ISDB and the proposed regulation
for medicines in children

Too much emphasis on medicines and not enough on health needs. All the more reason to switch EMEA from DG Trade to Health & Consumer Protection DG

Preamble

The ISDB welcomes the Commission’s decision to raise the issue of medicines in children. Clinical research on independently agreed needs in children is lacking. Some drugs are approved in children despite poor evaluation in this population. Sometimes drugs are used without proper approval (off-label use), without dose finding studies and child formulation. As in the elderly, treatments for serious illnesses are often inadequately studied. So encouraging research in children is a welcome move, provided that trials to be encouraged are for treatments for which there is a need as established independently of industry. To begin with, an inventory of current practices and needs should be drawn up, based on experience (especially off-label use) in all EU countries, as well as in Central and Eastern European countries. Such trials should be subsidised or completely paid for by public funds - which would also imply that the data from the trial would be public 'property', certainly not a company's intellectual property. That would apply with special force to drugs that are not, or no longer, in patent. Such trials of generic drugs are needed to underpin clinical use of many important drugs. They should be encouraged at least as much as trials of patented drugs.

We warn against repeating the same errors as in adults. Indeed, many drugs for adults are useless, or me-too products. Some of them are poorly studied, and others are too risky. Admittedly, drug consumption is too high in adults, non-drug options are disregarded, and some patients are not given essential drugs.

The Commission’s move is a good opportunity to perform better in terms of selection of helpful medicines and appropriate evaluation, as defined in the ISDB Declaration on Therapeutic Advance in Medicines. More attention should be drawn to information to professionals and the public, and to drug packaging.

We encourage the creation of a European Paediatric Therapeutic Formulary based on essential drugs and real health needs in children, and not only a further market niche.

True, there are around 75 millions children in Europe, but most of them do not need drug treatments. Worse, they probably receive too many antibiotics, cough medicines, antidepressants, etc. We would like to stress that rational drug use, including wrong use, overuse or lack of use, should start in children. The Commission should be wary of strengthening the belief that medicines are the only solution to all health problems.

On the other hand, many serious illnesses are not treated at all, or treated with inadequately established drugs (for example in children with cancer, cardiovascular diseases). Advances such as those of formulations for some antiepileptics are uncommon.

In order to have treatments that meet real health needs, the expert group who will decide on the choice of essential drugs and should include paediatricians working in hospital and the community, general practitioners, pharmacovigilance experts, as well as public-health scientists.

We welcome the Commission’s commitment towards greater transparency in regulation of medicines in children, but fail to understand why the same should not apply to adults as well. We also fail to understand why transparency of R&D costs is not ensured.

The cost of clinical trials as stated in the Commission’s proposals is overestimated and lacks hard evidence, even if we consider the need for pharmacokinetic and dose finding studies, 2 or 3 well conducted trials, and formulation studies. A reasonable price could be granted, however, for drugs concerning few children (as in orphan drugs), provided that transparency of trial results and R&D cost is ensured.

The extension of patent protection is an inappropriate measure because it does not direct research towards useful innovation and proper use of existing drugs. Moreover such incentives are difficult to control: the US "pediatric exclusivity" provision is estimated to give companies six times the amount in return of the money invested. It creates a lucrative incentive for companies to test their most valuable drugs on children, rather than those drugs most needed.

ISDB COMMENTS ON THE COMMISSION’S PROPOSALS

1. Incentives for research

The ISDB agrees that appropriate studies for medicinal products for which protection of intellectual property exists should be encouraged. [See below for definition of appropriate clinical trials]

But we are against systematically introducing an additional period of market exclusivity as a reward for submitting one or more validated clinical studies on children of one or more age groups.

We believe incentives should be based on drug price. Reasonable prices should be offered as a reward for medicines that provide substantial therapeutic advance compared to existing options, on conditions that appropriate clinical trials are done and transparency of trial results and R&D cost is ensured. Unless these conditions are met, we urge governments and organisations paying for medicines to refuse reimbursement of these products for children.

The ISDB welcomes the performance of appropriate studies for already marketed medicinal products for which no intellectual property exists, on condition that well designed clinical trials are carried out (see definition below) and trial results are made public.

We welcome the Creation of a fund by the European Community, whose resources should be dedicated to appropriate research and clinical trials for inadequately treated illnesses in children.

This fund must be managed by representatives of the public and professionals with no links with industry. A control procedure must be set up by a Commission of the EU Parliament to check that resources are dedicated to public-health need priorities.

We understand that this fund would be partly fuelled by EU citizens’ money. So drug companies benefiting from the fund must be requested to ensure access to trial data and transparency of R&D costs when negotiating drug prices.

2. New applications for marketing authorisations – legal requirement for clinical trials in children

We think research needs should be defined according to public health priorities. Need identification must be ensured in collaboration with expert paediatricians having no links with industry. Many drugs are currently used off the label. This experience must be evaluated and used in the design of clinical trials.

What are appropriate clinical trials?

Clinical trials are difficult to carry out in children. Parent consent may be hard to get, and the number of patients is often lower than in adults. So it is even more important than in adults that strict methodological and ethical requirements are met.

The questions tested must be clinically relevant, which means for example that equivalence trials must not be authorised.

Trial designs must be robust and capable of producing strong evidence. Unblinded trials or trials with ill-chosen comparator drugs, or non-comparative trials must not be authorised. Non comparative trials must not be authorised as well.

Enrolment criteria must be strictly defined to avoid problematic subgroup analysis.

Pharmacovigilance based on long-term follow-ups must be requested, especially in children treated with anticancer agents, or with drugs whose long-term toxicity is unknown but suspected.

We welcome the Use of the database foreseen by Directive 2001/20/EC for information on clinical trials.

But we recommend that the European Community set up a trial registry of all trials (completed or not) done in children. Every trial should be registered at inception. The child trial register must be regularly updated, showing whether the trial has begun, is still continuing or has been completed. It should be made accessible to health-care professionals and the public.

4. Developing European excellence –establishment of an EU scientific expert group

Based on past performance of the European agency, the ISDB is very sceptical about the creation of an EU expert group or working party within the European Medicines Evaluation Agency (EMEA) with specific responsibility for all aspects relating to the development, availability and follow up of paediatric medicines. Unless this working group includes a majority of representatives of the public and professionals with no links with industry, we would oppose its creation within the EMEA.

5. Encouraging submission of trials in Europe that have been accepted internationally

Avoiding duplicating clinical trials is a legitimate concern. But as in adults the relevance and the quality of these internationally accepted trials must be guaranteed, notably through properly implemented ICH paediatrics guidelines, strict supervision of trials and implementation of Good Clinical Practices. These conditions are not routinely fulfilled in all countries.

This proposal assumes that trials can be (or will be) submitted only by pharmaceutical companies applying for market authorisation. There seems however to be no reason why other interested parties should not submit relevant trial data – e.g. professional bodies, or academic institutions. ISDB suggests that submissions from such sources should be explicitly encouraged too.

6. Post-authorisation issues – possible need for long term follow-up

We understand that the Commission’s proposals have added pharmacovigilance as the traditional icing on the cake. More than in adults, pharmacovigilance must be planned when designing clinical trials (see above). EU citizens and professionals caring for children must have easy access to pharmacovigilance data, if only to encourage proper reporting of adverse events.

Pharmacovigilance requirements must be part of drug pricing negotiations.

7. Creation of a Pan-European network of clinical excellence for performance of paediatric studies

ISDB supports this proposal, but such a network should include physicians in primary care (GPs) as well as paediatricians, because far more prescriptions for children are written in primary care than in specialist paediatric practice.

As part of the network one or more training centres for investigators should be established. At present most countries have few trained and experienced clinicians who can perform good clinical studies.