About the proposals of the EU Commission
regarding drug approvals and pharmacovigilance

What are the consequences of EU commission's proposals on the health
of EU citizens, notably on drug safety?

Two proposals of the EU commission are potentially dangerous for EU citizens' health, namely accelerated drug approval without adequate guarantees regarding pharmacovigilance, and removal of the 5-year renewal of Drug approvals.

Accelerated drug approval

From the point of view of the needs of the citizens, it is not reasonable to let people believe that they need to have quick access to all new drugs or all new indications. Clearly, the public expects pharmaceutical treatments in certain fields where health care professionals still lack today the means to treat them, such as orphan diseases, certain types of cancer, some viral infections, etc. However, it would be untrue to say that all new drugs placed on the market bring improvements that benefit the public, in comparison with already existing therapeutics (1,2).

Accelerated drug approval may also lead to inadequate evaluation of drugs and potential safety problems (see the worldwide withdrawals of rapidly approved drugs). Inadequate evaluation exposes EU citizens to medicines that may be useless, or less beneficial than others, or even harmfull.

Accelerated approval should therefore be strictly restricted to drugs for life-threatening illnesses without adequate treatments, i.e. not vaguely to ‘highly innovative’ medicines and on condition that annual assessment of benefits and risks are carried out. Two binding conditions are essential if an accelerated procedure is to work in the public's interest; Firstly the decision to use an accelerated procedure must be the responsibility of the evaluation committee, and not the pharmaceutical company. Secondly assessment of benefits and risks of the drug must carried out annually.

No renewal of drug approval

The 5-year renewal of drug approvals is meant to protect citizen's health. Removing the obligation to renew approvals of drugs every five years, pretending that this would be offset by a stronger pharmacovigilance, is pure wishful thinking. Indeed ISDB and other organisations showed that the European medicines agency has failed to create a strong and transparent pharmacovigilance system in our region (3,4,5,6,7). Despite claimed intentions and communiqués on transparency and access to data, the European medicines evaluation agency remains secretive. As a result, health professionals and taxpayers of the European Union cannot trust the agency to provide reliable drug information, particularly on safety issues.

This 5-year renewal must be maintained and scientifically applied. It should allow the European medicines evaluation agency to reassess regularly the benefits and risks of a drug, help translate the results of this re-assessment in relevant changes of summaries of products characteristics and patient information leaflets.

The 5-year renewal of drug approvals should be an opportunity to clear the market of drugs with poorly proved efficacy, drugs with poor benefit-risk ratios compared to others, or of drugs whose companies fail to provide requested data (pharmacovigilance studies).

What are the consequences of the
co-existence of centralised, decentralised and national approval procedures?

The main problem is the co-existence of centralised and decentralised procedures far marketing drugs in EU Member States.

National marketing approvals have some limitations but citizens are in a position to identify the responsibilities of each party at national levels. Although citizens have to request more transparency of their drugs agencies, national approval procedures should be maintained.

The decentralised approval procedure (Mutual Recognition Procedure) induces inequality and lack of harmonisation in drug evaluation in the European Union. Indeed, independent experts have shown that pharmaceutical companies tend to choose the most favourable country in terms of approval rapidity and regulatory demands (6,7). Pharmaceutical companies are also likely to withdraw or abandon an application if an agency detects a problem, and try again with a more lax agency.

It is especially worrying, as many national agencies are increasingly dependent on application fees from pharmaceutical companies. As service providers, national medicines agencies compete among themselves for capturing application fees. This may lead some agencies to be less stringent vis à vis industry (8). It has also le ad to a worrying consensus among Member States and the Mutual Recognition Facilitating Group that approximate evaluation should be tolerated in order to keep the decentralised procedure operating, and ensure the incomes it generates (7).

In addition the decentralised procedure is a totally opaque system, with almost no information accessible to citizens. It will therefore be even more problematic in an enlarged European Union. We recommend that the decentralised procedure should be abolished and all approvals far drugs aimed at the EU are submitted through a centralised procedure. This can be done only if the European medicines agency's staff is substantially reinforced.

What are the consequences of the EU Commission’s proposals on innovation and industrial competitiveness?

The practices of the pharmaceutical industry and regulators tend to blur the distinction between genuine therapeutic advance and mere innovation (l). The pharmaceutical companies have also successfully swamped the drugs agencies with a mass of evaluation by artificially breaking up new indications in small dossiers, and by increasing unduly the number of applications for licence extensions.

The term ‘innovation’ covers three concepts. The commercial concept refers to any newly marketed me-too product, new substances, new indications (even when close to current ones), new formulations, and new treatment methods. The technology concept means any industrial innovation, such as use of biotechnology, or introduction of a new substance delivery system (patch, spray), selection of an isomer or a metabolite. Although industrial competitiveness based on purely commercial or technical innovation can generate profits in the short term, a strong industry can be sustained only through invention of genuine therapeutic advances. Shareholders arc beginning to take into account the longer-term mission of pharmaceutical companies.

The concept of therapeutic advance is the only one that concerns professionals: it means that a new treatment benefits the patient when compared to previously existing options. Unfortunately the quality and relevance of clinical data required far regulatory submission are inappropriate to identify genuine therapeutic advance. Policy makers under the influence of industry and the ICH process have watered down the definition of ‘innovation’ by requesting less and less comparative data. In Europe the requirement of ‘significant therapeutic interest’ in Council directive 87/22/EEC of 1986 has not survived in Council Regulation 2309/93 of 1993.

According to members of the International Society of Drug Bulletins (ISDB) about 80% of new products or new clinical uses approved each year in developed countries provide no advantage aver existing treatments. Around 2% of drug treatments offer a real advance to the patient, and 5% provide minor benefits (1,2).

When judging whether a new product is a therapeutic advance, it is crucial to consider efficacy, safety, and convenience. Efficacy, safety and convenience must be assessed concurrently and regularly re-assessed as new evidence emerges. Indeed, continuous evaluation of old substances is essential so that drugs that are no longer valuable can be eliminated, and new or better ways of using already approved drugs can be identified.

Does the EU Commission's proposals take sufficiently into account the coming enlargement of the European Union?

We explained in the above section that the decentralised procedure is not compatible with enlarged EU, both for technical and regulatory reasons.

The ISDB believes that the enlargement of the EU and the long-term removal of the decentralised procedure cannot be achieved unless the European agency is more democratically controlled.

What are the conditions for a democratic medicines agency in an enlarged European Union?

Accountability and transparency towards European citizens must be politically and technically ensured so that the European drug market is really oriented towards the interest of the public.

Accountability of the EU medicines agency can be ensured provided a number of legislative amendments are made so that:

1. representatives of the public and health professionals (interested parties) who are independent of pharmaceutical companies are involved in key management and working bodies of the European medicines agency.
2. the agency's activities are controlled annually by an ad hoc body of the European Parliament.
3. the medicines agency is attached to Health and Consumer DG instead of Enterprise DG in order to signal the political willingness to focus drug market regulation on patients and EU citizens, instead on the sole interests of industry.
4. freedom and independence of the medecines agency vis-à-vis industry and protection of the agency from conflicts of interest must be legally ensured and practically enforced. This entails increasing the EU contribution to the medecines agency budget so as to keep industry contribution below 50%.

Are information about drugs sufficiently accessible to health professionals
and the public?

Transparency of the EU medicines agency towards the public and professionals is neither ensured by the present legislation nor by the Commission's proposals. European legislation should be amended to provide EU citizens with full rights of access to information about efficacy, safety, and convenience of drugs.

The European medicines agency should establish a Freedom of Information Service, which would make all regulatory reviews available on request. Regulatory reviews include dissenting views; views expressed in meetings of Mutual Recognition Facilitation Groups (so long as the decentralised procedure is maintained); copies of the pharmacological, toxicological and clinical reports submitted to obtain the initial registration of drugs (or subsequent variations); all CPMP opinions on drugs, positive as well as negative; transcripts of CPMP meetings and of meetings resulting in decisions on marketing authorisations.

Exceptions to freedom of information must be restricted to protection of legitimate commercial interest and of confidential personal information.

Recommendations

1. As a rule, editorial procedures for finalising SPCs and preparing European Assessment Reports (EPARs) should be publicly accessible.
2. Detailed information on withdrawn or refused applications should be available on request.
3. The European medicines agency should report annually on how conflicts of interest have been managed. Lists of conflicts of interest involving EU regulators and CPMP members should be made systematically public, and not only on request. Selection of CPMP rapporteurs who handle drug evaluation dossiers should be transparent, and the industry should have no say in the selection of rapporteurs.
4. Strict follow up of conditional marketing authorisations must be carried out and results made public; measures and sanctions taken when requested studies are not conducted should be made public.
5. European Public Assessment Reports on marketing approvals should place the benefit-risk ratio of the new product in the context of existing treatments.
6. The European medicines agency should make available to professionals and the public a register of clinical trials submitted in the application dossiers. This should include all trials, completed or not, together with their protocols.

Is drug information adequately distinguished from drug advertising?

The WHO's Ethical Criteria for Medicinal Drug Promotion as agreed on by all WHO member states in 1988 is a standard far defining drug promotion.

ISDB has shown that the nature and the quality of the 'information' provided to professionals by medical representatives should qualify it as 'drug promotion' (10). Indeed 'information' from medical representatives is biased, while encouraging off-licence use and minimising adverse effects. Above all, this type of ‘information’ provides only non-comparative 'information', or falsely comparative information aimed at beating the competitor.

The de facto relaxation of the ban on direct-to-consumer advertising of prescription medicines, sometimes disguised as disease awareness campaigns, also provides biased information to the public.

As shown by experts and Health Action International, the project to officially remove the ban on direct-to-consumer advertising of prescription medicines is unacceptable. There is ample evidence coming from the USA and New Zealand that approving direct-to-consumer advertising of prescription medicines would lead to irrational prescribing and use of drugs, and would increase health care expenditures.

ISDB recommends that the EU encourages and supports the use of sources of independent comparative drug information. ISDB also recommends that initial and continuing medical education on medicines should be carried out independently of the pharmaceutical industry.

Is there still room far improving the EU pharmacovigilance system?

The main problem with the EU pharmacovigilance system is the almost total lack of transparency on information towards interested parties, namely health professionals and the public (3,4,5,7,8).

Recommendations

1. Co-ordination of national and regional pharmacovigilance systems should be ensured and funded by the EU. The ICH process should make co-operation of all international agencies (in the EU, USA, Japan) in pharmaçovigilance problems a priority.

The European medicines agency should be in a position to organise and fund well-designed pharmacovigilance studies such as case-control studies and large cohort studies, in order to provide a clear picture of adverse effects profiles of drugs.

2. Substances that require intensive monitoring should be listed by the EU agency, with the year of local introduction. The list should be made available to professionals and the public. A priority list of drugs to be monitored should be identified (as done in some EU countries), and substances on the priority list should be identified as such on the packaging and in the patient information leaflet.
3. Information about pharmacovigilance and minutes of meetings about pharmacovigilance problems should be accessible. The EMEA should establish a Freedom of Information Service making available reported adverse drug reactions on request.

References

1. "ISDB Declaration on Therapeutic Advance in the Use of Medicines" Paris. November 2001.
2. "Drugs in 2001" Prescrire International 2002: 11 (58): 58-60.
3. An ISDB survey to assess the degree of transparency of drug regulatory agencies "Inter J Risk and Safety in Medicine, 1966; 9 (3): 151-155.
4. "ISDB assessment of nine European public assessment reports published by the European Medicines Evaluation Agency (EMEA)".
5. ISDB European Group "The failings of the European Medicines Evaluation Agency" ISDB Newsletter 2001; 15 (1): 11-13.
6. Garattini S and Bertele V "Adjusting Europe’s drug regulation to public health needs" The Lancet 2001; 358:64-67.
7. John Abraham and Graham Lewis "Regulating medicines in Europe" Routledge 2000: 243 pages.
8. Statement of the International Working Group on Transparency and Accontability in Drug Regulation. Uppsala, September 14, 1996.
9. The Erice Declaration on Communicating Drug Safety Information. Erice, September 27, 1997.
10. "sales representatives – A Damning report by Prescrire Reps Monitoring Network" Prescrire International 1999; 8 (41): 86-89.

About the International Society of Drug Bulletins (ISDB)

Background
The international Society of Drug Bulletins (ISDB) is a world wide network of bulletins and journals on drugs and therapeutics that are financially and intellectually independent of pharmaceutical industry. It was founded in 1986, with the support of the WHO Regional Office for Europe.
The rationale for the Society is that drug bulletins independent of funding from industry experience problems not faced by editors and publishers of other journals.

Membership
The main requirements for membership are editorial and financial independence, and the quality of the information published. ISDB has two categories of members: full members who meet all membership requirements as set out in the Constitution; and recognised correspondents. Recognised correspondents are institutions or individuals who do not meet are sympathetic to the aims of the Society.

Aims
The overall aim of ISDB is to encourage and assist the development of independent drug bulletins in all countries and to facilitate co-operation amongst them.
ISDB’s priorities are:

Work of the Society
ISDB holds a General Assembly every three years, which provides an excellent forum for members to meet and exchange information. In addition, this allows ISDB members to meet with other attendees, such as producers of formularies, people in drug information centres and other publishers of independent drug and therapeutic information that are not already part of the ISDB network.
To help independent drugs bulletins achieve high professional standards, ISDB organises regional workshops where people working on long established bulletins can share their experience with those starting new ones. Such meetings have been held in Algeria, Hungary, Italy, Japan, Philippines, Holland and Spain.
To support the development of new drug bulletins, ISDB members also host visits from editors starting up new bulletins to help them gain experience. ISDB publishes newsletters which are distributed free to all members and recognised correspondents. This newsletter serves: to keep members and recognised correspondents informed of current editorial standards for the development of articles an information,

Through its meetings, workshops and newsletters, ISDB also encourages and facilitates discussion on sources of information, organisational structure, ways that bulletins can help health professionals communicate more effectively with patients and the public, financial support for member bulletins, and any other support for bulletins faced with particular difficulties.
To address public health and drug information issues, ISDB has developed links with many relevant organisations with members being involved in various activities and campaigns. Topics of particular interest are: access to information about medicines, including access to unpublished data held by drug regulatory agencies; identification of truly innovative drugs; the impact of undue promotion by the pharmaceutical industry; resistance to direct-to-consumer advertising of prescription medicines.
Other ISDB activities include the exchange of information on new drugs, adverse effects, and drug promotion and regulation.