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Comparison of Drug Approval Process in United States & Europe

Article in Journal of Pharmaceutical Sciences and Research · June 2013

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Uddalok Kashyap N. Vishal Gupta

Assam Engineering College JSS College of Pharmacy
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 U. Nitin Kashyap et al /J. Pharm. Sci. & Res. Vol.5(6), 2013, 131 - 136

Comparison of Drug Approval Process in

United States & Europe
U. Nitin Kashyap, Vishal Gupta*, H. V. Raghunandan
Pharmaceutical Quality Assurance Group,
Department of Pharmaceutics,
JSS College of Pharmacy,
JSS University, Sri Shivarathreeshwara Nagara,
Mysore - 570015, Karnataka, India.

Abstract:
This topic aims at reviewing the drug filing and different aspects of obtaining United States Food & Drug Administration
(USFDA) and European Medicines Agency (EMA) approval for a drug in order to get a Marketing Authorization in US &
Europe and their effective role in improving the standards laid down by them. All new / generic drug products must be
approved by the respective regulatory agency governing the respective market before a particular product can be introduced
into the market. By law, all new drugs must first be shown to be safe and effective before they can be approved by the
respective regulatory agency for marketing. USFDA is the regulatory agency which is responsible for safety regulation of the
food and drug products in US. EMA is the regulatory agency/ decentralized body which is responsible for safety regulation of
the food and drug products in Europe. Drug approval process in USFDA involves submitting of an Investigational New Drug
Application, followed by submission of New Drug Application. The applications are reviewed and agency officials examine
the drug’s safety and efficacy data and the drug is approved. EU establishes 4 different drug approval processes:
1) Centralized Procedure
2) Decentralized Procedure
3) National Procedure
4) Mutual Recognition Procedure
Keywords: Drug Approval, EMA, USFDA

INTRODUCTION:  The chemistry, manufacturing, and control of the

The United States of America & Europe are the two main investigational drug
regulatory agencies in the world apart from Japan. US is a Such a meeting will help the Sponsor to organize animal
single country but EU is a union of countries. Therefore the research, gather data, and design the clinical protocol based
Drug approval process in both the regulatory agencies has on suggestions by the FDA. A clear flowchart of the IND
been summarized for easy understanding.[1] The basic process is illustrated in figure 2.
regulation can be understood from Fig 1.
Drug Approval in United States:- New Drug Application (NDA)
The United States has perhaps the world’s most stringent If clinical studies confirm that a new drug is relatively safe
standards for approving new drugs. Drug approval and effective, and will not pose unreasonable risks to
standards in the United States are considered by many to be patients, the manufacturer files a New Drug Application
the most demanding in the world.[1-3] (NDA), the actual request to manufacture and sell the drug
Investigational New Drug (IND) Application in the United States.[5, 6] The process of NDA has been
It’s an application filed to the FDA in order to start clinical illustrated in figure 3.
trials in humans if the drug was found to be safe from the Abbreviated New Drug Application (ANDA)
reports of Preclinical trials. A firm or institution, called a It’s an application made for approval of Generic Drugs.
Sponsor, is responsible for submitting the IND The sponsor is not required to reproduce the clinical studies
application.[4] A pre - IND meeting can be arranged with that were done for the original, brand name product.
the FDA to discuss a number of issues: Instead, generic drug manufacturers must demonstrate that
 The design of animal research, which is required their product is the same as, and bioequivalent to, a
to lend support to the clinical studies previously approved brand name product.[7] The process of
 The intended protocol for conducting the clinical ANDA has been illustrated in figure 4.
trial

Figure 1: The Basic Regulation

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Figure 2: Investigational New Drug Application

Figure 3: New Drug Application

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Figure 4: Abbreviated New Drug Application (for Generic Drugs)

Drug Approval in Europe:- Mutual Recognition Procedure

Similar to the US requirements, there are two regulatory The Mutual Recognition procedure allows applicants to
steps to go through before a drug is approved to be obtain a marketing authorization in the member states
marketed in the European Union. These two steps are (Concerned Member State) other than the member state
clinical trial application and marketing authorization (Reference Member State) where the drug is previously
application. There are 27 member states in the European approved.[10]
Union (as of August 2007); Clinical Trial Applications are  Applicant submits identical dossier to all EU
approved at the member state level, whereas marketing member states in which it wants authorization,
authorization applications are approved at both the member including required information.
state or centralized levels.[8]  As soon as one Member State decides to evaluate
Centralized procedure the medicinal product (at which point it becomes
The centralized procedure is one which allows applicants to the "RMS"), it notifies this decision to other
obtain a marketing authorization that is valid throughout Member States (which then become the "CMS"),
the EU.[9] to whom applications have also been submitted.
 Results in a single authorization valid in EU,  RMS issues a report to other states on its own
Norway, Iceland and Liechtenstein. findings.
 Application evaluated by an assigned Rapporteur.  Generic industry is the major user of this type of
 Timeline: EMA opinion issued within 210 days, drug approval procedure.
and submitted to European Commission for final  This process may consume a time period of 390
approval. days.
Centralized process is compulsory for:  Nationalized Procedure
 Those medicines which are derived from any The Nationalized procedure is one which allows applicants
biotechnology processes, such as genetic to obtain a marketing authorization in one member state
engineering. only.[11,12]
 Those medicines which are intended for the  In order to obtain a national marketing
treatment of Cancer, HIV/Aids, diabetes, authorization, an application must be submitted to
neurodegenerative disorders or autoimmune the competent authority of the Member State.
diseases and other immune dysfunctions.  New active substances which are not mandatory
 Medicines officially designated 'orphan medicines' under Centralized procedure can obtain marketing
(medicines used for rare diseases). authorization under this procedure.
 Timeline for this procedure is 210 Days.

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Decentralized procedure Based on the assessment report which is prepared by the

Using this procedure, companies may apply for RMS& any comments made by the CMS, MA should be
authorization simultaneously in more than one EU country granted in accordance with the decision taken by the
for products that have not yet been authorized in any EU RMS&CMS in this decentralized procedure.
country and essentially do not fall within the centralized  Generally used for those products that has not yet
procedure’s essential drugs list.[13,14] received any authorisation in an EU country.
 Time: 210 days.

Figure 6: Mutual Recognition Procedure

Figure 5: Centralized Procedure

Figure 7: Decentralized Procedure

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RESULTS & DISCUSSION: Table 3: Finished Product Control Requirements

A Brief comparison is done for both the regulatory S.
Requirement USFDA EU
agencies is done for clear understanding in Table 1 No
Comparative study of Dossier submission of a drug product 1 Justification ICH Q6A ICH Q6A
Administrative 2 Assay 90 - 100 % 95 - 105%
This involves the administrative requirements like 3 Disintegration Not Required Required
application, number of copies, fees and type of presentation Color
required mentioned in Table 2 4 Not Required Required
Identification
Finished Product Control 5 Water Content Required Not Required
The requirements are clearly stated in Table 3
Manufacturing & Control Table 4: Manufacturing & Control Requirements
The requirements are clearly stated in Table 4 S.
Stability Requirement USFDA EU
No
The requirements are clearly stated in Table 5 Number of
Bioequivalence 1 1 3
batches
The requirements are clearly stated in Table 6 A minimum
World Pharma Market 2 Packaging of 1,00,000 Not Required
The World Pharma market share is depictive in the Figure 8 Units
Not required
Table 1: Principle differences between USFDA & EU Process
3 at the time of Required
USFDA EU Validation
submission
 Multiple Agencies
Minimum of
 EMEA Minimum of
 One Agency 4 Batch Size 1,00,000
 CHMP 1,00,000 Units
Units
 National Health Agencies
 Multiple Registration Process
Table 5: Stability Requirements
 Centralized -(European
S.
Community) Requirement USFDA EU
No
 Decentralized - (Atleast 2
 One Registration Number of
member states) 1 1 2
Process batches
 Mutual Recognition -
(Atleast 2 member states) 2 Condition 25/60 - 40/75 25/60 - 40/75
 National - (1 member 3 Months 6 Months
state) Date & Time Accelerate & Accelerate &
3
 TSE / BSE Study  TSE / BSE Study data of Submission 3 Months long 6 Months long
data not required required term term
 Braille code is not Container Inverted &
 Braille code is required on 4 Do not address
orientation Upright
required on
labelling Vol 4 EU
labelling
 The changes in 21 CFR part Guidelines for
5 Clause
the approved drug 210 & 211 medicinal
products
can be done by  The changes in the approved
filing drug can be done by filing QP
6 Not Required Required
 PAS  Type IA Variation Certification
 CBE - 30 /  Type IB Variation
CBE  Type II Variation
 Annual Table 6: Bioequivalence Requirements
Report S.
Requirement USFDA EU
No
Table 2: Administrative Requirements Audited by Audited by
1 CRO
S. FDA MHRA
Requirement USFDA EU 5 times the
No
1 Application ANDA / NDA MAA Reserve sample No such
2
Debarment Sample required for requirement
2 Required Not Required analysis
classification
Number of Must be as per
3 3 1 No such
copies 3 Fasted / Fed OGD
requirement
Approval recommendation
4 18 Months 12 Months 5 years from
Timeline Retention of No such
4 date of filing the
5 Fees No fees 10 - 20 Lakh samples requirement
application
6 Presentation eCTD& Paper eCTD

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 U. Nitin Kashyap et al /J. Pharm. Sci. & Res. Vol.5(6), 2013, 131 - 136

Figure 8: Pharma Market Share

CONCLUSION:
The Drug approvals in the United States & Europe are the
most demanding in the world. The primary purpose of the
rules governing medicinal products in US & Europe 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, trialed, and manufactured in
accordance to the guidelines so that they are safe and
patient’s well - being is protected.

ACKNOWLEDGEMENT:
The authors are thankful to JSS College of Pharmacy for
providing facilities for making this article a success.

REFERENCES:
1. Rick NG. Drugs from discovery to approval. 2nd ed. John Wiley &
Sons, Inc., (Hoboken, New Jersey). p. 201
2. Rick NG. Drugs from discovery to approval. 2nd ed. John Wiley &
Sons, Inc., (Hoboken, New Jersey). p. 202
3. IRA R Berry, Robert P Martin, editors. The Pharmaceutical
Regulatory Process. 2nd ed. Informa healthcare. p. 45
4. Rick NG. Drugs from discovery to approval. 2nd ed. John Wiley &
Sons, Inc., (Hoboken, New Jersey). p. 203-4
5. Rick NG. Drugs from discovery to approval. 2nd ed. John Wiley &
Sons, Inc., (Hoboken, New Jersey). p. 205-7
6. Rick NG. Drugs from discovery to approval. 2nd ed. John Wiley &
Sons, Inc., (Hoboken, New Jersey). p. 208-10
7. IRA R Berry, Robert P Martin, editors. The Pharmaceutical
Regulatory Process. 2nd ed. Informa healthcare. p. 46
8. IRA R Berry, Robert P Martin, editors. The Pharmaceutical
Regulatory Process. 2nd ed. Informa healthcare. p. 48
9. Rick NG. Drugs from discovery to approval. 2nd ed. John Wiley &
Sons, Inc., (Hoboken, New Jersey). p. 212-14
10. Rick NG. Drugs from discovery to approval. 2nd ed. John Wiley &
Sons, Inc., (Hoboken, New Jersey). p. 215-17
11. Rick NG. Drugs from discovery to approval. 2nd ed. John Wiley &
Sons, Inc., (Hoboken, New Jersey). p. 218-20
12. IRA R Berry, Robert P Martin, editors. The Pharmaceutical
Regulatory Process. 2nd ed. Informa healthcare. p. 49
13. IRA R Berry, Robert P Martin, editors. The Pharmaceutical
Regulatory Process. 2nd ed. Informa healthcare. p. 50
14. IRA R Berry, Robert P Martin, editors. The Pharmaceutical
Regulatory Process. 2nd ed. Informa healthcare. p. 51

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