Making the Paediatric Regulation Work

The success of the EU's new paediatric medicines legislation will depend on discipline, flexibility and good collaboration between regulators and industry, says Geneviève Michaux.

Geneviève Michaux is a lawyer at the Brussels and Paris Bars and special counsel, Covington & Burling.

The waiting is finally over. After two rounds of public consultations and four years of debates, the European Union (EU) has finally delivered a regulation on medicinal products for paediatric use.

The regulation promotes the development of medicines for children by requiring pharmaceutical companies to conduct paediatric studies when developing any new medicinal product or line extension. Unavoidably, significant extra effort and investment will be required from the industry. A reward is foreseen, but its availability is far from guaranteed.

Despite several legislative initiatives at the international, European and national levels, the pharmaceutical industry was reluctant to prioritise paediatric research^1,2,3. This research is often riddled with problems; for one, “children” cannot be considered one homogenous group. It also considerably increases the costs of development, which are already very high.

To address this problem, the European Commission was inspired by the “stick and carrot” approach adopted for paediatric research in the US and for the orphan medicine regime in Europe⁴. In the EC paediatric regulation, obligations are combined with rewards and incentives, but the structure differs depending on the status of the medicinal product. The new regulation distinguishes between new medicinal products, existing medicinal products still protected by a supplementary protection certificate (SPC) or a basic patent that qualifies for an SPC (on-patent medicines), and medicinal products no longer protected by an SPC or a basic patent that qualifies for an SPC (off-patent medicines)⁵.

The new European paediatric regime applies to all medicinal products for human use as defined under Directive 2001/83/EC except generics, biosimilars, medicines approved on the basis of bibliographical applications, homeopathic medicines and traditional herbal medicines. The regime will enter into force in early 2007, but it will only become mandatory six months later for off-patent medicines, 18 months later for new medicines, and 24 months later for on-patent medicines. The general understanding is that these transitional periods do not prevent companies from voluntarily complying with the new rules as of their entry into force or their practical implementation by the Commission and the European Medicines Agency (EMEA)⁶.

Key elements of the regulation include, naturally, obligations and rewards for the pharmaceutical industry, but also the creation of a paediatric committee at the EMEA as well as the interaction between the new paediatric system and the current approval procedures. This article examines the key elements of the regulation and underlines new legal and practical challenges facing pharmaceutical companies.

The regulation undoubtedly carries the potential to boost paediatric medicines in Europe. Yet, it creates new challenges for pharmaceutical companies in terms of the requirements that must be met to benefit from the rewards and the discretionary powers given to the regulatory authorities regarding the number, nature and timing of paediatric trials. The industry's capacity to accept these challenges - and therefore the success of the regulation - will depend primarily on the regulatory authorities' attitude in applying the new paediatric rules. Development of paediatric medicines will now rely on the authorities' flexibility and openness to dialogue with the industry.

Paediatric committee

The spine of the new system is the paediatric committee, which will be created within the EMEA and will replace the paediatric expert group. Beyond its general advisory mission for paediatric matters, the paediatric committee will issue opinions on proposed paediatric investigation plans (including deferrals) and requests for waivers. It will also give opinions on compliance with paediatric investigation plans (eg, whether the paediatric data filed by the applicant correctly reflect the implementation of the agreed plan) and on the quality, safety and efficacy of the paediatric use of the product. When giving an opinion, the paediatric committee may only be guided by two principles: (1) the therapeutic benefit that the paediatric research may provide to children, and (2) avoiding delays in the approval of adult indications.

Scope of the paediatric obligation

Companies must provide paediatric data when filing a marketing authorisation (MA) application for a new medicine or an application for a line extension of an on-patent medicine. This is in addition to the regulatory data required under Directive 2001/83 EC or Regulation (EC) No 726/2004. The term “new medicinal product” refers to a medicinal product “which is not authorised in the Community” when the regulation enters into force. The term should be specified because, first, several marketing authorisations may be granted for the same product and, second, it is intrinsically vague, particularly in view of the new definition of generic medicine and the concept of the “global marketing authorisation”.

Filing paediatric data is optional for off-patent medicines. If the applicant decides to comply voluntarily with the regulation, it may be granted a “paediatric use marketing authorisation” (PUMA), a new type of authorisation that exclusively covers paediatric indications (including the appropriate strength, pharmaceutical form or route of administration), and the applicant is eligible for a reward.

Subject to a waiver or a deferral, paediatric data must be submitted for every subset of the paediatric population (as defined by the International Conference on Harmonization (ICH) guideline E11) and for every indication, pharmaceutical form or route of administration of the new medicinal product. For on-patent medicines, the obligation also concerns existing indications, pharmaceutical forms or routes of administration (the regulation only foresees these types of extension). This requirement, added late in the legislative process, increases the financial investment from the industry and will delay the overall timing of the line extension that will be filed first.

The paediatric data are not just any paediatric data but those which result from implementing a paediatric investigation plan proposed by the company and agreed to by the EMEA based on the opinion of the paediatric committee. The EMEA may also grant a deferral to initiate or complete certain studies envisaged in the plan or a waiver from providing any or some paediatric data.

Paediatric investigation plans

Any paediatric development must be based on a paediatric investigation plan. The plan must specify the schedule and measures envisaged for assessing the quality, safety and efficacy of the medicine for the paediatric population concerned, and describe measures to adapt the formulation so that it is usable for children. The content and format of the request for agreement of a proposed plan and the request for a waiver are to be defined by the commission.

Although the plan is proposed by the applicant and agreed upon by the EMEA, the applicant will also have to follow the procedure set out in Directive 2001/20/EC on clinical trials before conducting the studies foreseen by the plan. An ethics committee could refuse to give a positive opinion on a paediatric study envisaged by the plan (for example because it considers that the timing of such study is not appropriate). In such a case, the applicant will have to seek amendments to the paediatric investigation plan because ethics committees (or regulatory authorities having to approve clinical trials) are not bound by the plan agreed upon by the EMEA.

Deferrals

The deferral system is designed to ensure that the paediatric trials are not harmful to children and also do not delay the approval of adult indications. With a deferral, the applicant is still eligible for the prescribed reward but it may only claim it after all the deferred studies are completed. This presupposes, of course, that the SPC remains valid for a sufficiently long period.

In the proposal for a paediatric investigation plan, the applicant indicates what studies should be deferred for scientific and technical or public health reasons. Grounds for deferral will be further specified, but already the regulation provides that a deferral is granted where the studies on children must be preceded by, or take longer than, the studies in adults. This requirement has to be read in light of the ethics rules set out by the ICH and the EU regarding clinical trials on children^7,8.

If the paediatric committee agrees to a deferral, its opinion must indicate the time frame for the completion of the plan, and the applicant must annually submit a report on the advancement of the paediatric research to the EMEA.

The regulation does not set a maximum duration for deferrals as the commission considered that the link between the reward and the full implementation of the plan would induce companies to complete it as soon as possible.

Waivers

The waiver system is designed to ensure that research matches the therapeutic needs of children. When a waiver is granted, a company is released from the obligation to provide paediatric data when filing an application; however, no reward can be claimed unless the waiver is partial. Indeed, a waiver may be granted for a specific indication and/or age group.

A list of waivers is published to inform the industry of the classes of medicines and/or medicines for which paediatric data are not required or only required for a specific subset of the paediatric population.

The EMEA may grant a waiver if the medicinal product or class of products meets the following criteria:

• it is likely to be ineffective or unsafe in part or in the entire paediatric population;
• the disease or condition for which it is indicated only occurs in adults; or
• it does not offer a significant therapeutic benefit compared to existing treatments.

1 Generally, the applicant requests a waiver for a specific medicine, but the paediatric committee may grant a waiver on its own initiative. At any time, the committee may also recommend the review or withdrawal of a waiver. If so, the marketing authorisation holder has 36 months from the withdrawal to propose a plan or a revision of the current one.

2 The committee's power to act on its own initiative and the obligation to base its decisions on the therapeutic needs of children could preclude companies from developing the paediatric medicine they want, at least to the extent that they seek the reward. For example, if a company decides to develop a paediatric indication that is financially sound but has already been developed by another company, the paediatric committee could refuse the plan and grant a waiver on the grounds that the research is useless, thereby depriving the company of the reward.

3 The withdrawal of a waiver triggers the obligation to conduct new paediatric research. This would de facto enable the EMEA to force, indication by indication and once a plan has been agreed, specific paediatric research on existing products without an application for a line extension being filed. However, it is doubtful that this is the intended effect of the regulation. A withdrawal of a partial waiver, of course, also would not result in a new reward.

4 Where an applicant has difficulties implementing the agreed plan, it can propose amendments to the paediatric committee. The criteria for approving an amendment - where the plan cannot be implemented or is no longer appropriate - are not detailed in the regulation. As the plan proposal is to be filed early in the development of the product, amendments to the plan are likely to become the rule rather than the exception, which makes the criteria for amendments all the more essential.

5 Paediatric procedure (see Chart 1)

6 The paediatric investigation plan (including deferrals) and waivers are subject to approval by the EMEA, based on the opinion of the paediatric committee. The procedure may take up to seven months. Except in cases duly justified, a plan proposal is submitted to the EMEA “not later than upon completion of the human pharmacokinetic studies in adults specified in Section 5.2.3 of Part I of Annex I to Directive 2001/83/EC”. These studies can be completed, for example, where the therapeutic dose range is developed in adults. Hence, the paediatric investigation plan proposal does not necessarily have to be filed before Phase II as initially thought. No specific sanction is set out should the deadline not be met. The scope of the exception to the mandatory timing is not clear and so gives the EMEA a wide range of discretion. A clear example of a “duly justified” case is where the indication is exclusively paediatric. Hopefully, the commission will provide some guidance for other, less obvious cases.

7 Within 60 days of receipt of a request for agreement of a paediatric investigation plan proposal, the paediatric committee gives a reasoned opinion or invites the applicant to amend the proposal. In the latter case, the time limit may be extended by up to 60 days maximum. The same deadline applies to requests for amendments.

8 The paediatric committee's opinion concerns the following:

• the adequacy of the studies proposed by the applicant for collecting the data relating to the use of the medicine for the paediatric population;
• the justification of the studies in respect of the expected therapeutic benefits;
• the appropriateness of the measures envisaged to adapt the formulation to paediatric use; and
• the deferral of studies.

If the paediatric committee considers a waiver appropriate, it gives an opinion against the proposed plan and, on its own initiative, suggests a waiver.

When assessing a paediatric investigation plan proposal or request for a waiver, the committee will take into account existing paediatric studies. The regulatory authorities will do the same when assessing applications. It is unclear to what extent data resulting from investigator-initiated studies in off-label uses would be taken into account.

The committee will also pay attention to any other available information, including the opinions and decisions of the authorities of third countries. As paediatric studies are already mandatory in the US, different requirements or positions of the regulatory authorities (EMEA and Food and Drug Administration) could lead to multiple clinical trials on children and thereby undermine one of the objectives of the regulation.

An applicant may appeal the paediatric committee's opinion on a specific medicinal product within 30 days of receiving the opinion by filing a request for re-examination with the EMEA. In this case, the committee appoints a new rapporteur and renders a new opinion within 30 days of receiving the request. The EMEA decides on the paediatric investigation plan proposal within 10 days of receipt of the committee's final opinion. The EMEA's decision may be challenged before the European Court of Justice.

Other obligations

The pharmaceutical industry is also subject to other obligations, such as pharmacovigilance adapted to the paediatric population, mandatory marketing of the new paediatric indication, and the communication of all paediatric studies to the regulatory authorities.

The applicant must provide precise information on the measures for long-term follow-up of the efficacy and possible adverse events of the paediatric use of the product⁹. Furthermore, where there is a “reason for particular concern”, the regulatory authority must require a risk management system or specific postmarketing studies as a condition for the approval.

On-patent medicines must be marketed with the new paediatric indication within two years of its approval. The obligation, which will be enforced through financial penalties, does not apply to new or off-patent medicines, which remain subject to the general rules (three years from the date of approval). Furthermore, a pharmaceutical company that has benefited from a reward must continue to market the paediatric medicinal product even after the protection gained from the reward expires; otherwise, it has to transfer the marketing authorisation to a third party or consent to abridged applications. It is unclear whether the obligation to market also applies in member states where the product (without the new paediatric indication) is not marketed. The medicine must be approved in all member states for the company to be eligible for the reward, but approval is not tantamount to marketing. Certain medicinal products can be authorised in all member states but marketed in only a few. In such cases, the obligation to market should only apply to the paediatric indication.

The labelling of paediatric medicines must bear a paediatric symbol, which is to be explained in the patient information leaflet. The symbol still has to be chosen by the commission, as the first one suggested was rejected. Companies will have two years from the publication of the symbol to affix it to the packaging of all existing paediatric medicines.

Increased information about the paediatric use of medicines is the second major objective of the regulation. This objective will be realised through the publication of paediatric studies, which will put an additional administrative burden on the industry. Precise information on the clinical trials foreseen by the paediatric investigation plan is recorded in the EudraCT database, and some of this information will be made public. The latter provision is a derogation from Article 11 of the clinical trials directive, which lists the information to be included in EudraCT and expressly requires the commission to ensure confidentiality of the other data. In addition, all other paediatric studies - past, ongoing and future - must be transmitted to the regulatory authorities, which could then update the summary of product characteristics or vary the marketing authorisations.

Rewards

To help sponsors develop and market paediatric medicines, the regulation provides for specific intellectual property rewards as well as regulatory incentives such as free scientific assistance from the EMEA and reduced fees. The reward varies according to the nature of the medicine and is subject to very stringent conditions.

New and on-patent medicines can benefit from a six-month extension of the SPC. The commission chose the SPC because it covers the active substance and thus prevents generic competition for the whole line of products based on the active substance. Although the SPC is indeed an appropriate reward, certain medicines do not have a patent or SPC in each member state (as shown by the “special mechanism” set out by Article 2 of Annex IV to the Accession Treaty). The issue will certainly arise again when the EU welcomes new members. Furthermore, the method for calculating the duration of the SPC is such that certain medicines are not covered by a certificate, so no extension can be obtained¹⁰. Currently, the problem only concerns a small number of products, but this number could well increase as conditional marketing authorisations are granted and the accelerated centralised procedure is used. This creates an imbalance as the paediatric obligation remains in force.

The paediatric nonclinical and clinical data contained in the PUMA dossier benefit from the general data exclusivity protection, ie eight years of data exclusivity followed by two years of marketing protection. In contrast with the reward provided to new or on-patent medicines, it is only granted where the paediatric clinical trials are conclusive and lead to a PUMA.

The PUMA provides a full, separate data exclusivity period for the new paediatric indication. A specific provision was needed, otherwise the global marketing authorisation provisions or, at best, the additional one-year data exclusivity for a new indication for a well-established substance would have applied.

The effectiveness of the PUMA exclusivity will depend on the special formulation for paediatric use as it may otherwise be circumvented via off-label use.

For orphan medicines, the regulation extends the market exclusivity from 10 to 12 years. As a result, orphan medicines that have a patent or SPC may not benefit from the six-month SPC extension. However, if the medicine has two marketing authorisations - one for the indication benefiting from the orphan designation and another for the other indications - the line extension of the latter authorisation should be subject to the general regime (six-month SPC extension).

Article 8 §2 of Regulation (EC) No 141/2000 authorises the commission to reduce the market exclusivity to six years if the orphan designation criteria are no longer met. The paediatric regulation does not grant two additional years of exclusivity but increases the basic duration of the exclusivity from 10 to 12 years. Could the commission still reduce the exclusivity to six years or should the reduction be limited to eight years to take the paediatric reward into account?

Legal requirements for the rewards

The rewards set out by the regulation are granted if the requirements below are met; they apply to new and existing on-patent medicinal products but will be more difficult for the latter.

• paediatric data result from the implementation of the paediatric investigation plan agreed by the EMEA;
• the medicine is approved in all the member states. This is a very stringent requirement as there are now 25 (soon to be 27) member states. Certain medicinal products are not approved in all the old member states, let alone the new ones. Furthermore, applicants have no control over the marketing authorisation procedure - they are dependent on the regulatory authorities for the authorisation to be granted and issued quickly. Therefore, this requirement risks compromising the efficiency of the reward for medicines that are not centrally approved. Also, the term “member states” normally excludes Iceland, Liechtenstein and Norway;
• significant paediatric studies contained in the paediatric investigation plan have been completed after the entry into force of the regulation. A commission guideline will define criteria for assessing the significance of studies. Based on the legislative history, the obligation seems to cover some but not all studies that are necessary or simply relevant for implementing the paediatric investigation plan. The guideline should also define “completed” as this term is very vague and can be interpreted in many ways and on the basis of different rules (clinical trials Directive, ICH guideline E11, etc). In any event, the requirement means that “old” studies, including those submitted to regulatory authorities of third countries before 2007, are lost as far as the reward is concerned;
• for on-patent medicines, where the paediatric research was not conclusive and so did not lead to an approval, the paediatric data must be reflected in the summary of product characteristics and in the patient information leaflet (if the regulatory authority considers it useful for patients);
• an SPC extension has not yet been granted. The duration of the SPC may only be extended once;
• compliance with the paediatric investigation plan and completion of significant studies after entry into force are mentioned in the marketing authorisation. If the application is rejected, the decision will nevertheless contain these statements as they are required for claiming the reward. The link between the SPC extension and the marketing authorisation results in a bizarre situation where the envisaged indication is exclusively paediatric and the results of the paediatric trials are not conclusive. In such a case, the company seems to have no choice but to file an application if it wants to get the reward, knowing that it will be rejected as it is not supported by the data. A paediatric committee opinion (or even decision) on paediatric investigation plan compliance and time of completion of significant studies should have been sufficient in such cases;
• the applicant did not choose to benefit from the additional year of marketing protection although the paediatric studies resulted in the approval of a new paediatric indication that provides a significant clinical benefit under Article 10 of Directive 2001/83/EC or Article 14 of Regulation (EC) No 726/2004. This requirement does not apply to existing medicines because they do not benefit from the new data exclusivity periods; and
• the application for the SPC extension must be filed at least two years before the expiry of the SPC. This time limit is very long, especially as the application is linked to the actual issuance of the MA. The objective of the commission is to inform generic companies early enough that the SPC protection is extended. However, in practice, a time limit of two years means that, even under the best circumstances, only medicinal products whose SPC expires in 2010 and afterward could benefit from the rewards. This would probably have deterred the conduct of paediatric studies for older medicinal products. To avoid this problem, a five-year transitional period is provided for, during which the application for the SPC extension may be filed at least six months before the expiry of the SPC.

Being contingent upon compliance with, and full implementation of, the agreed paediatric investigation plan, the rewards are not granted in cases of a full waiver and are postponed in cases of deferral.

Finally, the positive or negative outcomes of the paediatric studies are not relevant except for off-patent medicines. The objective of the regulation is to promote paediatric research and to better inform health professionals and patients about the safety and efficacy of the paediatric use of medicinal products. Thus, the reward is granted even where the paediatric research does not lead to a paediatric approval as long as the results of the research are disclosed (ie mentioned in the summary of product characteristics) and the studies are transmitted to the authorities. The situation is different for off-patent medicines because the reward is intrinsically tied to the PUMA.

Interactions between the paediatric regime and the current procedure (see Chart 2)

The regulation states that the marketing authorisation procedures are governed by Regulation (EC) No 726/2004 or Directive 2001/83/EC unless otherwise provided. The new paediatric system thus becomes an integral part of the existing approval procedures, triggering some modifications thereto, the most important of which is the validity of the application being contingent upon the fulfilment of the paediatric obligation. The specific provisions of the regulation favour the centralised procedure and entrust the regulatory authorities with new tasks.

First and foremost, the validity of any application is contingent upon the applicant filing, for every subset of the paediatric population and for every new (or, as the case may be, existing) indication, pharmaceutical form and route of administration, paediatric data or a waiver or a deferral, unless the medicinal product is off-patent.

Second, a marketing authorisation application that includes at least one paediatric indication may, at the applicant's choice, go through the centralised procedure or the mutual recognition/decentralised procedure. The use of the centralised procedure aims at accelerating the availability of paediatric medicinal products in the Community and is justified by the Community scale of the rewards. It also helps companies to comply with the requirement that the product be approved in all the member states.

An application for a line extension may not go through the centralised procedure (unless it qualifies for that procedure under the general rules), but the arbitration procedure of Articles 32 to 34 of Directive 2001/83/EC is available to the applicant. If the applicant uses it, the Community decision will impose a common summary of product characteristics. The regulation specifies that harmonisation of the summary of product characteristics will only concern the points to be amended for introducing the new indication, but, in practice, a complete harmonisation cannot be excluded.

The marketing authorisation holder of an off-patent medicine who develops a new paediatric indication has a choice between complying voluntarily with the new paediatric regime and filing a PUMA application, and not complying and filing a simple application for a line extension. In the latter case, the applicant will not benefit from the reward. The PUMA follows the existing authorisation procedures - centralised or mutual recognition/decentralised - and does not prevent the filing of another application for other indications.

The regulation expressly states that PUMA applications may be hybrid applications. Hybrid applications are already allowed under Article 10 of Directive 2001/83/EC, but no data exclusivity is associated with this marketing authorisation when filed by the marketing authorisation holder of the original medicine. The regulation departs from the general pharmaceutical rules by granting data exclusivity to the paediatric data provided in connection to a hybrid application for a PUMA. Recital (20) of the regulation and the “Frequently Asked Questions” published by the commission suggest that an application for a PUMA could also be bibliographical, but this is not confirmed, even implicitly, by a provision in the regulation¹¹. Nevertheless, bibliographical applications should be allowed pursuant to Article 10a of Directive 2001/83/EC.

Finally, the medicinal product approved through a PUMA may have the same denomination as the product for adults where the MA holder is the same person. This option enables companies to benefit from the reputation of the medicine for adults.

Where the paediatric data are consistent with the measures set in the agreed and completed paediatric investigation plan, the regulatory authority includes a statement of compliance in the marketing authorisation. The marketing authorisation will also contain a statement as to whether significant studies have been completed after the entry into force of the regulation as it is also a requirement for the reward.

As for the summary of product characteristics, it will contain the results of the paediatric studies as well as the waiver(s) and deferral(s).

The regulatory authority that grants the approval (marketing authorisation, line extension or PUMA) will decide on compliance with the plan; however, the paediatric committee's opinion may be requested by the applicant or the regulatory authority, depending on the stage of the procedure. In practice, plan compliance is checked in two steps - upon validation of the application and upon its scientific assessment - unless the applicant first requested the committee's opinion. Non-compliance with the plan does not trigger the refusal of the approval or dismissal of the application, but it will deprive the applicant of the reward.

Similarly, it is for the regulatory authority that grants the approval to decide on the quality, safety and efficacy of the paediatric use but, again, the paediatric committee's opinion may be requested.

Sanctions

Violations of the regulation are penalised like violations of Regulation (EC) No 726/2004: financial sanctions and a “list of shame”¹². Financial sanctions may be imposed by the member states but also by the commission at the EMEA's request. The scope of application of the future commission regulation on financial sanctions for pharmaceutical companies will probably be extended to the paediatric regulation¹³. The current draft regulation on financial sanctions sets the maximum financial sanction at 5% of the annual turnover of the marketing authorisation holder in the EU. In addition, the commission may publish the names of the marketing authorisation holders on whom financial sanctions are imposed as well as the amounts and reasons.

Conclusion

The regulation has its pluses and minuses. While the paediatric procedure is an improvement over the draft proposals, having been simplified and specified, the same cannot be said for the requirements to which the rewards are subject. First, three requirements have been added:

• significant studies must be completed after the entry into force of the regulation;
• paediatric data must also be provided for all existing indications, pharmaceutical forms and routes of administration; and
• the applicant must not have chosen the additional year of marketing protection for the same paediatric research.

Second, only one of the most stringent requirements contained in the draft proposals has been softened: a transitional period of five years has been granted for filing applications for SPC extension. Yet, the medicine still has to be approved in all the member states. This requirement will significantly reduce the availability of the rewards, while subjecting a company to its obligations. The industry's only solution is to immediately file marketing authorisation applications in the member states where the product is not yet approved. There is also no reward where a product was developed and approved so quickly that because of the method of calculation of the SPC, it does not have one.

Another possible drawback of the regulation is the large discretion granted to the regulatory authorities for determining both the required paediatric studies and the timing for their completion. This approach follows the general trend of transforming marketing authorisations into tools of public health policy. However, if the authorities are flexible and open to dialogue, this drawback may be transformed into an advantage.

The legal aspects of the regulation are complex and will undoubtedly lead to discussions by the different stakeholders. Furthermore, the debate has expanded to the practical organisation of paediatric studies and their use in both Europe and the US; indeed, organising paediatric research is difficult, and so regulatory authorities and companies are turning to their US counterparts for guidance.

Accentuating the importance of using the same paediatric research in the EU and the US is the difficulty of organising paediatric clinical trials, particularly recruiting patients, and the cost of paediatric research, both of which also affect the rapid availability of paediatric medicines. There also is a legal reason: ICH guideline E11 prohibits useless paediatric studies. This highlights the importance, in the short term, of the requirement relating to the completion of significant paediatric studies after the entry into force of the regulation and, in the long term, of collaboration between the European and US regulatory authorities.

That important point was not missed by the EU. For several years, the EMEA and FDA have exchanged paediatric data and recently EU personnel have been working closely with the FDA to be ready by the time the regulation enters into force. Ideally, the EU and the US would adopt the same or very similar paediatric rules rather than try to interpret or apply similarly different rules, but we are not there yet despite the increasing globalisation of regulatory issues.

What this means, in essence, is that the success of the regulation is not in the hands of the pharmaceutical industry but in those of the regulatory authorities. Flexibility and collaboration with both the applicants and the other regulatory authorities will be key.

This article has been written on the assumption that the final version of the regulation will be identical or very similar to the version adopted by the European Parliament at second reading.

References

1. ICH Guideline E11 (Harmonized Tripartite Guidelines on Clinical Investigation on Medicinal Products in the Paediatric Population), 19 July 2000, www.ich.org/cache/compo/475-272-1.html#E11

2. Note for guidance on clinical investigation of medicinal products in the paediatric population (CPMP/ICH/2711/99), 27 July 2000, www.emea.eu.int/pdfs/ human/ich/271199en.pdf

3. Directive 2001/20/EC of 4 May 2001, http://europa.eu/eur-lex/pri/en/oj/ dat/2001/l_121/l_12120010501en00340044.pdf

4. Best Pharmaceuticals for Children Act 2002 and Pediatric Research Equity Act 2003, G Michaux and R Miller, Promoting Paediatric Drug Research in the US and the European Union, The Regulatory Affairs Journal - Pharma, 2005, 16(6), 411-417

5. Regulation (EEC) No 1768/92 of 18 June 1992 on supplementary protection certificates for medicinal products, http://europa.eu.int/smartapi/cgi/ sga_doc?smartapi!celexapi!prod!CELEXnumdoc&lg=EN&numdoc=31992R1768&model= guichett

6. Joint European Commission/EMEA Document: Priorities for Implementation of the Regulation on Medicinal Products for Paediatric Use, published by the Commission on 25 September 2006, www.emea.eu.int/pdfs/human/peg/ EC_EMEA_Paediatric%20Regulation.pdf

7. Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the member states relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use, http://eudract.emea.eu.int/docs/Dir2001-20_en.pdf

8. Draft ethical considerations for clinical trials performed in children, recommendations of the ad hoc group for the development of implementing guidelines for Directive 2001/20/EC relating to good clinical practice in the conduct of clinical trials on medicinal products for human use, 4 October 2006, http://ec.europa.eu/enterprise/pharmaceuticals/paediatrics/docs/ paeds_ethics_consultation20060929.pdf

9. Guideline on the conduct of pharmacovigilance for medicines used by the paediatric population, 28 June 2006, www.emea.eu.int/pdfs/human/phvwp/ 23591005en.pdf

10. Article 13 of Regulation (EEC) No 1768/92

11. Regulation on medicines for children: frequently asked questions, 29 September 2004, p 12, http://ec.europa.eu/enterprise/pharmaceuticals/ paediatrics/docs/paeds_memo_29_sept.pdf

12. Article 84 of Regulation (EC) No 726/2004, http://ec.europa.eu/enterprise/ pharmaceuticals/eudralex/vol-1/reg_2004_726/reg_2004_726_en.pdf

13. Draft Commission regulation concerning financial penalties for infringements of certain obligations in connection with marketing authorisations granted under Regulation (EC) No 726/2004, http://pharmacos.eudra.org/F2/pharmacos/docs/Doc2005/02_05/Penalties%20-%20Public%20consultation%2002%202005.pdf