European pharmaceutical legislation is about to undergo fundamental reform. The planned changes relate in particular to the simplification and shortening of the approval procedure. But what exactly is changing?
The pharmaceutical package presented by the EU Commission on April 26 2023, contains far-reaching changes to the regulations governing the timeframe of the marketing authorization process for medicinal products. Relevant regulations find their way into the reform via the proposal of the recast of Directive 2001/83/EC (hereinafter: Directive Draft) and the proposal of a new Regulation amending Regulation (EC) No 1394/2007 and Regulation (EU) No 536/2014 and repealing Regulation (EC) No 726/2004, Regulation (EC) No 141/2000 and Regulation (EC) No 1901/2006 (hereinafter: Regulation Draft).
The aim of the reform of the marketing authorization procedure is - as can be seen from the recital (42) of the Directive Draft and recital (34) of the Regulation Draft - the fundamental reduction of the total duration of the marketing authorization procedure from 210 days to 180 days. This reduction is to be made without any negative impact on the standards or quality of the scientific evaluation of medicinal products in order to continue to ensure the quality, safety, and efficacy of medicinal products. The period between the opinion of the Committee for Medicinal Products for Human Use (CHMP) and the final decision of the Commission on national marketing authorizations, especially in the case of referrals, is to be reduced in principle to 46 days (cf. recital (146) Directive Draft and recital (49) Regulation Draft).
The Directive Draft itself regulates the procedure for national approval procedures only in a rather basic manner. The regulation of this procedure is to remain in the hands of the member states. Article 31 of the Directive Draft regulates the possibilities of national authorization procedures and the possibilities of extending national marketing authorizations across the EU and refers to the following regulations:
The centralized approval procedure, on the other hand, is conclusively regulated by the Regulation Draft. The relevant regulations can be found in Article 10-13 of the Regulation Draft.
The provision of Article 32 para. 1 Directive Draft is limited to the fact that the application for a national marketing authorization must be submitted to the competent authority of the Member State in which the marketing authorization is sought. The competent authority of the Member State concerned then examines the application and grants the marketing authorization in accordance with Articles 43 to 45 of the Directive Draft and the applicable national provisions.
However, neither Article 32 of the Directive Draft nor the referenced provisions set deadlines within the framework of the purely national procedure, so that the timing of the approval procedure remains in the hands of the respective member state. It remains to be seen which changes are to be expected in detail. In any case, the Member States are required by Article 30 of the Directive Draft to take all measures to guarantee a procedure duration of less than 180 days.
The drafts do not change the existing procedures currently in place at the EU level: decentralized procedure, mutual recognition procedure, or centralized procedure.
However, the decisive factor for the reduction of the duration of the procedure under the decentralized procedure and the mutual recognition procedure is the reduction of the period of cooperation of the Member States. In the framework of the centralized procedure, the shortening of the overall duration results from the accumulation of several small reductions in time.
Both in the previous procedure and in the procedure underlying the reform, the competent authority of the Reference Member State (RMS) chosen by the pharmaceutical entrepreneur undertakes the scientific evaluation of the medicinal product on behalf of the other Member States involved, coordinates the procedure and prepares the Assessment Report (AR).
In contrast to the previous legal situation, according to which the procedure at the European level pursuant to Article 17 of Directive 2001/83/EC should take a maximum of 210 days after the date of submission of the valid application, the procedure according to the intended reform pursuant to Article 30 of the Directive Draft should now take a maximum of 180 days after submission and validation of the valid application.
It remains the same that within 120 days after validation of the application, an Assessment Report, a summary of product characteristics, the labeling, and the package leaflet are to be prepared by the RMS and transmitted to the member states concerned and to the applicant, Article 28 para. 3 RL 2001/83/EC, Article 34 para. 5 Directive Draft.
New is, however, that the competent authorities of the Member States can then approve the Assessment Report, the summary of product characteristics, the labeling, and the package leaflet within 60 days of receipt of the Assessment Report within the Coordination Group for Mutual Recognition Procedures and Decentralized Procedures (CMDh). For this purpose, they inform the competent authority of the RMS, Article 34 para. 6 Directive Draft. Until now, the member states have had 90 days for this process, cf. Article 28 para. 4 RL 2001/83/EC. This reduction is the essential measure to reduce the duration of the procedure from 210 days to 180 days.
After completion of the procedure at the European level, the member states must grant a national marketing authorization within 30 days after confirmation of the agreement by the RMS, both according to the current legal situation and according to the intended reform, Article 28 Par. 5 Directive 2001/83/EC, Article 34 Par. 7 Directive Draft. The Directive Draft explicitly refers to the new Article 43-45 Directive Draft, according to which a marketing authorization can also be granted under conditions and with regard to exceptional circumstances.
If the member states disagree on the granting of the marketing authorization of the medicinal product, the procedure continues as before the CHMP, which prepares an opinion within 60 days, Article 32 Para. 1 Directive 2001/83/EC, Article 42 Para. 1 Directive Draft. New is, however, that the applicant can only file an objection within 12 days instead of 15 days after receipt of the opinion. It remains the same that the applicant has 60 days from receipt of the opinion to justify this objection. The CHMP will then continue to examine the justification within 60 days, cf. Article 41para. 4 of the Directive Draft.
The final opinion of the CHMP is then communicated within 12 days to the competent authorities of the Member States, the Commission, and the applicant, Article 41 para. 5 of the Directive Draft. The Commission then has 12 days to prepare a draft of its decision. A further change is that the Member States are no longer granted the 22-day period for comments specified in Article 34 para. 2(b) of Directive 2001/83/EC. Rather, it results from the interaction of Article 42 para. 1 subpara. 2 of the Directive Draft and Recital 150 of the Regulation Draft that the Commission may, in duly justified cases, refer the opinion of the CHMP back to the CHMP for reconsideration. However, this review period should not exceed 10 days. Following this, the Commission will no longer have 15, but only 12 days to make a final decision according to the planned reform, Article 42 para. 2 Regulation Draft. In Accordance with the current legal situation, this is followed by a 30-day period for national implementation, Article 42 para. 4 Directive Draft.
The duration of the mutual recognition procedure is currently 180 days. The member state in which a national marketing authorization was granted automatically acts as RMS and prepares the Assessment Report within 90 days on the basis of the marketing authorization granted, Article 28 para. 4 of Directive 2001/83/EC.
The new Directive Draft now regulates the mutual recognition procedure and the decentralized approval procedure in two separate standards: Article 34 Directive Draft for the decentralized procedure and Article 36 Directive Draft for the mutal recognition procedure.
Article 35 of the Directive Draft requires for the application of the mutual recognition procedure a national marketing authorization granted according to Article 43 to 45 of the Directive Draft and in accordance with Article 32 of the Directive Draft. The RMS has to update the Assessment Report only if requested by the applicant. The RMS has 90 days to do so, cf. Article 36 para. 5 Directive Draft. If the member states do not wish an update, the RMS submits the report within 30 days. This leads to a significant shortening of the procedure.
According to the current legal situation, the member states then have 90 days to approve the marketing authorization on the basis of this Assessment Report and the dossier, unless a member state identifies a "serious risk to public health" for the preparation, Article 28 Para. 4 Directive 2001/83/EC. The reform provides for 60 days after receipt of the Assessment Report for this process, Article 36 para. 6 Directive Draft. The standard also no longer provides an explicit exception for serious risks to public health.
However, Article 38 para. 1, 3 of the Directive Draft provides for the case of disagreement among the Member States within this period. According to this provision, all Member States concerned that do not agree shall use their best endeavors to reach an agreement on the measures to be taken. They shall give the applicant the opportunity to present their position orally or in writing. If the Member States reach a consensual agreement within 60 days of notification of the points of disagreement, the reference Member State shall record the agreement, close the procedure and inform the applicant accordingly. This extends the serious risk to public health exception to general disagreements. The time limit of 60 days for clarification by the coordination group corresponds to the case of Article 29 para. 3, 4 of Directive 2001/83/EC, according to which, in the case of an objection of a serious risk to public health, a clarification is made by the coordination group, which is to reach a decision within 60 days. If, under current law, the CMDh fails to reach a consensus on approval, the process leads to arbitration before the CHMP. This is different under the Directive Draft. According to Article 38 para. 4, the position of the majority of the Member States represented in the coordination group will be communicated to the Commission if no consensual agreement can be reached within the 60-day period provided. In this case, the member states that have agreed to the Assessment Report may grant a national marketing authorization upon request.
After completion of the procedure at the European level, the member states have 30 days, both according to the current legal situation and according to the intended legal situation, to grant a national marketing authorization, Article 28 Para. 5 Directive 2001/83/EC, Article 36 Para. 8 Directive Draft.
If the member states do not agree on the granting of the marketing authorization of the medicinal product, the procedure before the CHMP and the Commission described under the decentralized authorization procedure follows.
The centralized procedure is currently based on Regulation (EC) 726/2004, which is to be repealed by the new Regulation and the procedure is to be newly regulated.
According to the current legal situation, the duration of the procedure is to be limited to 210 days, Article 6 para.3 of Regulation (EC) No 726/2004. Article 6 of the Regulation Draft shortens this period to the effect that the EMA is to ensure that the opinion of the CMPH must be submitted within 180 days of receipt of a valid application.
The possibility to shorten this period to 150 days remains the same if the marketing authorization application concerns medicinal products that are of great interest from the point of view of public health and in particular from the point of view of therapeutic innovation and the applicant requests the shortening (so-called accelerated procedure, cf. Article 14 para. 9 of Regulation (EC) No 726/2004, Article 6 para.7 of the Regulation Draft). However, the possibility of applying the accelerated procedure to the priority medicinal products ('PRIME') is explicitly mentioned in Article 60 is entirely new.
According to the current situation, this period can be interrupted by one or two stops - the so-called "clock stop". During these stops, the applicant prepares their answers to the questions posed by the CHMP. The maximum duration of the stops depends on how much time the applicant believes it will take to answer the questions. The duration must be approved by the CHMP. Typically, the first "clock stop" lasts three to six months, and the second "clock stop" lasts one to two months. The reform also provides for clock stops to allow for the timely submission of missing information and documentation. This period may be extended once by the agency, Article 6 para. 5 Regulation Draft.
According to the current legal situation, the CHMP opinion is forwarded to the Commission, the member states, and the applicant within 15 days. If the assessment is negative, the applicant has 15 days to file an objection and 45 days to justify it, Article 9 para. 2 of Regulation (EC) 726/2004. Under the current and envisaged legal situation, the CHMP then has 60 days to deliberate and then issue a vote, Article 8 para. 2 of Regulation (EC) 726/2004, Article 12 of the Regulation Draft. The final opinion and the Assessment Report are then forwarded to the Commission, the Member States, and the applicant within 15 days, Article 10 para.1 of Regulation (EC) 726/2004. The Commission then drafts its decision within 15 days and forwards it to the applicant and the Member States, Article 10 para. 1 of Regulation (EC) 726/2004.
Here, too, the member states no longer have the 22-day period as specified in Article 10 para. 3 (b) of Regulation 726/2004 to submit comments. In line with the other procedures at European level, the interaction of Article 13 para.1 subpara. 2 of the Regulation Draft and Recital (150) of the Regulation Draft results in the Commission being able, in duly justified cases, to refer the opinion of the CHMP back to the CHMP for reconsideration. This review period may also not exceed 10 days.
The Commission then takes a final decision within 15 days, Article 10 para. 2 of Regulation (EC) No 726/2004. The Regulation Draft regulates the procedure in the same way but shortens all 15-day periods to 12 days, see Article 12 para. 2, 3 Regulation Draft, Article 13 para. 1 Regulation Draft.
The shortening of the approval procedure is to be welcomed because the planned reductions in time are by no means marginal. On the contrary, there will be an average reduction of 30 days, which will benefit patients who are dependent on the immediate supply of innovative drugs, especially since quality standards are to be maintained.