About Authors:
Jatin  Patel*, Krunal Parikh, Dhiren Shah
Seth G.L. Bihani S.D. College of Technical Education,
Institute of Pharmaceutical Sciences and Drug Research,
Sri Ganganagar, Rajasthan, INDIA

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 includes new drug approval process in different countries include India, Australia, European union, China etc.
New drug approval process in different countries are described in logarithmic representation.

Reference Id: PHARMATUTOR-ART-1531

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. [  Vyawahare.N.S, Itakar .S.C]


Drug Approval Process In USA
In 1820, the new era of USA drug regulation was started with the establishment of U.S. Pharmacopoeia. In 1906, Congress passed the original Food and Drugs Act, which require that drugs must meet official standards of strength and purity. However, in 1937, due to sulphanilamide tragedy, the Federal Food, Drug and Cosmetic Act (of 1938) was enacted and added new provisions that new drugs must be shown safe before marketing. Further, in 1962, the Kefauver-Harris Amendment Act was passed which require that manufacturers must prove that drug is safe and effective (for the claims made in labeling).

The Food and Drug Administration (FDA) is responsible for protecting and promoting public health. Like general drug approval process, FDA’s new drug approval process is also accomplished in two phases: clinical trials (CT) and new drug application (NDA) approval. FDA approval process begins only after submission of investigational new drug (IND) application. The IND application should provide high quality preclinical data to justify the testing of the drug in humans. Almost 85% of drugs are subjected to clinical trials, for which IND applications are filed. The next step is phase-I clinical trials (1-3 years) on human subjects (~100). The drug’s safety profile and pharmacokinetics of drug are focused in this phase. Phase II trials (2 years) are performed if the drug successfully passes phase I. To evaluate dosage, broad efficacy and additional safety in people (~300) are the main objective of the phase II. If evidence of effectiveness is shown in phase II, phase III studies (3-4 years) begins. These phase III concerns more about safety and effectiveness of drug from data of different populations, dosages and its combination with other drugs in several hundred to about 3,000 peoples. A new drug application (NDA) can be filed only when the drug successfully passes all three phases of clinical trials and includes all animal and human data, data analyses, pharmacokinetics of drug and its manufacturing and proposed labelling. The preclinical, clinical reports and risk-benefit analysis (product’s beneficial effects outweigh its possible harmful effects) are reviewed at the Center for Drug Evaluation and Research by a team of scientists. Generally approval of an NDA is granted within two years (on an average), however, this process can be completed from two months to several years. The innovating company is allowed to market the drug after the approval of an NDA and is considered to be in Phase IV trials. In this phase, new areas, uses or new populations, long-term effects, and how participants respond to different dosages are explored. Figure 1 represents the new drug approval process of FDA.

Drug Approval Process In Europe
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:

Centralized Procedure
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.

Decentralised Procedure
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. Figure 4 represent the decentralized procedure for marketing authorization in EU.

National Procedure
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.



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