Regulations for drug approval in USA, E.U & India
Pharmaceutical industry is the most regulated of all the industries. Regulations are put in order to develop the most efficient and safe pharmaceutical products. It takes more than 8 to 15 years to develop a new drug product & costs more than $ 800 million.
1. Pharmaceutical regulations for
drug approval in different countries
Prepared By;
Dr. Pankaj Bablani
1st Semester PhD Pharmaceutical Medicine
(Batch 2014 – 15)
Jamia Hamdard University
New Delhi 1
Name of the Guide/ Supervisor:
Dr. Manju Sharma
Assistant Professor
Department of Pharmacology
Faculty of Pharmacy, Hamdard University
New Delhi-110062, India
2. Regulation in the industry
• Pharmaceutical industry is the most regulated of
all the industries. Regulations are put in order to
develop the most efficient and safe
pharmaceutical products. It takes more than 8 to
15 years to develop a new drug product & costs
more than $ 800 million.
• Regulatory affairs provides insight/guidance into
this development through agency wisdom
collected in guidance, previous experience,
market precedence, etc. and hence helps to
reduce number of development failures.
2
3. A Historical Perspective of drug regulation
and approval
During the 20th century, there were no law’s & regulations to
protect the public from the unfavorable effects of the drugs.
Misfortune, disaster, and tragedy had triggered most of the
advances in drug regulation.
In a post-war era when sleeplessness was prevalent, thalidomide
was marketed to a world obsessed on tranquilizers and sleeping
pills. At the time, one out of seven people took them regularly. The
demand for sedatives was even higher in some European markets,
and the presumed safety of Thalidomide, the only non-barbiturate
sedative known at that time, gave the drug massive appeal. Sadly,
tragedy followed its release, catalyzing the beginnings of the
rigorous drug approval and monitoring systems in place.
3
4. Thalidomide tragedy (1962)
• Thalidomide was first marketed in 1957 in West
Germany.
• The German drug company developed and sold the
drug. Primarily prescribed as a sedative or
hypnotic, thalidomide also claimed to cure
“anxiety, insomnia, gastritis, and tension".
• Afterwards, it was used against nausea and to
ease morning sickness in pregnant women.
• Soon, Thalidomide became an over the
counter drug in Germany.
• Shortly after the drug was sold in Germany,
between 5,000 and 7,000 infants were born
with Phocomelia (malformation of the limbs).
• Only 40% of these children survived.
• Throughout the world, about 10,000 cases were
reported. Only 50% of the 10,000 survived.
• Their effects included deformed eyes and hearts,
deformed alimentary and urinary tracts blindness
and deafness.
4
5. JAKE-LEG” paralysis (1930)
The Ginger Jake poisonings
• A mysterious epidemic of paralysis was sweeping through 1920s America
that had the medical community baffled. The cause was first identified not
by physicians, but by blues singers.
• During the prohibition, alcohol was banned but people got buzzed the
best way they could. One way was through a highly alcoholic liquid
called Jamaica Gingeror ‘Jake’ that got round the ban by being sold as a
medicine.
• Eventually the feds caught on and even such poorly disguised medicines
were blacklisted but Jamaica Ginger stayed popular, and alcoholic, due to
the producers including an organophosphate additive called tricresyl
phosphate that helped fool the government’s tests.
• What they didn’t know was that tricresyl phosphate is a slow-acting
neurotoxin that affected the neurons that control movement.
• The toxin starts by causing lower leg muscular pain and tingling, followed
by muscle weakness in the arms and legs. The effect on the legs caused a
distinctive form of muscle paralysis that required affected people to lift
the leg high during walking to allow the foot to clear the ground.
5
6. Elixir Sulfanilamide: (1937)
Taste of Raspberries, Taste of Death
• In 1937, more than 100 US citizens—many of whom
were children—died after consuming Elixir
Sulfanilamide, a raspberry-flavored antibiotic syrup
manufactured by The S. E. Massengill Company of
Bristol, Tennessee. The new, difficult-to-dissolve
antibiotic, sulfanilamide, was mixed with the solvent
Diethylene glycol, a known toxin, by the company’s
• The company tested the elixir only for its appearance
and palatability before its nationwide distribution.
• The catastrophic event prompted the passage of
the 1938 Federal Food, Drug, and Cosmetic Act.
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7. Elixir Sulfanilamide: (1937)
Taste of Raspberries, Taste of Death
• In 1937, more than 100 US citizens—many of whom
were children—died after consuming Elixir
Sulfanilamide, a raspberry-flavored antibiotic syrup
manufactured by The S. E. Massengill Company of
Bristol, Tennessee. The new, difficult-to-dissolve
antibiotic, sulfanilamide, was mixed with the solvent
Diethylene glycol, a known toxin, by the company’s
• The company tested the elixir only for its appearance
and palatability before its nationwide distribution.
• The catastrophic event prompted the passage of
the 1938 Federal Food, Drug, and Cosmetic Act.
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8. Such incidences/ tragedies led to
introduction of rules for the
approval of new drug
Pharmaceutical regulations for
drug approval
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9. Pharmaceutical markets
• 1. Regulated -- USA, EU, Japan (Follows ICH paten. i.e. CTD)
• 2. Semi- Regulated – India, ASEAN-counties,
Russia, China, Brazil. (Country specific product registration guidelines are
followed)
• 3. Non-regulated -- African counties. (Minimum
documentation is required for drug approval process.)
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10. Pharmaceutical Regulatory Agencies
and Organizations around the World
• As the pharmaceutical industries throughout
the world are moving ahead towards
becoming more and more competitive,
regulatory agencies are being established in
various countries across the globe.
• Regulatory agencies and organizations play a
vital role to meet the requirements of legal
procedures related to drug development
process in a country.
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11. Pharmaceutical Regulatory Agencies
(Continue .. )
• In the present scenario, pharmaceuticals are
considered as the most highly regulated
industries worldwide.
• The regulatory body ensures compliances in legal
and regulatory aspects of a drug.
• Every country has its own regulatory authority,
which is responsible to enforce the rules and
regulations and issue the guidelines to regulate
drug development process, licensing, registration,
manufacturing, marketing and labeling of
pharmaceutical products.
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12. An Overview of the drug approval
process
• Developing a new drug requires great amount
of research work in drug chemistry,
manufacturing, controls, pre-clinical science
and clinical trials.
• Drug development can generally be divided
into phases.
The Preclinical phase
Clinical phases
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13. Subjects
Purpose
Time
corse
New
drugs
pass
Laboratory
&
Animal study
Access safety &
Biological activity
1-2 years
100 %
20-100
volunteers
Safety &
Dosage
3-4 years
70 % of IND
100-300
patients
Effectiveness.
Side effects
4-5years
33 %IND
1000-3000
patients
Verify effectiveness.
long term side effects
6-8 years
27 %
File
IND
File
N D A
Clinical
Phases
Phase 1 Phase 2 Phase 3
Pre-clinical
Phase
IND - Investigational New Drug
NDA - New Drug Application
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14. Review and Approval
• After phase III, the pharmaceutical company
prepares reports on all studies conducted on the
drug and submits the reports to the drug
authority in a New Drug Application (NDA).
• The drug authority then reviews this information
to determine whether the drug is safe and
effective for its intended use.
• If the drug passes this review, it is approved for
use in humans.
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15. Need for Regulation
• Drug reviewers in the regulatory agencies around the world have
responsibility of evaluating whether the research data support’s 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 issuance of guidelines to regulate the
marketing of the drugs.
• Currently different countries have to follow different regulatory
requirements for approval of new drug.
• For Marketing Authorization 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.
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16. Regulatory agencies and organizations
established in countries.
• USFDA (USA)
• EMEA (European Union) International Conference on Harmonization (ICH)
• MHLW (Japan) Permanent members
• CDSCO (India)
• MHRA (UK)
• TGA (Australia)
• HEALTH CANADA (CANADA)
• MCC (South Africa)
• ANVISA (Brazil)
• SFDA (China)
• SWISSMEDIC (Switzerland)
• KFDA (Korea)
• MoH (Sri Lanka)
• Others …..
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17. 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. 17
19. Drug approval in United States
• 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.
•
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20. Drug approval in United States
Different types of drug applications that
can be submitted to FDA
• Investigational New Drug (IND)
• It is an application filed to the FDA in order to start clinical trials in humans on the basis of the data
obtained from the Preclinical trials.
• Sponsor is responsible for submitting the IND application.
• New Drug Application (NDA)
• 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 NDA, This is the actual request to manufacture and sell the drug
in the United States.
• Abbreviated New Drug Application (ANDA)
• 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
• Biologic License Application (BLA)
• Biological products are approved for marketing under the provisions of the Public Health Service Act.
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24. Drug Approval in Europe
(28 member states)
• 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 Approved at the Member state level,
• Marketing authorization application. Approved at both
the Member state & at Centralized levels
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26. Drug approval in Europe Union
Centralized procedure
The centralized procedure is one which allows
applicants to obtain a marketing authorization
that is valid throughout the EU.
Results in a single authorization valid in EU, Norway,
Iceland and Liechtenstein.
Application evaluated by an assigned Reporter.
Timeline: EMA opinion issued within 210 days, and
submitted to European Commission for final approval.
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28. Drug approval in Europe Union
Centralized 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).
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29. Drug approval in Europe Union
Mutual Recognition Procedure
The Mutual Recognition procedure allows
applicants to obtain a marketing authorization
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
authorization, including required information.
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30. Drug approval in Europe Union
Mutual Recognition Procedure
• 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.
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32. Drug approval in Europe Union
Decentralized procedure
• Using this procedure, companies may apply for
authorization simultaneously in more than one EU country
for products that have not yet been authorized in any EU
country and essentially do not fall within the centralized
procedure’s essential drugs list.
• Based on the assessment report which is prepared by the
RMS & any comments made by the CMS, marketing
authorization should be granted in accordance with the
decision taken by the RMS & CMS in this decentralized
procedure.
• Generally used for those products that has not yet received
any authorisation in an EU country.
• Time: 210 days.
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34. Drug approval in Europe Union
Nationalized Procedure
• The Nationalized procedure is one which allows
applicants to obtain a marketing authorization in
one member state only.
• In order to obtain a national marketing
authorization, an application must be submitted
to the competent authority of the Member State.
• New active substances which are not mandatory
under Centralized procedure can obtain
marketing authorization under this procedure.
• Timeline for this procedure is 210 Days.
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35. • Through the International Conference on
Harmonization (ICH) process, the Common
Technical Document (CTD) guidance has been
developed for Japan, European Union, and
United States.
• Most of the countries including India have
adopted the CTD format. Hence, CDSCO has
also has CTD format for technical
requirements for the registration of
pharmaceutical products for use in humans.
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36. • Drug Regulatory Authority ensures that of
medicinal products are of acceptable Quality,
Safety and Efficacy which are Approved,
Manufactured and Imported.
• Drug Controller General of India (DCGI) is the
head of Central Drug Standard Control
Organization,(CDSCO) which regulates Drugs
& Device in India.
Drug Approval in India
36
37. DRUG REGULATION SYSTEM IN INDIA
• When a company in India wants to
manufacture/import a new drug it has to apply to
seek permission from the, Drug Controller General
of India (DCGI) by filing, Form 44 along with the
data mentioned in Schedule Y of Drugs and
Cosmetics Act 1940 and Rules 1945.
• In order to prove the efficacy and safety in Indian
population a clinical trial in accordance with the
guidelines specified in Schedule Y is to be
conducted and a report of the trial is to be
submitted in a specified format.
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38. Drug Controller General of India
Clinical (DCGI)
• The office is runs under CDSCO. It has main
responsibility of regulating clinical trials in
India.
• Matters related to product approval and
standards, clinical trials, introduction of new
drug, and import licenses of new drugs are
handled by the DCGI.
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39. Drug Controller General
of India
Deputy Drug
Controller
1. New Drug/
Ph’vigilance
3. Biological
& Vaccines
4. Drugs2. Medical
Device
Asst Drug Controller 39
40. Functions of CDSCO
• Approval of new drugs and clinical trials
• Import Registration and Licensing
• Licensing of Blood Banks, & Medical Devices
• Amendment to D &C Act and Rules
• Banning of drugs and cosmetics
• Grant of Test License, Personal License, NOCs for
Export
• Testing of Drugs
40
41. Product categories
• 1. New Drug
• 2. FDC
• 3. Biologicals
• 4. Medical Devices.
• 5. Old drugs / Generics
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42. Approval of Clinical Trials, Import, & Manufacture of New Drugs
Requirements and Guidelines - Schedule Y
• Rule 122 A -: Permission to import and market
new drug
• Rule 122 B -: Permission to manufacture new drug
• Rule 122 DA -: Permission of Clinical trials/IND
• Rule 122 E -: Definition of New Drugs
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44. Drug Approval in India
• But a provision is there in the Rule - 122A of the
Drugs and Cosmetics Act 1940 and Rules 1945
that the licensing authority can give waiver to the
trail.
–If the authority believes that, it is in the interest
of public health based upon the data of the
trials conducted in other countries.
–If the Drugs is approved and is being used for
several years in other countries.
44
45. TIME LINE & FEES FOR NDA
• It generally takes about one year to scrutinize
these documents by Data Associates/Drug
inspectors of CDSCO and during this period
clarification if any, are required by them are
answered and thereafter the importer gets the
Approval.
• Treasury Challan of Rs 50,000 – For fresh
application.
• Treasury Challan of Rs 15,000 – For subsequent
application.
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46. Drug Approval in India
• As per the Section 2.4 (a) of Schedule Y of Drugs and Cosmetics Act
1940 and Rules 1945, drug substances that are discovered in India
are required to conduct all phases of trials.
• Section 2.4 (b) of Schedule Y of Drugs and Cosmetics Act 1940 and
Rules 1945, drug substances which are discovered in countries
other than India; the applicant is to produce the data available from
other countries and the licensing authority may require him to
repeat the study or permit him to proceed to 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.
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47. Drug Approval in India
• 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.
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48. • Demonstration of safety and efficacy of the drug
product for use in humans is essential before the
drug product can be approved for import or
manufacturing of new drug by the applicant by
CDSCO.
• The regulations under Drugs and Cosmetics Act
1940 and its rules 1945, 122A, 122B and 122D
and further Appendix I, IA and VI of Schedule Y,
describe the information required for approval of
an application to import or manufacture of new
drug for marketing.
Drug Approval in India
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49. New Drug Application (NDA)
• It 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.
• There are 3 possible actions that can send to sponsor:
• Not approvable- List of deficiencies and explain the reason.
• Approvable – 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- The drug is approved.
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50. Drugs Technical Advisory Board (DTAB)
• Is a group of technical experts and they advice
the central and state governments on all
technical matters arising out of the
enforcement of drug control.
• No rules can be made by the central
government without consulting DTAB board.
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51. Drugs Consultative Committee
• It has central and state drug control officials as
members.
• Its main function is to ensure that the drug
control measures and it’s enforcement is
uniformly over all the states
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52. Different Phases of clinical trials:
• Pre clinical study - Mice, Rat, Rabbit, Monkeys
• Phase I - Human pharmacology trial -
estimation of safety and tolerability
• Phase II - Exploratory trial - estimation of
effectiveness and short term side effects
• Phase III - Confirmatory trial - Confirmation of
therapeutic benefits
• Phase IV - Post marketing trial - Studies done
after drug approval.
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55. Principal differences between
US, EU, & India
Requirements US EU INDIA
Agency One Agency USFDA
Multiple Agencies
EMEA
CHMP
National Health Agencies
One Agency DCGI
Registration Process One Registration Process
Multiple Registration Process
1. Centralized (E.U -
Community)
2. Decentralized (At least 2
member states)
3. Mutual Recognition (At
least 2 member states)
4. National (1 member state)
One Registration Process
Application ANDA / NDA MAA MAA
Debarment
classification
Required Not Required Not Required
Number of
copies
3 1 1
Approval
Timeline
~18 Months ~12 Months 12 - 18 Months
Fees
Under $2 million-NDA
Application
$51,520 – ANDA
Application
National fee (including
hybrid applications):
£103,059
Decentralised procedure
where UK is CMS: £99,507
50,000 INR
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56. Requirements US EU INDIA
CRO
(Audits)
Audited by
FDA
Audited by
MHRA
CDSCO
Reserve
Sample
5 times the sample
required for analysis
No such requirement -
Retention of
samples
5 years from date of filing
the application
No such requirement
3 years from date of filing
the application
Presentation eCTD & Paper eCTD Paper
(Now started with e-CTD)
Principal differences between
US, EU, & India
56
57. Thank You For
your time
57
Name of the Guide/ Supervisor:
Dr. Manju Sharma
Assistant Professor
Department of Pharmacology
Faculty of Pharmacy, Hamdard University
New Delhi-110062, India
