But finishing was never part of the (paediatric investigation) plan…

The High Court recently decided on Dr Reddy’s application to revoke the six-month paediatric extension of Warner-Lambert’s supplementary protection certificate (SPC) for atorvastatin (Lipitor), which is used for lowering blood cholesterol.

Background
SPCs are granted to compensate patent holders for the time taken to obtain marketing authorisation for a medicine covered by a patent. An SPC comes into effect at the end of the patent’s term. It extends the protection for the authorised medicine for a period equal to that between the filing date of the patent and the date of the first marketing authorisation, up to a maximum of five years.

Provision for the extension of SPCs was introduced by the EU Paediatric Regulation (1901/2006), which took effect in January 2007. The regulation’s purpose is to encourage research into the use of medicines in children. This research is considered to be important because, as noted in Recital 3 of the regulation, a lack of information in this area leads to increased risks of adverse reactions, ineffective treatment through under-dosage and the non-availability to the paediatric population of therapeutic advances, suitable formulations and routes of administration. However, in this regard there is no requirement that the medicine be authorised for paediatric use for an extension to the SPC to be granted following the research. The discovery that the medicine is ineffective in the paediatric population is also considered valuable information.

In order to obtain a paediatric extension, the applicant must complete a number of steps, including the following:

• Draw up a draft paediatric investigation plan (PIP) and submit it to the European Medicines Agency, through the Paediatric Committee, for agreement. The PIP should specify the timing and measures proposed to assess the quality, safety and efficacy of the medicine in the paediatric population. In addition, it should also describe any measures to adapt the formulation of the medicinal product to make its use more acceptable, easier, safer or more effective. The proposed PIP is assessed by the committee, which may request modifications to the plan. The committee then adopts an opinion as to whether the proposed studies will generate the necessary data and whether they are justified by the envisaged benefits. The European Medicines Agency issues a decision, annexing the committee’s opinion. 
• Apply for a marketing authorisation, including the decision agreeing to the PIP and the results of all studies performed and details of all information collected in compliance with the agreed PIP. The competent authority (ie, the body that grants marketing authorisations) which has received the application will verify that the PIP has been complied with. 
• Apply to the national patent offices for a paediatric extension to its SPCs, if the applicant has been issued a marketing authorisation indicating compliance with the PIP.

Paediatric extension for atorvastatin
Pfizer had proposed new pharmaceutical forms for oral atorvastatin, which was more appropriate for children aged six years and up than the previously authorised film-coated tablet.

The agreed PIP required three clinical studies:

• A bioequivalence study to check the bioavailability and effectiveness of the new form in comparison to the existing formulation in healthy adult volunteers.
• A pharmacokinetic study to determine dosing.
• A three-year study of safety and efficacy.

The PIP specified that the first study was to be completed by 30th September 2009 and the second study by 30th December 2009. However, the third study was required to be commenced by 31st March 2009. In due course an extension to the SPC was granted on the basis of a decision that the studies conducted by Pfizer were in accordance with the PIP, as the first and second studies had been completed and the third study had been started.

Court’s judgment
Three grounds for revocation were advanced by Dr Reddy’s, but all were dismissed by the court.

First, Dr Reddy’s argued that the European Medicines Agency acted incorrectly by approving a PIP that required Pfizer merely to commence the third study, and as such the PIP was not lawfully approved and Pfizer was not entitled to the extension. However, the court instead assessed that the relevant question was whether the requirements of the PIP had been fulfilled. In completing the first and second studies and initiating the third study, it judged that Pfizer had indeed complied.

Second, Dr Reddy’s argued that pursuant to Article 45(3) of the regulation, a paediatric extension should be granted only when "significant studies" contained in the PIP have been completed. It alleged that at no stage had any assessment been performed as to whether either of the two completed studies was significant; it further alleged that they were not significant. However, the court decided that Article 45(3) was a transitional provision which related to research performed before the regulation came into effect. Accordingly, it did not apply in this case.

Finally, Dr Reddy’s argued that even if it was legitimate for the European Medicines Agency to approve a PIP that required the initiation, but not completion of the third study, Pfizer was not entitled to an extension unless it included the results of the completed third study within its marketing authorisation application. Here, the court considered that this argument also failed once it had been decided that Pfizer had complied with the PIP.  

A further issue in this case related to the interpretation of Article 16 of the EU SPC Regulation (469/2009), which sets out that the paediatric extension may be revoked if granted contrary to the requirements of Article 36 of the paediatric regulation. Dr Reddy’s argued that this would oblige the court to revoke the extension of the SPC if it had been granted when this article of the paediatric regulation had not been complied with, but Pfizer argued that it merely gave the court discretion to do so. On this point, the court also agreed with Pfizer.

Comment
This decision is of interest in clarifying the interpretation that the UK courts will take with regard to whether a PIP has been completed. However, as SPCs are dealt with on a national basis, there is significant potential for contradictory judgments to be issued in different countries, meaning that it is only when questions of this type have been referred to the European Court of Justice that the issues raised in this case will be definitively addressed. Bearing in mind that this legislation is relatively new, it is likely that many further issues of interpretation will be raised in due course. This is even more so because the paediatric extension extends the SPC and so coverage for the authorised medicine, irrespective of the indication, at the tail-end and hence most valuable part of an SPC’s life.