It clearly emerged that, in the view of the European Parliament, "medicinal products are not commodities like other goods".
Overall, the amendments adopted at this first reading favoured strict drug evaluation, transparent decision-making, independent information for the public, and the vital interests of patients and health professionals alike.
Three items in the voted amendments are not welcome: excessive data protection will hinder development of generic medicines; compassionate use of drugs for patients lacking vital treatments will be too dependent on individual company strategies; and rejection of the concept of "added therapeutic value" will have major consequences on health budgets.
Health ministers of European Member States must be encouraged to amend these three points in order to confirm the public health orientation of the Directive and Regulation on human medications all along the co-decision procedure.

Public health put forward
• Clinical trials: more ethical, and more in line with daily practice
• Marketing authorisation procedures: no extra flexibility for drug companies
• Analysis of scientific data: an incompressible period
• Conditional marketing authorisation: greater clarity
• Five-yearly re-evaluation: obligatory and comparative
• Pharmacovigilance: reinforced, and made public
• Transparency and data access: major progress
• Functioning of the European Medicines Evaluation Agency (EMEA): more independent and more transparent
• More information, and no direct-to-consumer advertising
• International non proprietary names (INN)
• Miscellaneous

Marketing of generic medicines is delayed
• Data protection strengthened
• Added therapeutic value is not taken into account
• Compassionate use: no guarantee

An outstanding question: EMEA affiliation


Public health put forward

The voting reflected clear understanding of the underlying public health stakes, as illustrated by the first Recital to be adopted, namely that "medicinal products are not commodities like other goods" (Directive: amendment 1).

• Clinical trials: more ethical, and more in line with daily practice. Several of the amendments adopted in Strasbourg aim to guarantee:
-that clinical trials of new drugs follow internationally accepted ethical principles;
-that clinical trials should include women and children when the drug is developed for use by these population groups;
-that long-term clinical trials be conducted when a drug is designed to treat a chronic disorder;
-that clinical trials can be conducted in developing countries only if the local populations will be the first to benefit;
-that clinical trial protocols be mentioned in Summaries of Product Characteristics.

Directive: amendments 5, 29, 32 ,71, 135, 136, 176, 189.
Règlement: amendments 4, 5, 6, 10, 24, 25, 147.

• Marketing authorisation procedures: no extra flexibility for drug companies. When the drafts were examined and voted on by the Parliament ENVI Committee, drug companies pleaded for a 'competition' between the centralised and mutual recognition procedures, because the latter gives them more 'flexibility'.
In the event, the industry-supported amendments were rejected during the plenary session, and the centralised procedure was adopted for all new substances (as recommended in the European Commission's initial proposals). However, the fees relating to the application procedure will be adapted to the financial means of small and medium-sized enterprises. Systematic use of the centralised procedure for new substances could improve harmonisation of evaluations and expert activities, and lead to greater transparency.
As regards the mutual recognition procedure, an amendment was adopted stating that the Rules of Procedure of the coordination group (Mutual Recognition Facilitation Group) (which are currently anything but transparent) must be made public. Other amendments require greater transparency from national medicines agencies participating in the mutual recognition procedure (see below: Transparency and Data Access).

Directive: amendment 61.
Regulation: amendments 1, 129, 130.

• Analysis of scientific data: an incompressible period. The adopted amendments mean that the time allowed to examine marketing applications through the centralised procedure will remain 210 days, as at present. It can be shortened to 150 days by national medicines agencies (for applications not concerning new substances), but the amendments specify that, in both cases, a minimum of 80 days must be devoted to the analysis of scientific data and to the writing of the evaluation report. The only periods to be shortened are those provided for administrative purposes (communication of opinions, and preparation of documents and decisions).
Another amendment states that marketing authorisation committees can set a fixed deadline for companies to answer queries on their applications (presently companies are free to extend these periods).

Directive: amendments 49, 68, 69, 70.
Regulation: amendments 30, 32, 33, 45, 175.

• Conditional marketing authorisation: greater clarity. Many marketing authorisations are currently granted rapidly on condition that the product holder conducts further studies. However, it is impossible to know whether these studies are actually done, and what are their results. The adopted amendments make it obligatory to publish such conditions, deadlines, and the date at which requested studies are completed.

Directive: amendment 55.
Regulation: amendments 43, 44.

• Five-yearly re-evaluation: obligatory and comparative. The draft Directive and Regulation initially proposed that marketing authorisation be granted permanently for new drug products, thus removing the need for regular re-evaluation. The ENVI Committee had been unable to reach a compromise on this hotly debated issue. Compromises were reached during the plenary session, making re-evaluation obligatory once a drug has been on the market for five years. Marketing authorisation will be renewed "on the basis of a comparative re-evaluation by the competent authorities of the updated risk/benefit balance".
Following this re-evaluation, all available information on the drug must be updated, including the Summary of Product Characteristics and the patient information leaflet.

Directive: amendments 185, 186.
Regulation: 163/rev., 165/rev.

• Pharmacovigilance: reinforced, and made public. Many of the amendments concerned matters relating to pharmacovigilance. They were designed to empower patients and health professionals who, until now, have been kept in the dark by pharmaceutical companies and medicines agencies. The adopted amendments state that:
-patients will be able to notify side effects, to their physician or pharmacist, or directly to a medicines agency. In particular, they will be encouraged to report unexpected effects occurring with new drugs during the first five years on the market, by means of a special message printed on the packaging;
-all European Union Member States will place obligations on health professionals to report unexpected or serious side effects;
-periodical reports on drug safety provided to medicines agencies by the relevant companies (Periodic Safety Update Reports, PSUR) must be more frequent. Above all, the risk-benefit assessments that are attached to PSURs will be checked by medicines agencies, and all these documents will be made public;
-if it is decided to withdraw a drug, the firm must inform the relevant authorities first, before they inform the public and their shareholders;
-the safety profile must also comprise side effects reported outside the European Union, and take international data into account;
-the adverse drug reaction database of the European Medicines Evaluation Agency (EMEA) must be made public (see below: Transparency and Data Access), together with the opinions of the committee of the agency responsible for pharmacovigilance;
-other amendments aim to ensure that pharmacovigilance activities are publicly funded.

Directive: amendments 33, 80, 81, 114, 115, 116, 117, 119, 120, 122, 123, 124, 159, 172.
Regulation: amendments 14, 39, 42, 50, 51, 52, 53, 54, 56, 58, 59, 60, 62, 63, 64, 65, 66, 67, 141, 148.

• Transparency and data access: major progress. One of the main advances noted in the texts adopted by the European Parliament is the frequent use of the concept of transparency and the stress on the right of health professionals and the public to access drug-related data. Transparency is foreign to most European Member States, but the European Union now has a set of principles (Charter of Fundamental Rights) and acts (Regulation #1049/2001, among others) which demand that decisions, together with the underlying reasons and data, be made public.
Many amendments are intended to ensure access to registries of drug list (marketing authorisation, Summaries of Product Characteristics, etc.), clinical trials, pre-marketing authorisation evaluation reports (whether or not authorisation is finally granted), pharmacovigilance data, etc. held by both national medicines agencies and the European agency. The amendments also specify that stated conflicts of interest and national agencies' internal rules must be made public.

Directive: amendments 51, 52, 53, 54, 79, 116, 120, 123,124, 129, 130.
Regulation: amendments 36, 38, 51, 53, 174.

• Functioning of the European Medicines Evaluation Agency (EMEA): more independent and more transparent. In addition to amendments favouring the transparency of medicines agencies (including the European agency), amendments on the funding of EMEA, its budget, its control by the European Court of Auditors, and declarations of conflicts of interest by all personnel, experts, members of scientific committees and administrative bodies were all adopted.
Several amendments provide for the participation of patients and/or health professionals in various EMEA bodies and task forces. One provides for the presence of representatives of patients (patient groups were defined in a special amendment, which includes an obligation to declare funding sources) and health insurers on the management board, on an equal footing with representatives of the pharmaceutical industry.
According to one adopted amendment, the EMEA to organise public hearings, as is the case in countries where freedom of information is ensured. Others give the European Parliament more power to oversee EMEA activities. All the adopted texts aim to guarantee more independence for the European agency, and greater transparency and accountability.

Regulation: amendments 84, 86, 87, 88, 89, 90, 91, 92, 95, 96, 98, 99, 102, 104, 109, 110, 111, 112, 113, 116, 119, 121, 122, 124, 125, 126, 127, 131, 152, 157, 162.

• More information, and no direct-to-consumer advertising. All the amendments aimed at increasing the transparency of European medicines agencies are also designed to give the public access to reliable information. The hotly debated pilot project towards direct-to-consumer advertising (disguised as disease education) by pharmaceutical companies was massively rejected (494 votes to 42).
Amendments were also adopted reminding firms of their duties regarding the information they provide with their drugs (i.e. packaging and patient information leaflets). It has been decided that Information leaflets must be tested by groups of patients who are likely to receive the drug in question, and the results of these tests must be included in the marketing application file. Packaging must be designed for patients with visual impairment, and medicines agencies and companies must ensure that patients with poor hearing or vision are offered specific information (use of Braille, large print, telephone hotlines and audiovisual tools, in addition to agency websites).
Advertising will be more strictly controlled. Some amendments target advertisements aimed at health professionals, and are based on French regulation on prescribing incentives.

Directive: amendments 8, 9, 75, 76, 78, 79, 84, 85, 86, 87, 99, 102, 103, 104, 181.

• International non proprietary names (INN). Use of the INN will be obligatory in the generic names, on packaging (even if preparations contain several substances), and in all publicly accessible documents and databases. In particular, the list of marketing authorisations granted through the mutual recognition procedure must be accessible through the INNs (currently only trade names are provided).
Unfortunately, an amendment was adopted allowing sole use of trade names in reminder advertisements (on television, for example) aimed at the public, although this will only be possible for non prescription drugs.

Directive: amendments 16, 25, 72, 106, 108, 191.
Regulation: amendments 18, 22, 37.

• Miscellaneous. Other amendments provide for:
- access to generic medicines in developing countries (under compulsory licence);
-parallel imports, and measures that will help to avoid interruption in drug supply;
-incentives for research on drugs for tropical diseases;
-environmental protection against medicine-related pollution;
-clinical trial results and therapeutic indication must be worded in such a way that the true degree of efficacy of a drug is more clearly stated;
-legal recourse against firms that do not meet certain obligations, etc.

Directive: amendments 26, 27, 30, 60, 77, 94, 95, 127, 132, 190, 196, etc.
Regulation: amendments 7, 8, 26, 49, 94, etc.

Marketing of generic medicines is delayed

Only a few of the amendments adopted run counter to public health interests, but these carry major stakes for Member States' health systems.

• Data protection strengthened. The big drug companies' requests regarding data protection were largely supported by a majority of members of Parliament. Several amendments not only guarantee lengthy commercial protection of originator substances, delaying the marketing of generic medicines, but also further lengthen this protection each time a new therapeutic indication is granted.
Some adopted amendments refine the definition of generic medicines, introducing notions of isomerism, complexes, crystalline polymorphism, esters and salts, whereas the current definition is based only on bioequivalence of the substance.
More worrying as regards the development of generic medicines is the notion of "biosimilarity" introduced in another amendment. This term is only vaguely defined, with no clear criteria. It is simply stated that firms would have to conduct "appropriate pre-clinical tests and clinical trials" to show that a drug is equivalent to another "in terms of safety and efficacy", whereas companies have so far not been requested to conduct new clinical trials for generic medicines. This measure is probably intended to stifle copies of biotech products.

Directive: amendments 34, 35, 36, 40, 156, 167, 168, 202.

• Added therapeutic value is not taken into account. In the current regulatory framework, marketing authorisation is based on the demonstrated efficacy of a new drug and an acceptable level of documented risk. It is not necessary to show that a drug offers any therapeutic advantage over existing alternatives.
The increasing release of equivalent or me-too products that are more costly than reference medicines led members of Parliament to propose amendments on "added therapeutic value". The amendments were not meant to make added therapeutic value a criterion on which to grant or refuse marketing authorisation. It was simply requested that added therapeutic value be mentioned in the evaluation report, or at least in the five-yearly re-evaluation prepared by the agency that initially authorised the drug. In this way, health authorities and health insurance systems would have been in a position to decide whether or not to use or refund the product.
These amendments were strongly opposed by the industrial lobby, and were not finally adopted. One Article in the Regulation is supposed to merely discuss the issue.

Regulation: amendment 100.

• Compassionate use: no guarantee. The adopted texts clearly mention the possibility that patients with no therapeutic alternative will be able to receive "compassionate" treatment with drugs that have not yet been authorised but that may potentially improve their health. Nevertheless, the wording of the relevant amendment does not guarantee compassionate use in all possible situations. In particular, as companies will have to meet the cost of any compassionate use, patients will be dependent on their goodwill.

Regulation: amendments 34, 133, 134.

An outstanding question: EMEA affiliation

Since its creation the European Medicines Evaluation Agency (EMEA) has been part of the Enterprise DG rather than the Health and Consumer Protection DG (SANCO), which did not exist at the time. During discussions of the draft Regulation, some members of Parliament recommended that EMEA become part of DG SANCO.
No decision was made on this point, which relates to the internal organisation of the European Commission, and not to a medicines regulation proper. However, with the coming reorganisation of the European Commission, the time is ripe to address this issue.

©La revue Prescrire 1 November 2002