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  • a review on drug approval process for us, europe and india …

    This article focuses on drug approval process in different countries like USA, Europe and India. Keywords: MAA, USFDA, Drug approval, Clinical trial.

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    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 …

    The regulatory scenario in India is changing very fast and DCGI is coming up with precise guideline on each topic. The documentation for product registration in India has become at par with US FDA and seems to objective of DCGI so that data generated in India is acceptable globally. Ever-changing laws and regulations are driving demand for regulatory affairs professionals to cater the current needs of industries for the global competition and who can help pharmaceutical companies to effectively bring their medical products to the Indian market. In today’s competitive scenario, the reduction of the time taken to launch the product is imperative and hence vital for company’s success.  This post will be helpful to all pharma manufacturer/importer, regulatory, preclinical, formulation scientists, and clinical trial professional who are involved directly or indirectly in new drug registration process. The post covers new drug including fixed-dose combination in India and import & registration by foreign manufacturer. Need integrated knowledge and broad perspectives which you need to effectively manage the regulatory process for approval of new drugs in India.

    key points

    1. Regulatory Overview in India
    2. Regulatory Dossier
    3. Chemical, Pharmaceutical Information and Animal Studies data
    4. Clinical Trial Requirement and Documentation
    5. New Drug Application: IND developed in India
    6. New Drug Application: Marketed in other countries, not approved in India
    7. New Drug Application: New Indication, Dosage form or route of administration
    8. New Drug Application: Fixed dose combination of two or more drugs
    9. New Drug Application: Approved in India within four year and PSUR
    10. Import and Registration

Approval of New Drug in India (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 trails 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 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 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. 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 analyzing the drug information, description of manufacturing procedures. After NDA 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 3 possible actions that can send to sponsor:

Not approvable- In this letter list of deficiencies and explain the reason. Approvable – It means that the drug can be approved but minor deficiencies that can be corrected like-labeling changes and possible request commitment to do post-approval studies. Approval- It state that the drug is approved. If the action taken is either an approvable or a not approvable, then FDA provides applicant with an opportunity to meet with agency and discuss the deficiencies.







The Drug approvals in the US, Europe & India are the most demanding in the world. The primary purpose of the rules governing medicinal products in US, Europe & 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 patient’s well – being is protected.





The Procedure for Manufacturing Drugs in Mie Prefecture, Japan.


The Procedure for Manufacturing Drugs in Mie Prefecture, Japan.

The following details the necessary procedure for the commencement of manufacture (or importing) of drugs in Mie Prefecture, Japan.
Note: The procedures described below are applicable in Mie Prefecture, Japan, as of April 2002. Due to future amendments and the disparities of laws in different prefectures, it is necessary to be informed as to the correct application procedures directly by the relevant prefecture.

1. For Manufacture (or Importing) of Drugs

Approval for the manufacture (importing) of each item, and a manufacturing (importing) license are required for the manufacture (or importing) of drugs.

Drug Manufacture Approval The quality, effectiveness and safety of the drug under application must pass the examination. However, drugs listed on the Pharmacopoeia of Japan do not require approval.
License The structural conditions (building and facilities) and human resource requirements (e.g. Administrators) of the drug manufacturing facilities must pass the examination to acquire a business license.

2. Standard Period for the Administrative Process

There is a standard period for the administrative process of the approval and licensing examinations. Unless there are irregularities in the application or supplied data, the examinations are generally completed within the time specified.


*Approval Ethical Drugs (new drugs) 1 year
(branded generic drugs) 1 year
(modification) 1 year
Non-prescription drugs 10 months
IVD (in vitro diagnostic) 6 months
(approval for modification of storage conditions and period of effectiveness: 3 months)
*Mie Prefectural License
(for manufacture or importing)
Drugs, quasi-drugs, cosmetics, or new medical devices 56 days

(1) The above periods for approval and licensing are applicable only in Mie Prefecture. Be aware that the standard periods for the administration process may differ in other prefectures. Further, the above period may be extended where a replacement of the application documents is required.
(2) Please feel free to contact us if you have any further questions.

3. Drug Approval Inspection

Apart from those drugs which do not require approval, most drugs are approved by the Minister of Health, Labor and Welfare, and some are approved by the Governor. However, approval and receipt of applications based on both national and prefectural standards will occur at the prefectural government. The drug approval process is detailed below.
Quasi-drugs, and medical devices are approved under the same process as drugs. As for cosmetics, those which contain ingredients that are not displayed, require approval.

4. License for Drug Manufacture (or Importing)

Below is a flowchart illustrating the license application process in Mie Prefecture. Applications are accepted by the Mie Prefectural Government.

At present, provided that there are no problems found at the site inspection, licensing will take 2 weeks. If you require licensing within 2 weeks due to your production schedule, with advance notice, we may give you special consideration and shorten the duration of the licensing process.
The license is valid for 5 years, and must be renewed after 5 years. In addition, the application process for the business license for manufacturers (and importers) of quasi-drugs, cosmetics, and medical devices is the same as for a drug manufacturer (or importer).

Pharmaceutical Affairs Food Team, Mie Prefectural Government
13 Komei-cho,Tsu City,Mie Prefecture 514-8570 Japan
TEL +81-59-224-2330 or 2331/FAX +81-59-224-2344/E-mail yakumus@pref.mie.jp

WHAT IS MIE PERFECTURE..SEE………http://en.wikipedia.org/wiki/Mie_Prefecture




With an improved clinical trial infrastructure now a high priority, Japan offers an advantageous development environment for pharmaceutical, biotechnology, and medical device companies. To address a decade-long downward trend in trial applications and a lag in the availability of drugs within the country as compared to other developed nations, Japan’s Ministry of Health, Labor and Welfare (MHLW) has ushered in significant changes in recent years. These include bold steps to create a more welcoming and efficient approach to trials while maintaining global standards such as those of the International Conference on Harmonization/ Good Clinical Practice (ICH-GCP).

Revisions to the Pharmaceutical Affairs Law (PAL) of 2005 indicate that indeed the Japanese regulatory review process is in a new era. While the process continues to pose challenges, significant development opportunities now exist for organizations that successfully navigate this transitional terrain.

This article presents an overview of the Japanese population for clinical studies as well as the regulatory environment, with emphasis on how regulations differ from ICH-GCP standards.

Market Characteristics

The 127 million people of Japan make up a population whose total has remained unchanged for the last 20 years due to a declining birthrate. The population is aging and boasts the world’s longest average lifespan at 79.19 years for men and 85.99 years for women, according to the CIA World Factbook, 2009.

Japan is the second largest market worldwide in terms of pharmaceutical sales, behind the US and just ahead of China. According to IMS Health, sales grew 7.6% in 2009 over 2008. This high rate of pharmaceutical consumption is an irony given the fact that many top-selling products globally have not even been made available in Japan due to the lengthy and expensive trial and approval process.

Primary health conditions and treatment needs in Japan are in the areas of: Oncology, Diabetes, Gastroenteritis, Diseases of the Elderly, Respiratory Diseases, Cardiovascular Diseases, Hepatitis, Infectious Diseases, Central Nervous System (CNS) Diseases, Musculoskeletal and Joint Disorders, Immunology, and Vaccines.

National Healthcare Provision

Healthcare services in Japan are provided by national and local governments offering relative equality of access, with fees set by committee. People without insurance from employers can participate in a national program administered by the local government. All elderly are also covered by a government program. Patients may select physicians and facilities of their choice.

A Fresh, Welcoming Environment

With recent amendments to PAL, drug and device developers can now plan and conduct clinical trials in Japan under Clinical Trial Notifications (CTNs), which are reviewed in just 30 days, a turnaround time comparable to that achieved in the US. A grant program subsidized by MHLW is designed to accelerate the development of high-priority drugs and medical devices recommended by the member societies of the Japanese Association of Medical Sciences (JAMS) that are:

  • Widely used as standard treatment in the US or Europe but not yet approved in Japan
  • Already marketed in Japan and commonly used for off-label indications1

Interest in revitalizing the clinical trials process in Japan is increasingly obvious through improved infrastructure, IT investments, and education of physicians and patients on the need for reform. The Japanese market offers dedicated research teams within national and university hospitals across a variety of therapy areas. Networks such as the National Hospital Organization facilitate reaching into both large- and medium-sized cities with multiinstitutional studies and clinical trials. Such an environment offers direct access to healthcare professionals, including a solid network of primary care physicians.

The Japanese market also can make accessible large groups of aging, recurrent patients in specific therapy areas. And, although a variety of dialects are spoken, the Japanese communicate via one standard language, making communicating with patients and investigators easier.

Japanese investigators participate in international conferences and are ICH-GCP and Japan GCP compliant. As the government wants to maintain and encourage further research within the country, both on-site and centralized Institutional Review Boards (IRBs) convene regularly (as often as once a month) to keep the clinical study process moving. Centralized IRBs that are managed by Site Management Organizations (SMOs) are especially flexible in this regard.

Another advantage is that smaller communities within hospital regions develop strong patient/research links, so patients tend to be compliant, and sites increasingly deliver the predicted patient numbers.

Remaining Hurdles Require In-Country Expertise

Although Japan provides high-density populations in urban areas, patients can be difficult to recruit because of their easy access to healthcare coverage. The lack of an incentive to participate, coupled with little awareness of the need for trials, continues to be problematic and adds to the trial timeline.

What is more, the cost of conducting clinical trials in Japan remains higher than in the West because of the need to use SMOs, which add labor costs. There is no specialized research hospital in Japan, so SMOs, having access to a pool of patients, are essential.

Trials also tend to take longer for a range of reasons – from the lack of patient incentives and lower physician incentives to the still maturing infrastructure.

Due to the complexities of conducting research in Japan, corporate sponsors should ensure that they have ready access to in-country experts.

The Regulatory Landscape

Recent changes to the regulatory system for pharmaceuticals and medical devices have enabled Japan to align its safety measures more closely with those of other developed nations. Since its establishment in 2004, the Pharmaceuticals and Medical Devices Agency (PMDA) has provided comprehensive risk management from pre-clinical research to approval through three functions: review (risk reduction), safety (continuous risk mitigation), and relief (services for adverse health effects).

Improving the infrastructure for clinical trials has been a primary focus in Japan. The Center for Clinical Trials of the JMA (JMACCT) was also established in 2004 to promptly provide the public with medically necessary or new pharmaceutical products and medical devices, organize multiple medical institutions into a network, and conduct model clinical trials.

The current regulatory environment in Japan encompasses:

Procedures for Drug Approval Applications (NDAs)

  • The application is made after completion of nonclinical and clinical trials
  • Required GCP, GLP, and GMP surveys should be applied for immediately after the NDA submission
  • The manufacturer and/or distributor must be authorized and, if a manufacturing plant is overseas, the appropriate accreditation must be obtained
  • Information must include the origin or background of discovery, characteristics and efficacy, records of consultation with PMDA, a list of drugs of the same type/indication, conditions of use in other countries, and package inserts

navigating fig 1

navigating fig 2

NDA Review Process

PMDA frequently performs a team review with experts in quality, nonclinical, and clinical trials, biostatistics, and other fields.

navigating fig 3

Notification of Clinical Trial Plan

The Minister in charge of Clinical Trial Protocols must be notified in advance of trials for drugs with new active ingredients, new routes of administration, new combination drugs, new indications, new dosages, and biologics.

Scope of Reporting

When performing a clinical trial, the following information must be reported:

  • Unexpected death or cases of adverse experiences potentially leading to death
  • Other unexpected serious events, adverse experiences requiring hospitalization, disability, adverse experiences leading to disability, congenital disease or abnormality in a subsequent generation
  • Measures taken in foreign countries to prevent the occurrence or spread of risk to public health and hygiene (including discontinuation of manufacturing, import, or marketing or withdrawal or disposal of an item with ingredients equivalent to those of test products; also including revision of the precautions, accompanied by a letter to the distributing doctor)
  • Research reports indicating the possibility of the drug causing cancer or any other serious disease due to adverse reactions or showing a lack of anticipated efficacy or clinical benefit

While the precise wording differs, the reporting requirements in Japan reflect the spirit of those in Western markets. The EU, for example, requires that sponsors report untoward medical occurrences from any dose that result in death, are life threatening, require or prolong hospitalization, lead to persistent or significant disability, or a congenital anomaly or birth defect.

Differences Between Japan’s GCP and ICH-GCP

Japanese regulatory authorities are particularly eager to avoid any misconduct related to clinical trials, such as past deficiencies in case report forms (CRFs), informed consent, institutional review board practices, and protocol deviations. Transparency is a primary goal for the revised process.

Japan’s GCP places greater responsibility on the institute and its head such that:

  • The contract is between the sponsor and the institute, not between the sponsor and the investigator
  • Items covered in the contract must be defined
  • Each institute must have an IRB
  • The sponsor must prepare a policy for compensating trial participants for any injuries during the trial prior to submitting documents to the IRB. This policy must be included while obtaining informed consent. In the case of injury, “the subject should be adequately compensated regardless of whether or not the injury is due to negligence. The subject is not burdened with providing a causal relationship.”
  • A sponsor that does not have an address in Japan must select an In-Country Caretaker (ICC). A CRO in Japan can act as the ICC on behalf of the sponsor. (See sidebar on ICC Responsibilities.)
  • Product labels must be in Japanese.

Safety information must be reported periodically (such as every six months) after submission of the initial Clinical Trial Notification (CTN) and within two months after the study is completed.

According to the ICH guidelines, (sections, 5.16.1/2 and 5.17) sponsors are to promptly notify all concerned investigators, institutions, and authorities of findings that could adversely affect subjects’ safety or the course of the trial. Suspected, unexpected serious adverse reactions require expedited reporting, while all other safety information can be included in an annual safety report.

While many of the provisions are similar, any differences between Japan’s GCP and ICH-GCP must be understood and acted upon. The sponsor should be certain that a regulatory expert is engaged and available for consultation during the clinical trial process.


In the realm of clinical trials, Japan may still be a “developing” country, but is certainly one focused on revitalization and global harmonization. Increased demand and resources for pharmaceutical and medical device research have spurred a new era of reform with the budgets and resources required. Not all the challenges have been addressed, but a more stable and effective infrastructure, network, and standards are now in place. In planning for global studies, sponsors can now be assured that Japan is ready to participate from the outset and is governed by regulations that are tracked closely with the International Conference on Harmonization standards.


1. http://www.jmacct.med.or.jp/english/publications.html

ICC Responsibilities

The In-Country Caretaker (ICC) is responsible for the progress of clinical trials and must be the primary contact for any regulatory interaction on behalf of the sponsor company. The ICC oversees:

  • All clinical development work on behalf of the sponsor
  • Submission of a Clinical Trial Notification (CTN) to the PMDA
  • Replies to questions raised by the PMDA
  • Supply of the investigational drug, including customs clearance, requests made to the drug depot or the contract manufacturing organization (CMO), and the checking of manufacturing records and QC tests
  • Monitoring of the clinical trial and preparation of the Clinical Study Report (CSR)
  • Collection and reporting of information on adverse reactions, including from overseas
  • Translation of documents and data (English to Japanese / Japanese to English)