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Drug approval process - US, Europe & India
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Vishal Prajapati, Rahulgiri Goswami, Pratik Makvan
December 12 , 2014
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Abstract
Developing a new drug requires great amount of research work in chemistry, manufacturing, controls, preclinical science and clinical trials. Drug reviewers in regulatory agencies around the world bear the responsibility of evaluating whether the research data support the safety, effectiveness and quality control of a new drug product to serve the public health. 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 focusses on drug approval process in different countries like USA, Europe and India.
Currently different countries have to follow different regulatory requirements for approval of new drug. For marketing authorisation application (MAA) a single regulatory approach is applicable to various countries is almost a difficult task. Therefore it is necessary to have knowledge about regulatory requirement for MAA of each country. The basic regulation can be understood from Fig 2.
Drug Approval in US (1-3)
The United States has perhaps the world's most stringent standards for approving new drugs. Drug approval standards in the United States are considered by many to be the most demanding in the world.
Investigational New Drug Application
It's an application filed with the FDA in order to start clinical trials in humans if the drug was found to be safe from the reports of preclinical trials. A firm or institution, called a sponsor, is responsible for submitting the IND application. A pre-IND meeting can be arranged with the FDA to discuss a number of issues:
The design of animal research, which is required to lend support to the clinical studies
The intended protocol for conducting the clinical trial
The chemistry, manufacturing, and control of the investigational drug
Such a meeting will help the sponsor to organise animal research, gather data, and design the clinical protocol based on suggestions by the FDA. A clear flow chart of the IND process is illustrated in Fig 1.
New Drug Application
If clinical studies confirm that a new drug is relatively safe and effective, and will not pose unreasonable risks to patients, the manufacturer files a New Drug Application (NDA), the actual request to manufacture and sell the drug in the United States. The process of NDA has been illustrated in Figure 3.
Abbreviated New Drug Application
It's an application made for approval of generic drugs. The sponsor is not required to reproduce the clinical studies that were done for the original, brand name product. Instead, generic drug manufacturers must demonstrate that their product is the same as, and bioequivalent to, a previously approved brand name product. The process of ANDA has been illustrated in Figure 4.
Drug Approval in Europe (4-6)
Similar to the US requirements, there are two regulatory steps to go through before a drug is approved to be marketed in the European Union. These two steps are clinical trial application and marketing authorisation application. There are 28-member states in the European Union (as of July, 2013); Clinical Trial Applications are approved at the member state level, whereas marketing authorisation applications are approved at both the member state and centralised levels.
Centralised Procedure
The centralised procedure is one which allows applicants to obtain a marketing authorisation that is valid throughout the EU.
Results in a single authorisation valid in the EU, Norway, Iceland and Liechtenstein.
Application evaluated by an assigned rapporteur.
Timeline: EMA opinion issued within 210 days, and submitted to the European Commission for final approval.
Centralised Process is Compulsory For
Those medicines which are derived from any biotechnology processes, such as genetic engineering.
Those medicines which are intended for the treatment of cancer, HIV/AIDS, diabetes, neurodegenerative disorders or autoimmune diseases and other immune dysfunctions.
Medicines officially designated 'Orphan medicines' (medicines used for rare diseases).
Mutual Recognition Procedure
The Mutual Recognition Procedure allows applicants to obtain a marketing authorisation in the concerned member states (CMS) other than the reference member state (RMS), where the drug is previously approved.
Applicant submits identical dossier to all EU member states in which they want marketing authorisation, including required information.
As soon as one member state decides to evaluate the medicinal product (at which point it becomes the "RMS"), it notifies this decision to other member states (which then become the "CMS"), to whom applications have also been submitted.
RMS issues a report to other states on its own findings.
Generic industry is the major user of this type of drug approval procedure.
This process may consume a time period of 390 days.
Nationalised Procedure
The Nationalised Procedure is one which allows applicants to obtain a marketing authorisation in one member state only.
In order to obtain a national marketing authorisation, an application must be submitted to the competent authority of the member state.
New active substances which are not mandatory under centralised procedure can obtain marketing authorisation under this procedure.
Timeline for this procedure is 210 days.
Decentralised Procedure
Using this procedure, companies may apply for authorisation simultaneously in more than one EU country for products that have not yet been authorised in any EU country and essentially do not fall within the centralised procedure's essential drugs list.
Based on the assessment report which is prepared by the RMS and any comments made by the CMS, marketing authorisation should be granted in accordance with the decision taken by the RMS & CMS in this decentralised procedure.
Generally used for those products that has not yet received any authorisation in an EU country.
Time: 210 days.
Approval of New Drug (7-10)
When a company in India wants to manufacture/import a new drug it has to apply to seek permission from the licensing authority (DCGI) by filing in Form 44 also submitting the data as given in Schedule Y of Drugs and Cosmetics Act 1940 and Rules 1945. In order to prove its efficacy and safety in Indian population it has to conduct clinical trials in accordance with the guidelines specified in Schedule Y and submit the report of such clinical trials in specified format.
But a provision is there in Rule - 122A of Drugs and Cosmetics Act 1940 and Rules 1945 that the licensing authority may waive certain trials if he considers that in the interest of public health he may grant permission for import of new drugs basing on the data of the trials done in other countries. Similarly there is another provision in Rule - 122A which says that the clinical trials may be waived in the case of new drugs which are approved and being used for several years in other countries.
Section 2.4 (a) of Schedule Y of Drugs and Cosmetics Act 1940 and Rules 1945 says for those drug substances which are discovered in India all phases of clinical trials are required.
Section 2.4 (b) of Schedule Y of Drugs and Cosmetics Act 1940 and Rules 1945 says that for those drug substances which are discovered in countries other than India; the applicant should submit the data available from other countries and the licensing authority may require him to repeat all the studies or permit him to proceed from Phase III clinical trials.
Section 2.8 of Schedule Y of Drugs and Cosmetics Act 1940 and Rules 1945 says that the licensing authority may require pharmacokinetic studies (Bioequivalence studies) first to show that the data generated in Indian population is equal to data generated abroad and then require him to proceed with Phase III trials.
In summary, the exact requirements of clinical trials may change from case to case and depend on the extent to which licensing authority is satisfied about its safety and efficacy.
The process of approval of new drug in India is a very complicated process, which should meet necessary requirements along with NDA to FDA. The need of the present work is to study and document the requirements for the process of approval of new drug in India with emphasis on clinical trials as per Drugs Control department, Government of India.
New Drug Application
NDA is an application submitted to the FDA for permission to market a new drug. To obtain this permission, a sponsor submits preclinical and clinical test data to NDA for analysing the drug information, description of manufacturing procedures.
After NDA is received by the agency, it undergoes a technical screening. This evaluation ensures that sufficient data and information have been submitted in each area to justify "filing" the application that is FDA formal review. At the conclusion of FDA review of an NDA, there are three possible actions that can send to sponsor:
Not approvable - In this letter, list out deficiencies and explain the reason.
Approvable - It means that the drug can be approved but minor deficiencies that can be corrected like - labelling changes and possible request commitment to do post-approval studies.
Approval- It states that the drug is approved.
If the action taken is either approvable or not approvable, then FDA provides applicant with an opportunity to meet with agency and discuss the deficiencies.
Drug Approval Process in India
Conclusion
The drug approvals in the US, Europe and India are the most demanding in the world. The primary purpose of the rules governing medicinal products in the US, Europe and India is to safeguard public health. It is the role of public regulatory authorities to ensure that pharmaceutical companies comply with regulations. There are legislations that require drugs to be developed, tested, trailed, and manufactured in accordance to the guidelines so that they are safe and patients' well-being is protected.
References
1. Rick NG. Drugs from discovery to approval. 2nd ed. John Wiley & Sons, Inc.; 2008. p. 201-202.
2. IRA RB, Robert PM. The Pharmaceutical Regulatory Process. 2nd ed. Informa healthcare; 2008. p. 45.
3. Rick NG. Drugs from discovery to approval. 2nd ed. John Wiley & Sons, Inc.; 2008. p. 203-210.
4. IRA RB, Robert PM. The Pharmaceutical Regulatory Process. 2nd ed. Informa healthcare; 2008. p. 46-48.
5. Rick NG. Drugs from discovery to approval. 2nd ed. John Wiley & Sons, Inc.; 2008. p. 212-220.
6. IRA RB, Robert PM. The Pharmaceutical Regulatory Process. 2nd ed. Informa healthcare; 2008. p. 49-51.
7. Clinical Trial & Global Clinical Trial [Internet].[cited 2014 January].Available from: http://cdsco.nic.in/clinical_trial.htm.
8. The New Drug Approval Process [Internet].[cited 2014 January]. Available from:http://www.fda. gov/cder/ handbook.
9. CDER Guidance: IND application process (interactive session) [Internet].[cited 2014 January].Available from: www.fda.gov/cder/regulatory/ applications/ind_page_1.htm.
10. Guidance for industry on preparation of common technical document for import/ manufacture and marketing approval of new drugs for human use. (NEW DRUG APPLICATION- NDA) [Internet].[cited 2014 January].Available from: http://cdsco.nic.in/CTD_Guidance %20-Final.pdf.
(Prajapati, Goswami, Makvana are from L J Institute of Pharmacy, S G Highway, Ahmedabad, Gujarat. Badjatya is from Montajat Pharmaceuticals Co Ltd, Dammam, KSA. They can be contacted at vp46556@gmail.com)
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