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
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
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
Conditional marketing authorisation:
Five-yearly re-evaluation: obligatory
and made public
Transparency and data access: major
Functioning of the European Medicines Evaluation
Agency (EMEA): more independent and more transparent
More information, and no direct-to-consumer
International non proprietary names (INN)
Marketing of generic medicines is delayed
Data protection strengthened
Added therapeutic value is not taken into
Compassionate use: no guarantee
An outstanding question: EMEA affiliation
Public health put
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).
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
-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
Directive: amendments 5, 29, 32 ,71, 135, 136, 176, 189.
Règlement: amendments 4, 5, 6, 10, 24, 25, 147.
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
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.
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
Directive: amendment 55.
Regulation: amendments 43, 44.
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.
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.
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
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,
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
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.
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
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
Directive: amendments 16, 25, 72, 106, 108, 191.
Regulation: amendments 18, 22, 37.
Other amendments provide for:
- access to generic medicines in developing countries (under compulsory
-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
-legal recourse against firms that do not meet certain obligations,
Directive: amendments 26, 27, 30, 60, 77, 94, 95, 127, 132, 190,
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
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.
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.
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:
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