May 10, 2013 | By Márcio Barra
Last post of Regulatory Week. Hope you enjoyed all the articles, and if you missed any one of them, just go to “Original Articles”. Don’t forget to share!
Drug authorization procedures in the EU
Sponsors have several options when seeking market approval for a new drug in Europe: a national authorization procedure, a decentralized procedure, a mutual recognition procedure and a centralized procedure.
Depending on a product’s eligibility, each of these authorization routes offers different advantages and disadvantages to the sponsor, and these should be considered when setting up the market strategy of a product.
This procedure is used whenever a company wants to commercialize a product in only one EU Member State.
The National procedure is specific to each country. That is, each country within the EU has its own procedures for authorizing a marketing application for a new drug. Sponsors can find information regarding the requirements and procedure of each country on the websites of the regulatory agencies(1).
In the case of Portugal, the national authorization procedure is supervised and evaluated by INFARMED, the national competent authority. After a company fills a national Marketing Authorization Application to INFARMED, INFARMED has 10 days to verify if the request is within the required parameters, and send questions to the sponsor regarding the drug product. If the application doesn’t fulfill the requirements of Article 15th of the Estatuto do Medicamento, the request is deemed invalid and the reasons for the decision sent to the sponsor. If the request is deemed valid, INFARMED’S Direcção de Avaliação de Medicamentos (DAM, or Drug Evaluation Group) has 210 days to evaluate and give an opinion on the Market Authorization Application. Here, the drug product is evaluated under parameters of quality, safety and efficacy. During these 210 days, INFARMED may request further information from the sponsor, as well as request documents that it deems necessary, under a rejection penalty. Once INFARMED finishes its evaluation, the decision is sent to the applicant and published on INFARMED’s webpage.
A national market authorization is valid for five years. INFARMED also plays a role on the renewal of the authorization, through a risk-benefit evaluation of the data collected over the years. A renewal request must be presented by the AIM holder until the hundredth eightieth day before the date of expiry of the authorization. After the first renewal, the authorization is valid indefinitely, unless INFARMED, for pharmacovilgilance reasons, demands a renewal request for an additional period of five years (2).
Now, moving over to why a sponsor would choose the national procedure, there are some advantages in submitting a MAA through this procedure. First, it allows the sponsor to choose which country he will submit to first. This is especially advantageous when the sponsor can’t afford to go through the centralized or decentralized procedure, due to lack of resources of distribution infrastructure for example. Choosing the country that the sponsor is most familiar with in regards to its regulation can also be an important factor (3). The national authorization procedure also allows the sponsor to, further down the line, get his drug approved through the mutual recognition procedure, seeing as one country already approved its drug. Overall, this procedure is less resource heavy than the others, and thus it is the cheapest and safest alternative for a sponsor.
The disadvantages are obvious, seeing as this procedure only allows the sponsor to commercialize in one single market, cutting potential revenue streams it could have by bringing the drug to more markets.
The centralized procedure is a Europe wide authorization procedure, conducted by EMA’s Committee for Human Medicinal Products (CHMP), an organism containing representatives of all Member states, EEA members, patient organizations and health professionals.
When a sponsor applies for drug approval through the Centralized Procedure, two member states are first selected, a rapporteur and a co-rapporteur. These two member states will be responsible for the creation of an evaluation report that will be assessed by the CHMP. First, a draft report is prepared and sent to the committee for review. The committee prepares a set of questions to send to the sponsor. After receiving a response, further discussions continue and a final evaluation report is arranged, containing a positive or negative opinion. This whole process can take up to 210 days. After the report is completed, it is sent to the European Commission in less than 15 days. The European Commission has the final say on the matter, granting the MA or not after evaluation of the CHMP’s report (4, 5).The EC’s decision is applicable to all Member States of the European Union and EEA states – Iceland, Norway e Liechtenstein. After approval from the EC, the MA is valid for five years(2, 3).
The centralized procedure, when it was introduced by Regulation (EEC) no 2309/93(6), followed the footsteps first established by Directive 87/22/EEC with its concertation procedure (7), and it was first made obligatory to products made from Recombinant DNA technology, controlled gene expression and monoclonal antibodies(6).
Afterwards, Regulation (EC) No 726/2004 extended the scope of the procedure to include orphan medicinal products and new active substances for the treatment of acquired immune deficiency syndrome (HIV), cancer, neurodegenerative disorder or diabetes. It went into force in 20th November 2005(5).
Recital 8 and Point 3 of the Annex to Regulation (EC) No 726/2004 also established that, starting 20 May 2008, the centralized procedure would be obligatory for drug products containing new active substances for the treatment of autoimmune diseases and other immune dysfunctions and viral diseases(5).
Lastly, regulation EC No 1394/2007 made the procedure compulsory for Advanced Therapy Medicinal products, like gene therapy, tissue engineered and somatic cell therapy products(8).
Article 3(2) of Regulation (EC) No 726/2004 defines the optional scope of the centralized procedure. It states that the procedure can be followed optionally by medicines that contain a new active substance, or if the applicant shows that the therapeutic entity provides a significant therapeutic, scientific or technical innovation, and it would be in the best interest of public health if it was approved at a community level(5).
Products authorized through the centralized procedure are granted marketing authorizations that cover all EU member states and the EEA, a big, 500 million user market where the sponsor can potentially recoup the losses from drug development. The drug will be commercialized in all countries with a single, unique brand name (5).The convenience of the centralized procedure is however accompanied by fees that are significantly higher than the national procedure’s (9).
Also, it is also a very risky, all or nothing procedure. If the CHMP refuses an application, the drug is barred from sale in every EU country, whereas if the sponsor tried another authorization procedure, there was the possibility of getting approval in at least one country. Since the sponsor can’t choose the rapporteur countries like he can in other procedures, this also leaves him at a disadvantage (10).
Mutual recognition procedure
This procedure requires the drug to be already approved in a MS.
This procedure is based upon the principle that a marketing authorization and the evaluation in one Member State (the so-called reference Member State) ought to be recognized by the competent authorities of the other Member States (the so-called concerned Member States), that is, if a Member State concedes a national MA to a drug, other Member States can recognize the evaluation conducted by it and grant a MA for the drug themselves(11).
It’s also noteworthy to point out that both a Member State and the Sponsor can trigger the Mutual Recognition Procedure.
After the first marketing authorization in the Community is granted, the marketing authorization holder may request one or more Member State(s) to recognize an authorization approved by the reference Member State, by submitting an application in accordance with Article 28 of Directive 2001/83/EC(12).
Within 90 days of receipt of a valid application, the reference Member State will provide the assessment report together with the approved summary of product characteristics, labeling and package leaflet to the concerned Member States and to the marketing authorization holder(13).
Within 90 days of the receipt of these documents, the concerned Member States shall recognize the decision of the reference Member State and the approved summary of product characteristics, package leaflet and labeling by granting a MA.
If any country refuses to grant a MA by safety reasons, the matter will be taken to The Co-ordination Group for Mutual Recognition and Decentralized Procedures, which will attempt to make all member states reach a consensus in 60 days. If it fails, the request will be taken to the CHMP and treated like a centralized procedure(2, 13).
The decentralized procedure works in a similar way as the mutual recognition one, except here the medicinal product in question has not yet received a marketing authorization in any Member State at the time of application. Like the MRP, a reference member state is chosen, which will evaluate the MAA. The remaining member states then proceed to give their opinion on the evaluation. If all concerned member states agree on the evaluation by the reference member state, the drug will be approved and allowed for sale in those countries(14). If a member state disagrees, the Co-ordination Group for Mutual Recognition and Decentralized Procedures will, like in the MRP, play a referee role (2, 4, 11).
Both the MRP and the decentralized procedure carry a set of advantages and disadvantages that sponsors ought to know before setting their product market strategy. Both of them allow a sponsor to avoid the need to go through different national procedures in each country. Moreover, they aren’t as risky as the centralized procedure, and, in the case of the MRP, the sponsor can choose the reference member state that will conduct the evaluation of the drug product (by first attaining a MA in that country). In both these procedures, fees have to be paid to all Member states who participate in the process, and, unlike the centralized procedure, the sponsor may have to attribute a different name for its drug product in different Member States., which may hurt brand awareness.
The MRP often sees disagreements between member states, holding up the procedure and causing delays. In these occasions, a lengthy dispute solving mechanism has to be employed, costing both time and money to the sponsor
The decentralized procedure avoids some of the potential disputes between member states by engaging each of the member states the applicant wishes to apply to at the time the first marketing authorization is made. Disputes are this less common in the decentralized procedure than in the MRP(10). Lastly, the decentralized procedure is faster than the MRP. The first can take up to 210 days to complete its two steps. The MRP, on the other hand, a national MA is first needed, which can take up to 210 days, alongside the update period of the MA license before the MRP procedure starts proper, which can take more 180 days. The take home message is that there is no one-size fits all in regards to drug authorization procedures. Each one of the four available has different advantages and disadvantages, which have to be carefully weighed out by the sponsor(14).