to ensure continuous availabil- principles of the EU Treaty and Charter be interesting to see how this applies ity of their products (no supply inter- of fundamental rights, such as the in practice. ruption) (D article 81), and must notify public right to access official documents A further year of data protection can agencies of temporary or permanent (21). Fragile, because it may not be also be given to companies that are grant- market interruption at least two months ed a new indication for an old, “well- in advance, except in exceptional cir- established substance” (D article 10-5). This cumstance (D article 23a; R article 13-4); extra year may encourage companies to – Member States must create systems for conduct further research on substances collecting unused or expired drugs they had previously considered unprof- (D article 127b), but the relevant article itable. Article 10-5 of the Directive states does not state how these drugs are to be e- “Data protection” consists of prohibiting competitors from using clinical trial data on an originator drug for a that this work must include “significant disposed of; number of years. This means that generics manufacturers pre-clinical or clinical studies”. – Marketing application files must include cannot use such data in their applications (ref 18). information on the environmental impact f- In France, data protection used to last 10 years, and not 15 years as stated by the Minister of Health in a television A gift to self- industry. of the products (D article 8-3), especial- interview in May 2004. Patents last 20 years. A far more debatable new measure is that ly drugs containing genetically modified g- This means that a generics manufacturer can use the re- an extra year of data protection can be organisms (R article 6-2); sults of clinical trials conducted with an originator drug, at granted to a firm for a prescription drug – The management board of the Euro- the end of the 8-year data protection period. It can thus ob- tain marketing authorisation, and prepare to market its ge- that is switched to over-the-counter (OTC) pean Medicines Evaluation Agency will neric, but actual market release can only take place ano- sale; this protection covers data from now include two representatives of patient ther two years later. Originator drugs are now therefore trials done specifically to support the organisations and one representative of protected for 10 (8 + 2) years. switch (D article 74a). It generally organisations; neither group The new Directive also allows the clinical trials necessary for marketing authorisation to be conducted before the concerns substances that have been in was represented in the past (R article 65) patent or complementary protection certificate expires (equi- use for a long time, for which new trials (i). valent to the “Bolar exception” in the United States) (D ar- are not necessary (19). ticle 10-6). Such trials can now be conducted in the Euro- pean Union, instead of outside as previously (ref 23). h- A chapter of the 2004 Directive, not discussed here, is de- Protectionism aggravated by the voted to homeopathic drugs. Plant-based drugs are the invention of “biogenerics”. The defi- subject of another Directive, also published on 30 April 2004, nitions of “generics “ and “biogenerics” to which we will return later. i- There are no representatives of pharmaceutical compa- (the latter term was invented for the nies or health insurers on the board , despite recommen- occasion) have been rendered sufficiently dations to the contrary in several drafts of the Regulation.

PRESCRIRE INTERNATIONAL AUGUST 2004/VOLUME 13 N° 72 • PAGE 158-7 Ouvertures e UROPE 6- Prescrire Rédaction “Résultats du vote en pre- 15-Byrne D “Patient centred in Europe” fully applied in practice: transposition mière lecture sur les projets de Directive et de Règle- European Federation of Pharmaceutical Industries of European directives into national ment relatifs aux médicaments à usage humain” Rev and Associations (EFPIA) Public Conference, Dublin legislation is often slow (particularly in Prescrire 2002; 22 (234): 852-854. 27 May 2004: 6 pages. 7- Prescrire Rédaction “Future réglementation 16- Medawar C et al. “Paroxetine, Panorama and France), and the law and regulation are européenne du médicament: restons vigilants” Rev user reporting of ADRs: Consumer intelligence mat- often simply ignored. Prescrire 2003; 23 (239): 346. ters in clinical practice and post-marketing drug sur- It is up to patients, health care pro- 8- Prescrire Rédaction “Redresser le cap de la poli- veillance” Journal of Risk and Safety in Medicine 2002; tique du médicament: l’action porte ses fruits” Rev 15: 161-169. fessionals, consumers, health insurers Prescrire 2003; 23 (242): 623-625. 17-Prescrire Rédaction “Le renforcement tous azimuts and responsible politicians to ensure that 9- Prescrire Rédaction “Premier bilan” Rev Prescrire des brevets dans le domaine pharmaceutique” Rev the “competent authorities” fulfil their 2004; 24 (247): page IV of Lettre aux Abonnés. Prescrire 1999; 19: (197): 544-546. 10- “Directive 2004/27/EC of the European Parlia- 18-Prescrire Editorial Staff “Data protection: an anti- new obligations, and that the ment and of the Council of 31 March 2004 amend- generic weapon” Prescrire Int 2003; 12 (68): 235. pharmaceutical companies observe the ing Directive 2001/83/EC on the Community code 19- Prescrire Rédaction “L’exclusivité commerciale legal framework. relating to medicinal products for human use” Offi- après un “switch”: autre moyen de protectionnisme cial Journal of the European Union 30 April 2004: L industriel” Rev Prescrire 2003; 23 (245): 827. ©Review prepared by 136/34-L 136/57. 20- Prescrire Rédaction “L’invention du la revue Prescrire and translated 11- “Regulation (EC) No 726/2004 of the European “biogénérique”: une autre arme au service du pro- by the Prescrire editorial team Parliament and of the Council of 31 March 2004 tectionnisme industriel” Rev Prescrire 2003; 23 (244): laying down Community procedures for the autho- 742. risation and supervision of medicinal products for 21- “Charter of Fundamental Rights of the Euro- Selected references from Prescrire’s document human and veterinary use and establishing a Euro- pean Union (2000/C364/01)” available at watch. pean Medicines Agency” Official Journal of the Euro- http://www.europarl.eu.int/charter/default_en.htm. 1- Prescrire Editorial Staff “Reorienting the course of pean Union 30 April 2004: L 136/1-L 136/33. 22- Prescrire Rédaction “Médicaments orphelins - European medicines policy” Prescrire Int2003; 12(67): 12- Prescrire Editorial Staff “Funding of medicines Le règlement européen enfin adopté” Rev Prescrire 192-194. agencies” Prescrire Int 2000; 9 (46): 34. 2000; 20 (206): 382-383. 2- “Directive 2001/83/EC of the European Parlia- 13- Prescrire Rédaction “Conflits d’intérêts à l’Agence 23- European Generic medicines Association “EGA ment and of the Council of 6 Novembre 2001 on the du médicament” Rev Prescrire1999; 19(194): 301-302. board of directors urges early implementation of “EU Community code relating to medicinal products for 14- Prescrire Rédaction “Médicaments sans AMM Bolar provision” for generics to ensure the future of human use” Official Journal of the European Commu- mais avec ATU (autorisation temporaire d’utilisa- European research & development” Press release 25 nity 28 November 2001: L 311/67–L 311/128. tion)” Rev Prescrire 1996; 16 (158): 41-43 et (166): March 2004. Website http://www.egagenerics.com 3- “Council Regulation (EEC) n° 2309/93 of 22 July 693-694. consulted on 26 May 2004. 1993 laying down Community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a Euro- pean Agency for the Evaluation of Medicinal Prod- Annexe Revealing extracts on our website www.prescrire .org ucts” Official Journal of the European Community 24 August 1993: L 214/01-L 214/21. 4- Prescrire Rédaction “Redresser le cap de la poli- The EU co-decision process that resulted in the new Directive and Regulation on me- tique du médicament (suite)” Rev Prescrire 2002; 22 dicines lasted more than 2 years. Representatives of the European Commission, of mi- (230): 540-547. nisters and other interested parties expressed their views at length: some of their sta- 5- Prescrire Rédaction “Redresser le cap de la poli- tique du médicament (suite)” Rev Prescrire 2002; 22 tements are worth reading. (232): 703-706.

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