A regulatory process by which a person/organization/sponsor/innovator gets authorization to launch a drug in the market, is known as drug approval process. In general, a drug approval process comprises of various stages: application to conduct clinical trials, conducting clinical trials, application to marketing authorization of drug and post-marketing studies. Every country has its own regulatory authority, which is responsible to enforce the rules and regulations and issue the guidelines to regulate the marketing of the drugs. This article will focus the similarities and differences in drug approval process of various regulatory bodies.
In the present scenario, countries have different regulatory requirements for approval of a new drug. The single regulatory approach for marketing authorization application (MAA) of a new drug product applicable to various countries (on the basis of single dossier) is utmost difficult. Therefore, the knowledge of exact and detailed regulatory requirements for MAA of each country should be known to establish a suitable regulatory strategy .
The new drug approval is of two phase process – the first phase for clinical trials and second phase for marketing authorization of drug. Firstly, non-clinical studies of a drug are completed to ensure efficacy and safety, and then application for conduct of clinical trials is submitted to the competent authority of the concerned country. Thereafter, the clinical trials can be conducted (phase I to phase IV). These studies are performed to ensure the efficacy, safety and optimizing the dose of drug in human beings. After the completion of clinical studies of the drug, then an application to the competent authority of the concerned country for the approval of drug for marketing is submitted. The competent authority review the application and approve the drug for marketing only if the drug is found to be safe and effective in human being or the drug have more desirable effect as compare to the adverse effect .
Even after the approval of new drug, government should monitor its safety due to appearance of some side effects, when it is used in larger population. The interactions with other drugs, which were not assessed in a pre-marketing research trial and its adverse effects (in particular populations) should also be monitored.
In European Union (EU), the medical products were approved for marketing at the National level initially. The mutual recognization procedure was introduced in 1983 and a single national review in case of pharmaceutical/medicinal product for marketing authorizations in all EU’s countries was made feasible. The primary aim of this procedure was to create a united standard for product review among national regulatory authorities. In 1987, for high-technology or biologically derived products, the concertration procedure was established by directive 87/22, in which product assessment should be completed by Committee for Proprietary Medicinal Products (CPMP) besides the the normal national regulatory review. Further, in 1993, by council regulation (EEC) 2309/93, the concertration procedure was replaced with centralised procedure, by which all the high-tech and biologically derived product was reviewed and granted EU’s wide marketing authorization by the EU’s CPMP.
Similarly, the drug approval process in European countries is also accomplished in two phases: clinical trial and marketing authorization. A clinical trial application (CTA) is filed to the competent authority of the state to conduct the clinical trial within EU. The competent authority of that member state evaluates the application. The clinical trials are conducted only after the approval. The purpose and phases of clinical trials are similar as specified in FDA drug approval process. Figure 2 represent the clinical trial authorization process in EU.
After completing of all three phases of clinical trial, marketing authorization application is filed including all animal and human data, its analyses, as well as pharmacokinetics, manufacturing and proposed labelling. In the EU’s countries, the company have a choice of following regulatory procedures:
The Committee for Human Medicinal Products (CHMP) evaluate the applications received by the EMEA. In view of the applicant’s preference, CHMP contracts out assessment work in one of the member states (the “rapporteur”). After the complete assessment, the CHMP deliver opinion to EU Commission within 210 days. The EU Commission requests comments from other member states, if a positive opinion from CHMP is received. The other member states can respond in about 28 days. When a licence is recommended, a European Public Assessment Report (EPAR) is produced and marketing authorisation is issued. This authorisation is valid throughout the European Union and is for five years, however, the extension can be applied to the EMEA three months before the expiration of this period. Figure 3 represent the centralized procedure for marketing authorization.
In order to obtain marketing authorizations in several member states, the centralised procedure is not mandatory; in such case the decentralized procedure is to be used. An application is submitted to competent authorities of each of the member states, where a marketing authorization is to be sought. The information like quality, efficacy, safety, administrative information shall be submitted and a list of all Concerned Member States (CMSs) and one member state to act as Reference Member State (RMS). A draft assessment report on the medicinal product is prepared and the CMSs and the RMS validate the application within a time frame of 14 days. The RMS prepare draft summary of product characteristics, labeling and package leaflet within 120 days. This report can be approved within 90 days. However, if a medicinal product is supposed to cause potential serious risk to public health, CMS(s) will inform to other CMS, RMS and applicant and further decision in this regard is taken within 30 days. Within 60 days of the communication of the points of disagreement, all member states reach to an agreement on the action to be taken. After reaching to an agreement of the member states, the RMS records the agreement and informs to the applicant. However, if the member states could not reach an agreement, then CHMP intervenes and take a final decision keeping in view of the written or oral explanations of the applicant[15,16,17,18]. Figure 4 represent the decentralized procedure for marketing authorization in EU.
This type of authorization is granted on country-by-country basis by the competent authorities, in each member state. Products only intended for one market and not obliged to use the centralized procedure.
The mutual recognition procedure (MRP) is similar to the de-centralized procedure with some differences. The mutual recognition procedure is applicable to medicinal products which have received a marketing authorization in any member state whereas the decentralized procedure is applicable to those products which were never approved in any member states of the European Union. The MRP is used to obtain marketing authorizations in various several member states. The evaluation of application by RMS can be taken within 90 days instead of 120 days (in decentralized procedure). After the grant of marketing authorization, the product can be marketed, which may be called as Phase IV trials, wherein new uses or new populations, long-term effects etc. can be explored.
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20.European Commission: Notice to Applicants: Volume 2A; Procedures for Marketing Authorisation; Chapter 2; Mutual Recognitionhttp://www.imb.ie/images/uploaded/documents/Chap2NTA.pdf. (assessed on May 08th 2010).
Figure 2: Clinical Trial Authorization Process of EU
MAA-Marketing Authorization Application, EMEA-European Medicine Evaluation Agency, EU-European Unionion in EU
Figure 3:Centralized Procedure for Marketing Authorizat
CMS(s)-Concerned Member State(s), RMS-Reference Member State, CHMP-Committee for Human Medicinal Products
Figure 4: Decentralised Procedure for Marketing Authorization in EU