More Obligations for the Same Reward?

On 26 April 2023, the European Commission published its long awaited proposal to revise the EU’s general pharmaceutical legislation.  As expected, the Commission’s proposal represents a significant overhaul of the EU medicine rules.  Not least the incorporation of the EU’s amended paediatric and orphan medicine rules into a single new draft Regulation that will amend and replace Regulation (EC) No 726/2004 (the draft Regulation).  The proposal also includes a new draft Directive that will amend and replace Directive 2001/83/EC (the draft Directive).  For an overview of the Commission’s proposal and its potential impact on orphan medicines, see our blogs here and here, respectively.

For paediatric medicines, the draft Directive and Regulation introduce several key changes, especially for paediatric investigation plans (PIPs).  Overall, the theme is more stringent obligations and scrutiny of PIPs countered somewhat by a “new evolutionary [step-wise] PIP system” to ease the regulatory burden.  These changes are accompanied by a general increase in transparency and an explicit obligation to place an authorised product with a paediatric indication on the market in every Member State where the adult presentation is marketed.  However, the main potential reward remains unchanged in the form of a 6-month supplementary patent certificate (SPC) extension, but importantly it will also apply to orphan medicines (i.e., the current separate reward of two years market exclusivity for paediatric indications of orphan products will no longer apply).  That said, the 6-month SPC extension will not apply if an applicant obtains a 12-month extension of data protection on the basis of the new paediatric indication “bring[ing] a significant clinical benefit in comparison with existing therapies.”  Failure to comply with certain obligations risks the Commission imposing a financial penalty. 

The Commission contends the proposed changes will achieve its objectives to: (i) foster innovation and research to address unmet medical needs in the paediatric population; and (ii) increase access to innovative paediatric medicines, whilst at the same time streamline regulatory procedures.  Although industry will welcome changes that simplify the PIP procedure, it is disappointing that the main incentive remains the same despite the proposed increase in obligations and commensurate efforts that will be required.  On the other hand, the potential 6-month SPC extension will now also apply to orphan products and there is scope for the EU and Member States to provide further incentives for the research and development of paediatric medicines.

Below we have highlighted some key points for paediatric medicines together with our headline observations.

1. General Principles & Paediatric Requirement

• The draft Regulation builds on the current system of obligations and rewards under the Paediatric Regulation (EC) No 1901/2006.  These are underpinned by themandatory requirement for marketing authorisation applications (MAAs) for new medicinal products, and for certain variations to authorised products covered by a SPC or a patent qualifying for a SPC, to include studies completed in compliance with a PIP (the Paediatric Requirement). 

• Under the draft Directive, the Paediatric Requirement will be extended to apply to:

• variation applications for new strengths (in addition to currently new indications, new pharmaceutical forms and new routes of administration) of authorised products covered by a SPC or a patent qualifying for a SPC; and

• hybrid and bio-hybrid MAAs where the medicinal product is protected either by a SPC or a patent qualifying for a SPC.

• Also, there is scope for the Paediatric Requirement to be temporarily waived in the case of public health emergencies for medicinal products “intended for the treatment, prevention or medical diagnosis of a serious or life-threatening disease or condition which are directly related to the public health emergency.”  

• The current Paediatric Committee (PDCO) will disappear.  The European Medicines Agency (EMA) can consult the Committee for Medicinal Products for Human Use (CHMP) or working parties, before taking a decision on a PIP, but this is optional.

2. Increased PIP Obligations & EMA Scrutiny

• Under the draft Regulation, the EMA may impose a PIP based on a mechanism of action when a waiver is sought.  That is,where the medicinal product is directed at a molecular target that is “responsible for a different disease or condition in the same therapeutic area in children” than the one for which the product is intended for in adults and that does not occur in children.

• PIPs will need to be more prescriptive and “describe any measures to adapt the pharmaceutical form, the strength, the route of administration and the eventual administration device” of the product for the paediatric population.

• Except in duly justified cases, PIPs (or an application for a waiver) must be submitted to the EMA “before the initiation of safety and efficacy clinical studies” in the adult population.  Notably, late submission of a PIP may be subject to a financial penalty.

• The EMA, as part of its assessment of a PIP application, “may request the applicant to propose modifications to the plan.”  Also in respect to an agreed PIP, the Agency can request the applicant to propose changes.

• Discontinuation of a PIP triggers a reporting obligation to the EMA “no less than six months before the discontinuation” and the applicant must provide reasons.  The EMA will publish this information.  Also, failure to notify the EMA of an intention to discontinue a PIP may be subject to a financial penalty.

3. New Adapted PIP Procedure

• To reduce the regulatory burden of the above increased PIP obligations, in particular with respect to the timing of a PIP submission, an applicant may submit “an initial” PIP:

• when the active substance is not yet authorised in any medicinal product in the EU and is intended to treat a novel paediatric condition; or

• when it is not possible to submit the PIP in accordance with the standard timelines “on the basis of scientifically justified reasons.”

• An initial PIP will “contain only the details and timing of the measures proposed to assess the quality, safety and efficacy of the medicinal product” at the time of submission.  However, the PIP will need to include “precise timing[s]” of when updated PIPs, and the final PIP, are expected to be submitted to the EMA.  Failure to provide updates per the agreed timeline may incur a financial penalty.

• The ability to submit an initial PIP will provide applicants with flexibility to amend and modify a PIP in line with the clinical development of a product and should reduce the administrative burden for companies, at least for the initial PIP application.

4. Deferrals & Waivers

• The draft Regulation, like the current regime, empowers the EMA to grant waivers and/or deferrals from the Paediatric Requirement, but introduces some key changes, including:

• Product or class waivers for diseases and conditions that occur only in adults will be only granted in circumstances where a PIP cannot be imposed based on the product’s or class’ mechanism of action for another disease or condition in children (see above).  This provision is intended to increase the number of medicines studied for use in the paediatric population and will align the EU regulatory framework with an existing similar mechanism of action obligation in the US.

• The EMA can “at any time adopt a decision reviewing an already granted waiver.”  Where a waiver is revoked, the Paediatric Requirement will not apply for 36 months from the date of its removal from the EMA’s list of waivers.

• Deferrals will be time specific and limited to a maximum initial period of 5 years, but may be prolonged “in duly justified cases.”  A prolongation of the derogation cannot exceed 5 years.

5. Rewards & Placing on the Market

• The main incentive for completing paediatric studies in compliance with a PIP will remain the same in the form of a 6-month SPC extension.  This will also apply to orphan medicines, which under the current regime have a separate reward in the form of two years market exclusivity.  However, the 6-month SPC extension will not apply if an applicant obtains a 12-month extension of data protection on the basis of the new paediatric indication “bring[ing] a significant clinical benefit in comparison with existing therapies.”  

• For products granted a paediatric use marketing authorisation (that include the results of studies conducted in compliance with an agreed PIP), independent data and marketing protection periods proposed by the Commission in the draft Directive will apply (see our blog here).

• Paediatric medicines also will be eligible for incentives made available by the EU and by Member States “to support research into, and the development and availability of, paediatric medicinal products.”  It is not yet clear what form these incentives might take.

• The obligation on marketing authorisation holders (MAHs) to place an authorised product with a paediatric indication on the market within 2 years will be clarified to specify:

• the deadline will run from the date on which the paediatric indication is authorised; and

• require the MAH to “place the medicinal product on the market taking into account the paediatric indication in all Member States where the medicinal product is already placed on the market.”  In other words, it will not suffice to place the product with the paediatric indication (where appropriate, a new paediatric presentation or formulation) on the market in any single Member State.  The proposed change is consistent with current EMA guidance, but changes the existing wording in Article 33 of the Paediatrics Regulation.

• Failure to comply with the obligation to place the product on the market within 2 years of the date on which the paediatric indication is authorised may be subject to a financial penalty.  Also, failure to notify the EMA of an intention to discontinue to place a product on the market, no less than six months before the discontinuation, may be subject to a financial penalty.

6. Clinical Trials & Transparency

• The current obligation to submit the results of paediatric trials conducted in a third country included in an agreed PIP to the Clinical Trials Information System (CTIS) (within 6 months from the end of the trial) will be extended to include MAH-sponsored paediatric studies conducted in third countries where they form the basis of a variation, irrespective if they are included in a PIP.

• In addition, certain information on paediatric trials conducted in a third country (e.g., clinical trial protocol, investigational product, therapeutic indication, trial population etc.) must be submitted to CTIS before the trial starts.

• The draft Regulation includes other transparency enhancing provisions, including:

• the publication of information on discontinued PIPs (see above); and

• requires the EMA to publish “at least on an annual basis” information regarding the number of PIPs agreed and completed, details of waivers, deferrals, renewals, rewards and incentives granted and companies that have failed to comply with their obligations.

Finally, we note that the draft Regulation includes the option for the Commission to adopt implementing acts and guidelines to further clarify and prescribe arrangements for certain aspects of the revised paediatric rules e.g., adapted PIP procedure, content of PIPs etc.  We are therefore likely to see further developments for paediatric medicines in future legislation and guidelines.

This blog is based on the wording of the EU’s proposal published on April 26, 2023.  This wording could significantly change during the legislative process.  Our Dublin, Brussels, Frankfurt and London teams will continue to monitor this legislation.  We will be hosting a webinar to discuss the impact on 9 May.  To sign up for the webinar please click here.

In the meantime, if you would like to discuss the proposed changes, please contact our specialist EU life sciences lawyers: Peter Bogaert, Grant Castle and Marie Doyle-Rossi.