Understanding

the Regulatory
Landscape
Group 8:
Aakanksha 03
Sharyn 06
Anupma 11
Zarah 15
Kanaka 17
Manish 40
Process of Regulatory Approval

STEP 1 IND Approval

Reason: . When drug's

Data 1: Animal sponsor (usually the Data 3: Clinical Protocols
Data 2: Manufacturing
Pharmacology and manufacturer
Information -  or potential and Investigator
Toxicology Studies Data - Informationmarketer)
pertaininghaving
to Information –
Preclinical data to permit screened the new “investigator brochure”
the composition,
an assessment as to manufacturer, molecule for
stability, a. Detailed protocols for
whether the product is pharmacological
and controls used for activity proposed clinical studies .
reasonably safe for initial and acute
manufacturing toxicity b qualifications of clinical
the drug
testing in humans. substance potential animals, investigators. C. Obtain
and theindrug
wants to test its review of the study by an
product. 
diagnostic or therapeutic institutional review board
potential in humans. (IRB)
• Once the IND is submitted, the sponsor must wait 30 calendar days
before initiating any clinical trials. 
• FDA  has an opportunity to review the IND for safety to assure that
research subjects will not be subjected to unreasonable risk.
IND CONTENT REQUIREMENTS

• Cover Sheet (and Form FDA 1571)

• Table of Contents
• Introductory Statement and General Investigational Plan
• Investigator's Brochure
• Clinical Protocol
• Chemistry, Manufacturing and Control Information
• Pharmacology and Toxicology Information
• Previous Human Experience
• Additional Information
• ICH-Common Technical Document Format
PROCESS OF REGULATORY APPROVAL

STEP 2 NDA Approval

Goal 1: Whether the drug is

Reason: The NDA Goal 3: Whether the
Goal 2:Whether the
Data 1 : The data application is the vehicle methods used in
safe and effective in its drug's proposed labelling
gathered during the through which drug manufacturing the drug
proposed use(s), and (package insert) is
animal studies and sponsors formally and the controls used to
whether the benefits of the appropriate, and what it
human clinical trials of propose that the FDA maintain the drug's
drug outweigh the risks. should contain.
an Investigational New approve a new quality are adequate to
Drug (IND) pharmaceutical for sale preserve the drug's
and marketing  identity, strength,
quality, and purity.

The FDA has 60 days to decide whether to review the NDA. After
deciding that it will review an NDA, the FDA has 10 months to make a
determination (6 months for priority drugs)
PROCESS OF REGULATORY APPROVAL

• Post marketing (Phase IV) Studies

As part of the approval process, the FDA may obtain
commitments from the sponsor to do additional Phase 4
studies after the product is marketed
• However, the FDA cannot enforce compliance
• The FDA also monitors adverse events through an
adverse event surveillance program
• Reporting is voluntary for health care providers
mandatory for drug manufacturers
• Epidemiologists review adverse event data
Registration Process in India
Regulatory Affairs Organization Chart
• Approx duration of registration of a new
Generic API is 3-9 months
• Duration for the renewal of the registration:
max. 3 months
DCGI provides NDA approval for 2 categories of products
The process for the approval of category A products is fast track approval and includes:
In case of category B the process is slightly longer and
more tedious & takes almost double the time
PHARMACOVIGILANCE IN INDIA

• In 1998 India established a pharmacovigilance national center at

AIIMS
• There was also a WHO Special Center at KEM Hospital
• In 2004, India established a National Pharmacovigilance
Program, on 23rd November 2004
• National Pharmacovigilance Advisory Committee consisted of:
– Advisory Committee to Government
– 16 members
– Supervise activities of National Pvig Program
REGULATORY ASPECTS IN USA
Drug Safety and Effectiveness

US is one of the most strictly regulated markets, most

stringent rules

All drugs ,prescription, or sold more widely as OTC

products – must be proven safe and effective.

Prescription and nonprescription drugs are quite different,

particularly in terms of their ingredients, labeling, and availability

However many of the statutory requirements for marketing

approval apply to both classes
 THE US-FDA IND AND NDA
APPROVAL PROCESS
Filing of IND No intimation of
for clinical trials a clinical hold

File NDA based

on the result of
Start clinical
the clinical trials testing

60 days Approve /
application approvable/ non
review period approvable letter

180 days to
Feedback by
complete
approval the sponsor

Grant of
approval
A team of CDER physicians, statisticians, chemists, pharmacologists, and other
scientists reviews the sponsor's NDA containing the data and proposed labelling. 
 ●
● When decision to go ahead with clinical trials
●
● exemption from the statutory prohibition against shipping experimental drugs
in interstate commerce
IND FILING ●
● the various tests required are Laboratory tests Pharmacological animal tests,
Acute toxicological animal tests and Sub-acute and sub-chronic toxicological
animal tests

●
● FDA requires clinical trials be conducted
CLINICAL TESTING according to formal protocols that the drug
sponsor submits as part of the IND application

●
● Appropriate data from clinical testing is
FILING OF NDA
applied as an NDA
 ●
● CDER has 60 days from the date a company submits an NDA to
decide if it contains sufficient information
60 days review period ●
● logs the application into its management tracking system and refers
it to the appropriate review division based on its intended use.

●
● approve the product for market
●
● declare that the FDA would approve the drug once the company
FDA INTIMATION allays lingering concerns about effectiveness or safety (called an
‘‘approvable letter’ ‘) or
●
● state that the drug is “un-approvable”

●
● must respond within 10 days to an
RESPONSE OF SPONSOR ‘‘approvable’ or ‘‘un-approvable” letter by
providing information
Because pro approval testing affords only a limited view of a drug’s benefits and
risks, the research process usually does not stop at the point of market approval,
Post-approval research can involve both clinical trials, referred to as Phase IV
studies, and new animal toxicity studies (21 C.F.R. 310.303)
CERTAIN CHANGES IN POLICY

Eliminated or simplified some prior regulatory requirements;

Opened the door for improved communication between the agency and
pharmaceutical sponsors;

Established specific time limits for industry and agency action at various points
in the regulatory review process;

Altered the format and content of the NDA and IND applications to facilitate
review by the FDA; and

Clarified or codified other FDA policies and practices (such as the conditions under
which the agency issues approval and approvable letters and administrative
procedures sponsors may use to resolve scientific disputes with FDA review staff)
THE APPROVAL FOR GENERIC DRUGS

• A drug product that is comparable to a

brand/reference listed drug product in dosage form,
strength, route of administration, quality and
performance characteristics, and intended use

When can a Generic Drug be Marketed?

 After patent & exclusivity protection ends, or
 patent owner waives its rights, and
 FDA requirements are met
 NDA ANDA
REQUIREMENTS REQUIREMENTS
●
●LABELLING ●
●LABELLING
●Pharm/Tox
●
●Pharm/Tox
●
●Chemistry
●
●Chemistry
●
●Manufacturing
●

●Controls
● ●Manufacturing
●

● Microbiology
● ●Controls
●

●Inspection
●
●Microbiology
●

●Testing
●
●Inspection
●
●Animal Studies
●
●Testing
●
●Clinical Studies
●

●Bioavailability
● ●Bioequivalence studies
●
REGULATORY REQUIREMENTS- AUSTRALIA AND NEW ZEALAND
THERAPEUTIC GOODS ADMINISTRATION-
AUSTRALIA
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REGULATORY REQUIREMENTS- JAPAN
 JAPANESE REGULATORY BODIES

NATIONAL INSTITUTE
MINISTRY OF HEALTH & NATIONAL INSTITUTE
OF INFECTIOUS
WELFARE OF HEALTH SCIENCES
DISEASES
 MINISTRY OF HEALTH & WELFARE
• Japan has a welfare government.
• Main body in-charge of all health related activities: MHLW
• The MHLW is comprised of various sub-departments such as:
Dept. of Food Safety,
 Health Service Bureau
 Industrial Safety & Health Dept.
 Pharmaceutical & Food Safety Bureau, etc..

• The regulatory authority in Japan is the Pharmaceutical and Medical Devices Agency
(PMDA)
• The basis for market regulation is the 1960 Pharmaceutical Affairs Law (PAL)
• Crucial problem is the delay of over two years between the launch of a drug in a
foreign market and its launch in Japan
•Various causes for the so-called ‘drug lag’, include:
 The relative inefficiency of the regulatory and reimbursement listing process,
 staff shortages,
Japan’s conservatism and
 The delays as a result of the requirement to provide post-marketing clinical data for
products that are already approved in other major advanced markets.
 RECENT REGULATOY DEVELOPMENTS IN JAPAN

• Japan aims to cut two and a half years off the time taken to approve new
medicines by 2012, bringing it in line with the US and the EU.

• Following the implementation of the new PAL in Japan on April 1 2005,

foreign companies that register and market their products in Japan are required
to be aware of the new regulatory changes that have taken place:
 The requirement to appoint a Marketing Authorisation Holder (MAH),
which is designed to act as a regulatory control mechanism;
 New good manufacturing practice (GMP) requirements;
 and changes to the classification and labelling of medical devices.

• At the PMDA First International Symposium on Biologics in Tokyo in March

2007, the agency outlined a framework for approving biosimilars, or
subsequent-entry protein products.

• There will also be a need to show comparable safety and efficacy for each
intended indication, while dosage forms or indications different from those of
the original product are likely to require extensive conventional registration
data.
NATIONAL INSTITUTE OF HEALTH SCIENCES
• The National Institute of Health Sciences (NIHS) conducts testing, research, and
studies toward the proper evaluation of the quality, safety, and efficacy of
pharmaceutical products, foods, and the numerous chemicals in the living
environment.

INFORMATION ON DRUGS

• Overseas Drug Safety Information (in Japanese)

•The Japanese Pharmacopoeia Fifteenth Edition
(The Japanese Pharmacopoeia Fifteenth Edition Name and Structure Database)
•Japanese Accepted Names for Pharmaceuticals (JAN) Database
•Pharmaceutical Administration and Regulations in Japan
 NATIONAL INSTITUTE OF INFECTIOUS
DISEASES

• The Institute aims at carrying out extensive and original research projects
on a variety of contagious diseases from the standpoint of preventive
medicine, improving human health and welfare by suppressing infectious
diseases, and clarifying and supporting the scientific background of health
and medical administration of the country.

• These functions may be summarized into

Research activities,
Reference services for infectious diseases,
Surveillance of infectious diseases,
National control tests and other tests,
International cooperation, and
Training activities.
THE EUROPEAN UNION

EMEA GUIDELINES
The EU presents complex challenges from a regulatory perspective.

There is over-arching legislation which is then implemented at a local level by the 27

individual member states, Iceland, Liechtenstein and Norway.
• The registration file relating to any particular
product must contain medical data related to
product efficacy and safety, including results
of clinical testing and references to medical
publications, as well as detailed information
regarding production methods and quality
control
 EU Dossier Review times

Types of submissions
Mutual recognition
Decentralized
Centralized procedure
• -Receive approval from all members states simultaneously with same label,
tradename
• -Mandatory for biologics
• -Submissions can only be made on certain days of the month
Approx. 12 months for procedure
• -Day 120: assessment report with list of questions → clock stop until submission of
response document
• -Day 210: CHMP opinion
• -Day 270: European Commission decision
BIOTECHNOLOGY INNOVATIVE
PRODUCTS PRODUCTS

Mandatory Optional

Application dossier to agency

210 days net time
Clock stopped for additional information
Oral explanation hearing with company
VALIDATION
Evaluation CPMP
•Appointment of 2 assessment teams
•Production of assessment reports
•Validation of questions by CPMP
•Consideration of company responses

CPMP Opinion
Favourable
Unfavourable

60 days max
Company Appeal Within 30 days, transmission of:
•Opinion
•Assessment report
60 days max •Summary of product characteristics
•Labeling and package insert
To Commission, Member States and Applicant
Second Opinion

Decision making process

Revised legislation introduced the mutual recognition (“MR”) procedure

After submission and approval by the authorities of the so-called reference member
state (“RMS”), further applications can be submitted into the other chosen member
states (known as concerned member states (“CMS”)).

Theoretically, the authorization of the RMS should be mutually recognized by the

CMS.
In November 2005, this legislation was further optimized.

In addition to the MR procedure, the new decentralized procedure was introduced.

This second procedure is also led by the RMS, but applications are simultaneously
submitted to all selected countries.

From 2005, the Centralized Procedure operated by the European Medicines Agency
(“EMA”) became available for generic versions of innovator products approved by
the Centralized Procedure.
• Neither the MR or decentralized procedures
result in automatic approval in all member
states.
• If any member state has objections,
particularly in relation to potential serious risk
to public health, which cannot be resolved
within the procedure scope and timelines,
they will be referred to the coordination group
for MR and decentralized procedures (“CMD”)
and reviewed in a 60-day procedure.
TRENDS IN R&D AND REGULATORY APPROVALS
New Drug Approvals Are Not Keeping Pace
with Rising R&D Spending
60 40

R&D Expenditures
45

R&D Expenditures
(Billions of 2004$)
NCE Approvals

30 20

New Drug Approvals

15

0 0
1963 1968 1973 1978 1983 1988 1993 1998 2003

R&D expenditures are adjusted for inflation

Source: Tufts CSDD Approved NCE Database, PhRMA, 2005
Transition Probabilities for Clinical Phases
83.7%
71.0%
Transition Probability

68.5%
64.2%
56.3%
44.2%

30.2%
21.5%

Phase I-II Phase II-III Phase III- Phase I -

Approval Approval

Biotech Pharma

Source: DiMasi and Grabowski, Managerial and Dec Econ 2007, in press
 CLINICAL DEVELOPMENT AND APPROVAL TIMES

Biotech 19.5 29.3 32.9 16 97.7

Pharma 12.3 26.0 33.8 18.2 90.3

0 120
Months

Phase I Phase II Phase III RR

Source: DiMasi and Grabowski, Managerial and Dec Econ 2007, in press
 Some Aspects of the Regulatory World Are
Becoming Homogeneous
• International Conference on Harmonization
• Non-clinical, Quality, Safety
• Memorandums of Understanding Between
Governments (e.g. Australia/Canada)
• Sharing of Safety Signal Detection / Review
• Mutual Inspections
• Paediatrics
EMEA and FDA meeting monthly to discuss programs
CHANGES AND CHALLENGES

• Strive for Transparency

• Greater global connectivity on safety related aspects
• Demand for more transparency around HA decision making
• Increased information needs of patients
• Cost-containment in Healthcare Sector
•Healthcare budget constraints demand robust proof of relative-/ cost-effectiveness / QOL data
•HA cooperation and knowledge-sharing
• Resource constraints
•More work-sharing across Member States

• Advances in Science
•Preparation of regulatory environment for innovative development approaches

•Engagement in Innovative Medicines Initiative (IMI)

• FDA Leadership Change / Obama Administration
• A stronger FDA re-establishing credibility as a “public health protector”
• Increased transparency
• Enforcement which is “quick, strategic, visible”
• New budget resources directed to restore FDA role as a gold standard in
ensuring safety of regulated products
• Growing scope of responsibility -new Tobacco Center, food safety,
pandemic preparedness
• US Health Care Reform
• Changing relationships with health care providers
• Global environment -FDA increasing pressure on manufacturers to ensure
integrity of product supply chain