New Drug Approval Process: Regulatory View
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.
Key Words: Drug approval process, clinical trials, marketing.
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.
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 labelling)[5,6].
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[8, 9, 10]. 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[10, 11]. 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:
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.
Mutual Recognition 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.
Drug Approval Process In China
In 1963, for the management of new drugs, Chinese Ministry of Health planned drug regulation. The China's State Pharmaceutical Administration in collaboration with Ministry of Health, in 1979, published the New Drug Management Regulations (no need to conduct systematic scientific experiments on new drugs). In view of protecting the public health and promoting the economic developments in pharmaceuticals, the first comprehensive Drug Administrative Law was framed in 1985. This law was amended in 1999 by two additional provisions for new drug approval and provisions for new biological product approval. The approval process of New Drug Applications (NDA) includes sufficient preclinical data for verification of drug's safety and justification of the commencement of clinical trials. The Drug Administrative Law was further revised in 2001 requiring premarket testing, approval for new drug products, and prohibits drug adulteration.
The Drug Administrative Law authorizes the State Food and Drug Administration (SFDA) to approve new drugs for marketing. The new drug registration process also consists of the clinical study application and the new drug application. The Provincial Drug Administration Authorities (PDAAs) should organize the works of the formal review of submitted materials i.e. on-site examination and sampling just after receiving the drug registration application. The aim behind the formal review is to guarantee the content and format of the submitted materials is in line with the requirements and all the required materials have been submitted. After formal review, the PDAAs send the qualified applications to the SFDA for further review. The import drug registration application should be directly submitted to SFDA by the applicant. SFDA's Department of Drug Registration carefully reviews the completeness of the submitted materials, files the qualified applications and transmits all the materials of qualified applications to the Center for Drug Evaluation (CDE) directly attracted to SFDA. CDE determine whether the safety and effectiveness information submitted for a new drug are adequate for manufacturing and marketing approval and send the report of review to SFDA. SFDA Carefully consider the recommendations and review results of CDE and makes a decision whether or not the drug registration application can be approved and issues the certificate of drug approval and drug approval number to the qualified applicant. Figure 5 -6 represents the clinical trial approval process and new drug approval process of China, respectively[22,23,24,25].
Drug Aproval Process In Australia
In the history of drug regulatory system in Australian, thalidomide disaster was a key factor. In 1948, the first advisory committee to review drugs was set up and further in 1964, the first Commonwealth advisory committee in Australia was established. The first federal act relating to therapeutic goods was enacted in 1965. In response of lacking control over locally manufactured products, the Therapeutic Goods Act was changed in 1989 and the Therapeutic Goods Administration (TGA) was created .
Any person seeking approval of a new drug in Australia should first file a clinical trial application for conducting human studies. The clinical trials in Australia can be conducted under two schemes, i.e. either under the Clinical Trial Exemption (CTX) Scheme or under the Clinical Trial Notification (CTN) Scheme. In the latter scheme, application is directly submitted to the Human Research Ethics Committee (HREC) which assesses the validity of design of clinical trial, its ethical acceptability, approval, safety and efficacy of the drug as well. The final consent for conducting trial is given by the approving authority after due advice from the HREC. The commencement of clinical trial takes place only after the due notification to the TGA and the appropriate notification fee to be paid. In CTX scheme, an application to conduct clinical trials is submitted to the TGA for evaluation and comment. The clinical trials can be conducted (under the CTX application) without further assessment by the TGA and the conduct of each trial should be notified to the TGA[27,28]. Figure 7 represents the CTA by CTX scheme. An application is submitted to TGA to register the drug in Australian Register of Therapeutic Goods (ARTG) after the completion of clinical trials. The application consists of data to support the quality, safety and efficacy of the product for its intended use. The application is assessed (on an administrative level) to make sure for compliance with basic guidelines and further evaluated by different sections and advice can also be sought on key issues to take final decision. A company can make comments on the evaluation report, if necessary. A delegate (decision-maker) within the TGA after due advice of the ADEC, take a decision to approve or reject the product. The Australian Drug Evaluation Committee (ADEC) usually gives advice for new medicines. Figure 8 represent the new drug approval process in Australia. When the drug is approved and distributed in the market the drug, it is considered to be in Phase IV trials. In this phase, new uses or new populations, long-term effects, etc. can be explored[29,30].
Drug Aproval Process In India
The Drug and Cosmetic Act 1940 and Rules 1945 were passed by the India's parliament to regulate the import, manufacture, distribution and sale of drugs and cosmetics. The Central Drugs Standard Control Organization (CDSCO), and the office of its leader, the Drugs Controller General (India) [DCGI] was established. In 1988, the Indian government added Schedule Y to the Drug and Cosmetics Rules 1945. Schedule Y provides the guidelines and requirements for clinical trials, which was further revised in 2005 to bring it at par with internationally accepted procedure. The changes includes, establishing definitions for Phase I-IV trials and clear responsibilities for investigators and sponsors. The clinical trials were further divided into two categories in 2006. In one category (category A) clinical trials can be conducted in other markets with competent and mature regulatory systems whereas the remaining ones fall in to another category (category B) Other than A. Clinical trials of category A (approved in the U.S., Britain, Switzerland, Australia, Canada, Germany, South Africa, Japan and European Union) are eligible for fast tracking in India, and are likely to be approved within eight weeks. The clinical trials of category B are under more scrutiny, and approve within 16 to 18 weeks.
An application to conduct clinical trials in India should be submitted along with the data of chemistry, manufacturing, control and animal studies to DCGI. The date regarding the trial protocol, investigator's brochures, and informed consent documents should also be attached. A copy of the application must be submitted to the ethical committee and the clinical trials are conducted only after approval of DCGI and ethical committee. To determine the maximum tolerated dose in humans, adverse reactions, etc. on healthy human volunteers, Phase I clinical trials are conducted. The therapeutic uses and effective dose ranges are determined in Phase II trials in 10-12 patients at each dose level. The confirmatory trials (Phase III) are conducted to generate data regarding the efficacy and safety of the drug in ~ 100 patients (in 3-4 centers) to confirm efficacy and safety claims. Phase III trials should be conducted on a minimum of 500 patients spread across 10-15 centers, If the new drug substance is not marketed in any other country[32,33,34,35]. The new drug registration (using form # 44 along with full pre-clinical and clinical testing information) is applied after the completion of clinical trials. The comprehensive information on the marketing status of the drug in other countries is also required other than the information on safety and efficacy. The information regarding the prescription, samples and testing protocols, product monograph, labels, and cartons must also be submitted. The application can be reviewed in a range of about 12-18 months. Figure 10 represents the new drug approval process of India. After the NDA approval, when a company is allowed to distribute and market the product, it is considered to be in Phase IV trials, in which new uses or new populations, long-term effects, etc. are explored[33,37].
The drug approval process varies from one country to another. In some countries, only a single body regulates the drugs and responsible for all regulatory task such as approval of new drugs, providing license for manufacturing and inspection of manufacturing plants e.g. in USA, FDA performs all the functions. However in some counties all tasks are not performed by a single regulatory authority, such as in India, this responsibility is divided on Centralised and State authorities. Other issues where the difference appears are, time taken for the approval of a CTA application, time taken in evaluation of marketing authorization application, registration fee, registration process and marketing exclusivity (Table 1).
Some counties have two review processes as normal review process and accelerated review process as in USA, China etc. and some countries have only a single review process as in India. Similarly, the format used for the presentation of dossier submitted for approval of drug is also different. In some countries like as in USA, EU, and Japan , it is mandatory that the dossier prepared in CTD format, however, in some countries it is optional such as in India.
Generally, the drug approval process comprised mainly the two steps, application to conduct clinical trial and application to the regulatory authority for marketing authorization of drug. The new drug approval process of various countries is similar in some of the aspects whereas it differs in some aspects. In most of the counties, sponsor firstly files an application to conduct clinical trial, and only after the approval by the regulatory authority, the applicant conducts the clinical studies and further submits an application to the regulatory authority for marketing authorization of drug. In all countries, information submitted to regulatory authorities regarding the quality, safety and efficacy of drug is similar; however, the time, fee and review process of clinical trials and marketing authorization application differs. For the purpose of harmonisation, the International Conference on Harmonisation (ICH) has taken major steps for recommendations in the uniform interpretation and application of technical guidelines and requirements. This step will ultimately reduce the need to duplicate work carried out during the research and development of new drugs. Therefore, harmonization of drug approval processes either by ICH or WHO may be initiated at global level.
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Table 1. Comparison of Drug approval process.
Time for Regulatory Approval of CTA/IND Application
Time for Evaluation of MAA
*By Centralized Procedure; MAA-Marketing Authorization Application, IND-Investigational New Drug, CTA-Clinical Trial Authorization, DNA-Data Not Available.
IND-Investigational New Drug, FDA-Food and Drug Administration, NDA-New Drug Application, CDER-Centre for Drug Evaluation and Research
Figure 1: New Drug Application Approval Process of FDA
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
CDE-Centre for Drug Evaluation, SFDA-State Food and Drug Administration
Figure 5: Clinical Trial Application Approval Process of China
Figure 6: New Drug Registration Process of China
Figure 7: Clinical Trial Authorization Process of Australia under CTX Scheme
NDA-New Drug Application, DSEB-Drug Safety and Evaluation Branch, TGA-Therapeutic Goods Administration, ADEC-Australian Drug Evaluation Committee
Figure 8: New Drug Registration Process of Australia
IND-Investigational New Drug, DCGI-Drug Controller General of India, CDSCO-Centre for Drug Standards Control organization.
Figure 9: New Drug Registration Process of India.
Dr. Harish Dureja studied Pharmacy at C. C. S. University (India) and earned his Masters Degree in Pharmaceutics from Punjabi University (India). During his association with Dr. Sunil Gupta, he got interested in application of experimental designs for formulation and process development. He developed novel fourth generation graph invariants and various models for the prediction of biopharmaceutical, pharmacological and physiochemical properties of drugs during his Ph.D. work with Prof. A. K. Madan at M. D. University, Rohtak. He has authored/coauthored more than 60 publications in various International and National journals to his credit. He has written two monographs in the book entitled " Mathematical Chemistry Monographs, No. 9" email@example.com
Dulichand studied B.Pharmacy from Guru Jambheshwar University of Science and Technology, Hisar. He is presently M. Pharm. Pharmaceutics (Drug Regulatory Affairs) student at Maharshi Dayanand University, Rohtak. Dulichand can be contacted at firstname.lastname@example.org