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Paediatric regulation

2 February 2016 www.scripregulatoryaffairs.com © Informa UK Ltd 2016

Complying with post-marketing requirements under Article 33 of the EU Paediatric Regulation can be a confusing affair for drug companies. The wording of Article 33 is unclear and can be interpreted in ways that would impose a heavy additional burden on companies and defeat the objective of the provision which is to ensure that pediatric medicines are available to children who need them.

Over the next few years, many more pediatric medicines are expected to start appearing on the European Medicines Agency's register of deadlines for putting such products on the market. As such, the need for clarification on how to interpret Article 33 is becoming more pressing.

Placing Products on the Market The Paediatric Regulation (Regulation (EC) No 1901/2006), which came into force in 2007, is designed to improve the availability of medicines for children1. It requires that pharmaceutical companies test in children new medicinal products (i.e., medicines containing a new active substance for the applicant) as well as new indications, pharmaceutical forms or routes of administration of "old" medicinal products that are still protected by a supplementary protection certificate (SPC) or a patent that qualifies for an SPC.

The tests have to conform to a pediatric investigation plan (PIP) agreed upon by the European Medicines Agency. In exchange for the tests and subject to certain conditions being met, the company is eligible for a six-month extension to the SPC or, if the product has an orphan designation, two additional years of market exclusivity (i.e., market exclusivity extension).

"Old" medicinal products that are not protected by an SPC or a patent that qualifies for an SPC are not subject to mandatory pediatric testing but in these cases the company may opt to implement a PIP in exchange for a pediatric use

marketing authorization (PUMA), which triggers data exclusivity for the new pediatric data.

If the pediatric studies mandated in the PIP are successful, a new pediatric medicinal product or a new pediatric indication, form or route of administration can be authorized. Typically, a PIP includes the deferral of one or more pediatric studies so that, in practice, a pediatric product is often authorized several years after the adult version of the product (if any).

Developing and gaining authorization for pediatric products, however, is not the end of the story: pharmaceutical companies are also required to place the drug on the market and to continue marketing it. Article 33 of the Paediatric Regulation provides that:

[W]here medicinal products are authorised for a paediatric indication following completion of an agreed paediatric investigation plan and those products have already been marketed with other indications, the marketing authorisation holder shall, within two years of the date on which the paediatric indication is authorised, place the product on the market taking into account the paediatric indication. A register, coordinated by the Agency, and made publicly available, shall mention these deadlines.

Once the pediatric product is on the market, Article 35 of the regulation ensures that it remains there. According to Article 35, marketing authorization holders who intend to discontinue placing a product on the market must either transfer the pediatric marketing authorization or to give consent to a third party to use the pharmaceutical, preclinical and clinical documentation contained in the file of the medicinal product. This obligation, however, only applies if the company has benefited from an SPC or market exclusivity extension.

The EMA's register of deadlines for putting pediatric medicinal products on the market in accordance with Article 33 currently lists

fewer than 30 pediatric products. However, many more products are expected to appear on the list in the coming years as around 1,300 PIPs have been agreed on by the EMA since the entry into force of the Paediatric Regulation and around 100 of these PIPs have already been completed.

As such, Article 33 will become increasingly important. Yet, its wording is unclear and to our knowledge, neither the European Commission nor the EMA has adopted an official guideline on the provision.

Several interpretations of Article 33 are possible depending on whether the focus is on: • internalconsistencywithinArticle33;• thebalancebetweenpediatricobligationsandrewards;

• sunsetclauses;or• publichealth.Moreover, all of these interpretations would impose a heavy additional burden on companies, thereby conflicting with the principle of proportionality as applied in light of the objective sought by Article 33. Under this principle, companies should not be required to place pediatric products on the market in more than one EEA country provided that they can ensure supplies to the other national markets in a timely fashion, and in more than one pediatric form or strength.

What products? According to Article 33, the obligation to place on the market applies to (i) a pediatric indication of (ii) an authorized medicinal product that (iii) has already been marketed with other indications. In other words, Article 33 concerns medicinal products that have already been placed on the market and to which a new pediatric indication is added. It does not cover a new pediatric medicinal product or a new pharmaceutical form of an existing pediatric product.

When? With regard to the time period for placing on the market, Article 33 refers to both the authorization of the pediatric

The Need For Clarification On Post-Market Requirements For Pediatric Medicines Geneviève Michaux explains why guidance is needed to interpret the post-marketing requirements for drugs under the EU Paediatric Regulation.





product and the completion of the PIP. It assumes that the completion of the PIP occurs before the authorization of the pediatric product, but this is not always the case. A PIP can be completed after the authorization of the pediatric indication, depending on its content. This was especially the case before the EMA adopted its policy on the scope of PIP decisions in September 2009, before which a PIP could cover several conditions, meaning that companies could finish the studies for one pediatric indication but still need several more years before they could complete the PIP. Now the content of the PIP is tied much more closely to that of the marketing authorization application. Pursuant to Article 33, the obligation to market applies two years after the authorization of the pediatric product or upon completion of the PIP, whichever is the latest.

The two-year period does not take into account the time required for national decisions on pricing and reimbursement so that, in some cases, companies may have to market a pediatric product that is not yet reimbursed. This is not an issue in countries, such as Italy, where the health authority only considers the variation to the marketing authorization after pricing and reimbursement have been decided. Yet, proceeding in this manner delays the authorization of the variation, i.e., of the pediatric indication, and thereby jeopardizes the reward.

How? An ancillary but important question relates to the form of the pediatric product. The new pediatric indication may be available in more than one pharmaceutical form, e.g., the form which was initially developed for adults (for example, tablets) and a specific form that was mandatory under the PIP (for example, a syrup). What form should be placed on the market? The same kind of question applies to the strength of the pediatric product.

Under a teleological interpretation of the Paediatric Regulation, both forms (in this case tablet and syrup) should be marketed on the grounds that the pharmaceutical forms which were expressly developed for the pediatric indication are tied to, or embedded in, that indication.

But under a teleological interpretation of Article 33, one form is sufficient, provided that it is the form which is especially designed for children. Under a sunset clause-like interpretation (see below), one form is sufficient at the company’s choice. Yet, Article 33 is silent on this issue and,

therefore, it can be argued that it does not impose any obligation on companies.

on What Market? While it is clear that a company must place the pediatric product on the market, what is not clear is on which market the product must be placed. Should it be marketed in each EEA country, the EU, or only certain EEA countries? Several interpretations are possible depending on the focus adopted as discussed below.

Internal Consistency in Article 33: Article 33 uses the terms "marketed" and "place on the market". Contextual interpretation calls for internal consistency, which requires that the same term be given the same meaning throughout a piece of legislation and even more so throughout a legal provision. The wording of Article 33 thus suggests that the pediatric product must be placed on those markets of the EEA countries in which the medicinal product has already been placed.

Sunset Clause: The term "market" in Article 33 can also be read in light of the interpretation of general sunset provisions, as they contain the same obligation (i.e., to place on the market within a certain time limit) and use a similar wording.

Pursuant to sunset clauses, a marketing authorization ceases to be valid if: (i) the authorization is not followed by the actual placingoftheproductonthemarket;or(ii)if the medicinal product is no longer actually present on the market for three consecutive years.

For products approved under the EU's centralized procedure, the sunset provisions are contained in Article 14 (4) to (6) of Regulation 726/2004 and, according to the EMA's post-authorization Q&A document on the so-called "sunset clause", the marketing authorization remains valid if at least one presentation/pack size of the product is placed on the market in the EEA (in at least one EEA country)2. For nationally approved products, the sunset provisions are contained in Article 24 (4) to (6) of Directive 2001/83. The obligation is met if, in the EU member state that has granted the marketing authorization, at least one presentation is placed on the market and at least one of the pack sizes of this presentation is marketed3. In short, the reference is one national market for centrally approved medicinal products and, for nationally approved products, the national markets where the product is authorized.

However, the legislative history of the Paediatric Regulation suggests that Article 33 should not be treated as a sunset clause.

During the legislative process for the regulation, the European Parliament amended the initial version of Article 33 so that regulators could be allowed to grant derogations under exceptional circumstances. The commission and the Council of the European Union, however, rejected parliament's amendments on the ground that such derogations would conflict with sunset clauses in general, indicating that these clauses also apply to pediatric medicinal products.

Balance Between Obligations and Rights: The Paediatric Regulation uses the carrot and stick approach, forcing pharmaceutical companies to fulfill stringent obligations in exchange for rewards. This approach makes it necessary to maintain a balance – or a parallelism – between obligations and rewards, including with regard to territorial scope. This interpretation is supported by Article 35, which restricts the obligation to continue marketing a pediatric product to companies that benefitted from the pediatric reward.

The market exclusivity extension has an EU-wide scope as it is specific to orphan medicines, which are products that fall under the mandatory scope of the centralized procedure. The situation is more complex for the SPC extension. Although the SPC results from the SPC Regulation (Regulation (EC) No 469/2009) and thus is technically available in all member states and the three EFTA states, it is not automatically granted in all EEA countries.

In each EEA country, an SPC may only be granted if the substantive and procedural conditions are met, in particular a national patent and a national marketing authorization. If a patent or a marketing authorization has not been granted in an EEA country, the company will not have a SPC in that country. Thus an SPC extension may well not be granted in all the EEA countries. In fact, an SPC in all the 31 EEA countries would be the exception rather than the rule. In short, for the SPC extension, the obligation to market the pediatric medicinal product should be limited to the EEA countries where an SPC extension was actually granted for the active substance.

Protection of Public Health: The commission appears to consider that the reference to the "interest of public health" in Recital 25 of the Paediatric Regulation, together with Article 35's aim to ensure the "continuing availability of safe and effective medicinal products authorised for





paediatric indications developed as a result of [the Paediatric] Regulation", suggest that the pediatric products should be available in all EEA countries.

Principle of Proportionality The principle of proportionality "requires that measures adopted by Community institutions do not exceed the limits of what is appropriate and necessary in order to attain the objectives legitimately pursuedbythelegislationinquestion;when there is a choice between several appropriate measures recourse must be had to the least onerous, and the disadvantages caused must not be disproportionate to the aims pursued."4 The objective of Article 33 is to ensure that the pediatric product is available to children who need it. This objective can be reached if the pediatric product is placed in one of the pediatric forms mandated by the PIP, on one national market and the company can organize efficient and timely supplies to the other national markets. All the interpretations discussed above would impose a heavier burden on companies and, as such, would infringe the principle of proportionality.

Sanctions While companies that fail to comply with Article 33 of the Paediatric Regulation will not lose their pediatric authorization (Article 33 is not a sunset clause) or their eligibility for the pediatric reward, they do face sanctions in the form of financial penalties and/or they can be named and shamed. This is confirmed by Article 1(25) of Commission Regulation No 658/2007 on financial penalties5.

As more and more pediatric medicines start to appear on the EMA's register of deadlines for putting such products on the market, the need for clarification on how to interpret the provision will become increasingly important.

references1. Regulation (EC) No 1901/2006 of 12

December 2006 on medicinal products for paediatric use, OJ, Dec. 27, 2006, L378, 1-19, http://ec.europa.eu/health/files/eudralex/vol-1/reg_2006_1901/reg_2006_1901_en.pdf

2. EMA, Questions and answers on the application of the so-called “sunset clause” to centrally authorised medicinal products, Feb 23, 2006, www.ema.europa.eu/docs/en_GB/

document_library/Medicine_QA/2009/10/WC500004122.pdf

3. European Commission, Notice to Applicants, Volume 2A, Procedures for marketing authorisation, Chapter 1 – Marketing Authorisation, Section, 2.4.2, July 2015, http://ec.europa.eu/health/files/eudralex/vol-2/a/vol2a_chap1_201507.pdf

4. CJEU, Etimine, C-15/10, § 124, July 22 2011, See also, for example, CJEU, Afton Chemical, C-343/09, §45, July 8, 2010; CJEU, Maizena and Others, C-137/85, § 15, Nov. 18, 1987; CJEU, Pfizer Animal Health v Council, Case T 13/99, § 411, Sept. 11, 2002; GC, Cheminova and Others v Commission, T-326/07, § 194, March 26, 2009; GC, Bayer CropScience and Others v Commission, T-75/06, § 223, Sept. 9, 2008

5. Commission Regulation (EC) No 658/2007 of 14 June 2007 concerning financial penalties for infringement of certain obligations in connection with marketing authorisations granted under Regulation (EC) No 726/2004 of the European Parliament and of the Council, OJ, June 15, 2007, L 155, 10-19, http://ec.europa.eu/health/files/eudralex/vol-1/reg_2007_658/reg_2007_658_en.pdf

Geneviève Michaux


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