in brief about Introduction and Histroy of Regulatory Affairs, NDA Application Process

1. INTRODUCTION TO
Drug Regulatory Affairs (DRA) &
NDA
Mr.B.Brahmaiah
Assistant Professor
Department of Pharmaceutical
Regulatory Affairs & Pharmaceutics
Shri Vishnu College of Pharmacy,
Bhimavaram

2. 2

3. 3

4. Regulatory System
4
YES YES YES
Govt. Prescriber Distributor Patient
YES
Govt.
YES
Prescriber
YES
Distributor
Patient

6. Role of Regulatory Affairs
What is this?
Registration
documents to
regulatory
agency.
To keep track
on every
change in
legislation.
To give strategic
& technical
advice to R&D,
Production & QC
Dept.

7. Positive participation for regulation making.

8. WHAT WE NEED
Procedures ( Path) should be very clear

9. WHAT WE NEED
Consumer safety is priority

10. NO OVER LOADING OF REQUIREMENTS

11. MEANING OF DRUG REGULATION
 Drug
“All medicines for internal or external use of human beings or animals and
all substances intended to be used for diagnosis, treatment, mitigation or
prevention of any disease or disorder in human beings or animals”
 Regulation
“To regulate means to control something so that it functions properly”
 Key functions of drug regulatory agency
o Product registration
o Regulation of drug manufacturing, importation, and distribution
o Regulation & Control of drug promotion and information
o Adverse drug reaction (ADR) monitoring
o Licensing of premises, persons and practices
o To guarantee the safety, efficacy and quality of drugs available to public

12. WHY REGULATE?
“All substances are poisons; there is none which is not a poison.
The right dose differentiates a poison and a remedy (medicine)”-
Anonymous
Need for Regulation:
 To ensure quality, safety and efficacy of drug products in order to assure the
continued protection of Public Health.
 No drug product is completely safe or efficacious in all circumstances, but there
is a moral, as well as legal, expectation that appropriate steps are taken to assure
optimal quality, safety and efficacy by the producers concerned.
“BENEFIT VERSUS RISK”

16. • Tunisia first introduced drug regulation in 1942, in the form of a decree on medical and pharmaceutical
promotion and drugs control.
• All finished pharmaceutical products, whether manufactured in Tunisia or imported, must undergo a
technical committee review and obtain a certificate of approval from the ministry of health before they
may be placed on the market.
• Registration is also required for homeopathic drugs, and some herbal medicines are registered with the
status of allopathic medicines.
• Key legislation includes the 1961 law on inspection of pharmacies and manufacturers, the 1969
poisonous drug law and the 1985 law on production of drugs for human use.Between 1985 and 1991,
several legal texts were promulgated concerning GMP, clinical trials, and medical and scientific
information, procedures to obtain licensing of manufacturing and registration.
• New organizations were also created by law, for example the pharmacy and medicines directorate in
1981, the national Pharmacovigilance centre in 1984 and the national medicines control laboratory in
1990.

17. • Regulatory controls over the pharmaceutical sector in Malaysia were introduced in the
1950s, starting with the promulgation of three ordinances: the sales of food and drugs
ordinance if 1952, the poisons ordinance of 1952 and the dangerous drugs ordinance of
1952.
• These were followed by the medicines (advertisement and sale ) ordinance of 1956.
• Combined, the laws provided a legal frame work to regulate the general handling of
pharmaceuticals, including poisons and narcotics, in respect of importation, manufacture,
compounding, storage, distribution and transportation.
• They also covered advertising, sales. Record – keeping and use of pharmaceuticals.

18. • The next way wave of major legislative activities and capacity –building relating to drug
regulation came in the late 1970s and 1980s.
• The national pharmaceutical control laboratory was set up in 1978 for the purposes of
regulatory control, new legislation was introduced in 1984 in response to increased concerns
about the infiltration of products in to the market and the inaccuracy of information provided
in the pharmaceutical industry.
• This legislation was promulgated under the control of drugs and cosmetics regulations 1984.
• This act provided for the establishment of the drug control authority (DCA), which started
registering pharmaceutical products in January 1985.
• But the initial implementation of this law was limited only to the states of sabah, Sarawak and
the federal territory of labuan (in east Malaysia).
• The poisons ordinance, revised to become the poisons act 1952, was again revised in 1989, to
include the poisons regulations (psychotropic substances act 1989).

19. • Similarly, the sales of food and drugs ordinance was revised in 1959 to become the
sales of drugs act 1952 (revised 1989).
• In the Netherlands, the legal basis for licensing of pharmaceutical manufacturing and
distribution was established in 1956.
• The medicines act of 1958 there after regulated the admission of medicines to the dutch
market through the MEB.
• But the board started to operate only after 1963, triggered by the thalidomide disaster of
1961.
• European drug regulation is now playing a growing role.
• In 1995, the European medicines evaluation agency was founded to co-ordinate the
tasks of the drug regulatory authorities of European union member states.

20. • Certain aspects of Netherlands drug regulation now follow European union rules. For example, GMP
inspection is based on the 1983 European union guidelines for GMP.
• Since 1 January 1995 a European procedure for registration has operated in the Netherlands.
• Now two types of trade licenses exist: a European license and a national license. Products with a
european license may be sold throughout the whole European union, while the national licenses are
only valid for the country in which the license was issued by means of the national registration
procedure.
• In Cyprus, the pharmacy and poisons law was first promulgated in 1959. It established the framework
for regulation of pharmacy practice, drug distribution, prescription and labelling.
• The principal legislation regulating pharmaceuticals today- the drug law –was introduced in 1967
following the thalidomide disaster.
• Several major regulatory activities, e.g. drug registration and licensing of manufacturers, began in
1970.

21. • The thalidomide disaster was also a key factor in the development of the Australian drug
regulatory system.
• Before the 1960s, drug regulation was predominantly the responsibility of the states and
territories, rather than the Australian commonwealth.
• There was considerable diversity in the level of control exercised. The first advisory
committee to review drugs was set up by the state Victoria in 1948.
• This committee reviewed all products sold in the state of Victoria, but had no jurisdiction
over other states in Australia.
• The first commonwealth advisory committee in Australia was established in 1964.
• Because of the legislative process, the commonwealth limited its control to imported
products and those included in the government reimbursement list.

22. • The national biological standards laboratory (the forerunner of the mechanisms established
under the therapeutic goods act ) was established to test drugs provided on the schedule for
quality. The first federal act relating to therapeutic goods was enacted in 1965.
• Lack of control over locally manufactured products emerged as a public policy issue in the
mid-1980s, and the therapeutic goods act was changed in 1989 in response.
• Under the terms of the act, the TGA was created. It combine the old therapeutics division
within the department of health with the national biological standards laboratory.
• Uganda passed its first drug regulation law in 1952.
• A poisons guide was issued in 1960, a dispensary tariff imposed in 1962 an da trade guide in
1963.
• In 1970, the pharmacy and drugs act was enacted to regulate in use is the national drug
authority statute of 1993.

23. • Regulation of medicines in Zimbabwe started in 1969, with the promulgated of the drugs and allied
substances control act, chapter 320.
• This act created the drugs control council ( a body corporate), which started operations in 1971.
• The 1997 amendement transformed the drugs and allied substances control act into the medicines and
allied substances control act (MASCA), chapter 15:03, which established the medicines control agency
of Zimbabwe (MCAZ), with increased authority.
• Estonia’s drug regulatory framework has begun to take shape only the last decade, since the country
gained independence. However, the pace of regulatory development has been rapid.
• The licensing board of pharmaceutical activities and the centre of medicines were both created in
1991. registration and licensing were introduced that year. In 1993, the SAM was created to become
the DRA.
• The main legislation-the medicinal products act came into force in 1996.

24. CRISIS-LED CHANGE
Regulatory policies are often developed in response to problems.
• Significant changes in drug regulation in Australia, Cyprus and the Netherlands were made as
a result of the thalidomide disaster that occurred in Europe in 1961.
• This is a classic example of a crisis-led change.
• The disaster increased public concerns about pharmaceutical safety: governments responded
by imposing more stringent controls on the pharmaceutical sector, and with less resistance
from the industry than would normally have been the case.

25. TREND TOWARDS HARMONIZATION
• International collaboration in drug regulation has led to the creation of international
instruments to facilitate cross-border drug control, particularly for narcotics.
• All the 10 countries in this study have signed a number of international conventions.
• The most commonly endorsed of these conventions relate to narcotic drugs and psychotropic
substances, and illicit trafficking.
• Recent regional activities indicate a trend towards harmonization of standards and laws.
• The European union is the most advanced in fostering regional harmonization of drug
regulation.
• In 1995, the European medicines evaluation agency was created to –ordinate drug regulatory
affairs in its member states.
• The influence of European union guidelines and rules is evident in Estonia and Netherlands.

26. • In the Netherlands, on the other hand , the main regulatory framework was created in
the 1960’s so that the country currently recognizes two drug regulation systems.
• Drugs registered by the MEB, and those registered by the European commission (on the
recommendation of the European medicines evaluation agency) are both available on
the Netherlands market.
• For GMP Inspection, the Dutch regulatory body follows the relevant European union
guidelines .
• The Netherlands is also involved in the process initiated by the international
conference on harmonization of technical requirements for registration of
pharmaceuticals for human use (ICH) by virtue of its membership of the European
union .
• Venezuela also observes harmonization decisions made by a regional body, Namely the
Andean community.

27. • Australia has a federal process for adopting European guidelines for drug development and
evaluation , including the ICH guidelines. It also has bilateral agreements with a number of
countries, and its membership of the pharmaceutical inspection convention allows it to
exchange GMP information with other members.
• Members of the Association of south –east Asian nations (ASEAN), Malaysia included, have
yet to formulate common rules for regulation. Nonetheless, efforts have been made towards
harmonization in terms of voluntary standards.
• Through the ASEAN technical cooperation project in pharmaceuticals, a number of reference
substances and guidelines have been developed.
• Furthermore, aggreements for the ASEAN free trade area have harmonized and reduced
import tariffs on a number of goods, including pharmaceutical raw materials and finished
products.

28.  MOH&FW comprises 04 departments each of which is headed by a
Secretary to the Govt. of India
 Department of Health & Family welfare
 Department of AYUSH
 Department of Health Research
 Department of AIDS Control
 CDSCO is a separate division comes under DGHS, headed by DCG(I)
 Public health is one of the major objectives of Govt. of India and to
achieve this it is important that drugs/vaccines are available to the public
are Quality, Safety, Purity and Efficacious.
Introduction to Ministry of Health & Family Welfare
(MOH&FW) in INDIA

29. Major Regulatory Agencies of the world are:
INDIA: Central Drugs Standard Control Organization (CDSCO)
USA : Food and Drug Administration (FDA)
EUROPE: European Medicines Agency (EMA)
JAPAN: Pharmaceuticals and Medical Devices Agency (PMDA)
UK: Medicine and Healthcare Products Regulatory Agency (MHRA)
AUSTRALIA: Therapeutic Goods Administration (TGA)
CANADA: Health Canada
International Conference on Harmonization (ICH)
 A network of the authorities in EU, US, Japan and industry organizations
 Provide guideline on Quality, Safety, Efficacy and CTD
 No authority – recommendations which will have to be regionally
implemented

30. DRUGS REGULATORY SYSTEM IN
INDIA

31. DRUG REGULATION SYSTEM IN INDIA
• When a company wants to manufacture/import a new drug in India, 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
DRUG APPROVAL IN INDIA
• 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

32. Goa
New Delhi
Chennai
CDSCO North Zone (Ghaziabad)
Kolkata
.
CDSCO West Zone (Mumbai)
CDSCO South Zone (Chennai)
CDSCO East Zone (Kolkata)
CDSCO, HQ
• Hyderabad
Ahmedabad
*New Zonal Offices : 2
(Ahmedabad & Hyderabad)
*Sub- Zonal Office : 3
*Port Offices/Airports : 11
*Central Laboratories : 6
35 SLAs= 29 States+ 6 UTs
Bengaluru
Geographical Location of CDSCO
Chandigarh
J&K
HQ

33. Functions of CDSCO
Approval of new drugs and clinical trials
Import Registration and Licensing
License approving of Blood Banks, LVPs, Vaccines, r-DNA
Prdts. & Medical Devices (Central Licensing Approval Authority)
Amendment to D &C Act and Rules
Banning of drugs and cosmetics
Grant of Test License, Personal License, NOCs for
Export
Testing of New Drugs

34. Functions of State Licensing Authorities
Licensing of Manufacturing Site for Drugs including API and
Finished Formulation
Licensing of Establishment for sale or distribution of Drugs
Approval of Drug Testing Laboratories
Monitoring of Quality of Drugs and Cosmetics marketed in
the country
Investigation and prosecution in respect of contravention of
legal provision
Recall of sub-standard drugs

35. Functions of Drug 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

36. DRUG APPROVAL PROCESS

37. Expanded
Programme
on
Immunization
.

38. Evolution of Indian Drug Legislation
Objective
The Objective of Drugs & Cosmetics Act 1940 is to ensure that public are
supplied with Quality, Purity, Identity, Safety and efficacy of Pharmaceutical
Products & Cosmetics.
Basic Philosophy
The basic philosophy of Drugs & Cosmetics Act is that the manufacturer is
responsible for the quality of drugs manufactured by them and the
Government/Regulatory Agencies will monitor the quality of drugs by
periodic inspections of the manufacturing and sales premises for
confirmation to the provisions of Drugs & Cosmetics Act and monitoring the
quality of drugs moving in the market by carrying out post market
surveillance.

39. Evolution of Indian Drug Legislation Cont..
Principle
The principle on which the Drugs & Cosmetics Act function is by a system of
licensing under which all the activities involved in manufacture, sale and
distribution of Drugs & Cosmetics are controlled.
Drug regulatory system in India
Drug is in concurrent list of Indian Constitution. It is governed by both Centre
and State Governments under the Drugs & Cosmetics Act 1940 & Rules 1945
there under.

41.  Introduction
Critical component for drug approval
process which required to submit to
USFDA before drug commercialization.
The data gathered during the animal
studies and human clinical trials of an
Investigational New Drug (IND) become
part of the NDA.
 Goal
The NDA provide enough information
to permit FDA reviewer to reach safety,
efficacy and quality for pharmaceutical
production
41
New Drug Application

42.  New Molecular Entity
 New Salt of Previously Approved Drug (not a new molecular entity)
 New Formulation of Previously Approved Drug (not a new salt OR a new molecular entity)
 New Combination of Two or More Drugs
 Already Marketed Drug Product - Duplication (i.e., new manufacturer)
 New Indication (claim) for Already Marketed Drug (includes switch in marketing status from
prescription to OTC)
 Already Marketed Drug Product - No Previously Approved NDA
42
NDA Classifications

54. Product Life Cycle - Regulatory Affairs
Perspective
Development
Phase
 Advice on development
 Scientific Advice
 Clinical Trial Applications
 Project management /
Strategy
 Product Information -
Claims
Approval Phase
• Application Procedure
• Authority meetings/hearings
• Electronic submission
• Readability Testing / Labeling
Support
Post Approval Phase
• Life Cycle Management/
Compliance
• Post-approval Commitments
• Clinical Trial Applications
• New Indications

55. Preclinical trial - a laboratory test of a new drug or a new
medical device, usually done on animal subjects, to see if
the hoped-for treatment really works and if it is safe to test
on humans.
Preclinical trials or non clinical trials – are laboratory
test of a new drug substance or medical devices, usually
done on animal subjects, to see whether the treatment
really works and if it is safe to test on humans.
The main goals of pre-clinical studies are to determine a
product's ultimate safety profile.
Products may include new medical devices, drugs, gene
therapy solutions, etc.

56. Pre-Clinical Trials and Clinical Trials are the processes by which
scientists test drugs and devices to see if they are SAFE and
EFFECTIVE.
Preclinical trial - a laboratory test of a new drug or a new medical
device, usually done on animal subjects, to see if the hoped-for
treatment really works and if it is safe to test on humans

57. IMPARTANCE OF PRE-CLINICAL
TRAILS
 To determine the dose, toxic dose,
pharmacological action, etc
 It is the requirement of regulatory body for
performing clinical trials
 As ethical view point, it is necessary to
check safety of drug on animals before
starting to check on human being
 To check the kinetic profile of drug
& based on it, select the route of
administration in human for clinical
trials(Absorption, distribution ,
elimination studies )
 Therapeutic index (safety & efficacy

58. 58
New Drug Development and Review
Process
Steps from Test Tube to New Drug Application Review
Have you ever had to take a medicine to treat an illness?
Have you ever wondered how researchers determine if the medicines you
take are safe or not?
Pre-Clinical Trials and Clinical Trials are the processes by which scientists
test drugs and devices to see if they are SAFE and EFFECTIVE.

60. CLINICAL TRAILS
 Clinical trial is a systematic investigation in
human subjects for evaluating the safety &
efficacy of any new drug.
 Clinical trials are a set of tests in medical
research and drug development that generate
safety and efficacy data for health interventions in
human beings.
 Clinical trials are conducted only whenSatisfactory
information has been gathered onthe quality of the
nonclinical safety
 Health authority/ethics committee approval is
granted in the country where approval of the drug
is sought.
 Clinical Trial is the mainstay for bringing out

61. DRUG REVIEW STEPS
 Preclinical (animal) testing.
 An investigational new drug application (IND) :
outlines what the sponsor of a new drug proposes for
human testing in clinical trials.
 Phase 1 studies
 Phase 2 studies
 Phase 3 studies
 Submission of New Drug Application (NDA) is the
formal step asking the FDA to consider a drug for
marketing approval.
 FDA reviewers will approve the application or find it
either "approvable" or "not approvable.“
 Phase-4 Studies ( Post marketing Surveillance)

62. PHASES OF CLINICAL TRIALS

63. PHASE 0 STUDY/MICRODOSING
 Study of new drug in micro doses to derive PK information in human
before undertaking phase I studies is called PHASE O
 Micro dose: Less than 1/100 of the dose of a test substance calculated
to produce pharmacological effect with a max dose ≤100 micrograms •
 Objective: To obtain preliminary Pharmacokinetic data.
 Advantages:
 § Less chances of adverse effects
 § Short duration
 § Less no. of volunteers
 § Reduced cost of development
 § Reduced drug development time
 Limitations:
 § Study mainly based on PK parameters - not efficacy and safety based
 § Agents having different kinetic characteristics between micro dose and
full dose are not evaluated by phase 0 trials

64. PHASE-1
 First stage of testing in human subjects.
 Designed to assess the safety, tolerability, PK and PD of drug.
 20-25 healthy volunteers; Duration: 6-12 months.
 Patients: Anticancer drugs, AIDS therapy.
 The aim of a Phase I trial is to determine the maximum tolerated dose
(MTD) of the new treatment.
 Kinds of Phase I:
 SAD: Single ascending dose studies.
 MAD: Multiple ascending dose studies.
 Food Effect: Investigates differences in absorption caused by food
 SUBJECTS:
 Healthy human volunteers: Commonly used.
 Patient Volunteers: Cytotoxic drugs, AIDS therapy, Patients in
advanced stage of disease.
 LIMITATIONS:
 Trial restricted to homogenous subjects.
 Performance extrapolated to heterogeneous market place

65. PHASE-2
 It is a Therapeutic Exploratory Trial consists of 20-300 Subjects.
 To confirm effectiveness, monitor side effects, & further
 evaluate safety.
 First in patients (who have the disease that the drug is expected
to treat).
 Duration: 6 months to several years.
 Optimum dose finding:
 Dose efficacy relationship
 Therapeutic dose regimen
 Duration of therapy
 Frequency of administration
 Therapeutic Window
 Phase II Study Types:
 Phase IIA: Designed to assess dosing requirements.
 Phases IIB: Designed to study efficacy

66. PHASE-3
 It is a Therapeutic confirmatory trial.
 Target population: several 100’s to 3000 patients.
 Duration: Takes a long time, up to 5 years.
 To establish efficacy of the drug against existing therapy in
larger number of patients, method of usage, & to collect
safety data etc.
 • To assess overall and relative therapeutic value of the
new drug Efficacy, Safety and Specal Properties.
 Subtypes:
 Phase IIIA: to get sufficient and significant data.
 Phase IIIB: allows patients to continue the treatment, Label
expansion, additional safety data.
 Phase III B studies are known ass"label expansion” to
show the drug works for additional types of
patients/diseases beyond the original use for which
the drug was approved for marketing.

67. NDA (New Drug Application)
 NDA Refers to New Drug Application.
 Formal proposal for the FDA/DCGI to approve
a new drug for sale.
 Sufficient evidences provided to FDA/DCGI to
establish:
 Drug is safe and effective.
 Benefits outweigh the risks.
 Proposed labeling is appropriate.
 NDA contains all of the information gathered
during preclinical to phase III.

68. PHASE-4
 Post Marketing Surveillance (PMS).
 No fixed duration / patient population.
 Helps to detect rare ADRs, Drug interactions and also to explore new
uses for drugs [Sometimes called Phase V].
 PERIODIC SAFETY UPDATE REPORTS :
 To be submitted by the manufacturer every 6 months for 2 yrs and then
annually for next 2 yrs after marketing approval.
 Harmful effects discovered may result in a drug being no longer
sold, or restricted to certain uses
 OBJECTIVES OF PHASE 4
 Confirm the efficacy and safety profile in large populations during
practice.
 Detect the unknown/rare adverse drug reaction/s.
 Evaluation of over-dosage.
 Identifications of new indications.
 Dose refinement: Evaluation of new formulations, dosages, durations of
treatment.
 REPORTING OF ADR

70. Phase Number of
patients
Length Purpose Percent
successfully
completing
Phase1 20-100 Several months Mainly safety
67
Phase2 Up to several
hundred
Several months
to two years
Some short-
term safety but
mainly
effectiveness
45
Phase3 Several
hundred to
several
thousand
1-4 years Safety,
effectiveness,
dosage
5-10
70
Phases of clinical testing

71. 71

72. 72
NDA Review Process

76. Thank You
76