Regulatory requirement for drug product approval: US and Canada College of Pharmacy PPT/PDF

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Regulatory requirement for
drug product approval:

US and Canada

College of Pharmacy





• Today, the regulatory requirements for approval of a new
drug in the various countries of the world are quite

• To develop one single regulatory approach for marketing
authorization application (MAA) of a new drug product for
various countries is utmost difficult task- especially for
companies with global activities.

• Therefore, it is very important to know in detail the
regulatory requirements in each country where an MAA
should be submitted to establish a suitable regulatory
strategy before the submission in order to avoid any major
difficulties. 3


US FDA Agency Overview

Formed 1906

Preceding agencies Food, Drug, and Insecticide Administration (July 1927 to July 1930)

Bureau of Chemistry (July 1901 through July
1927) Division of Chemistry, USDA (Established

Jurisdiction 1862)

Head quarters Federal government of the United States

Employees 10903 New Hampshire Ave, Silver Spring, MD 20903

Annual budget 11,516

Agency executive $2.3 billion

Parent agency Margaret A. Hamburg, Commissioner of Food and Drugs

Website Department of Health and Human Services 4



• The Food and Drug Administration (FDAor USFDA) is an agency of the
United States Department of Health and Human Services, one of the
United States federal executive departments.

• The FDA is responsible for protecting and promoting public health
through the regulation and supervision of food safety, tobacco
products, dietary supplements, prescription and over-the-counter
pharmaceutical drugs (medications), vaccines, biopharmaceuticals,
blood transfusions, medical devices, electromagnetic radiation
emitting devices (ERED), veterinary products, and cosmetics.

• The FDA also enforces other laws, notably Section 361 of the Public
Health Service Act and associated regulations, many of which are not
directly related to food or drugs.

• These include sanitation requirements on interstate travel and control of
disease on products ranging from certain household pets to sperm
donation for assisted reproduction. 5



• In June 1906, President Theodore Roosevelt signed into law the Food
and Drug Act, also known as the “Wiley Act” after its chief advocate

• The act applied penalties to the interstate marketing of “adulterated” drugs,
in which the “standard of strength, quality, or purity” of the active ingredient
was not either stated clearly on the label or listed in the United States
Pharmacopoeia or the National Formulary

• The act also banned “misbranding” of food and drugs. The responsibility for
examining food and drugs for such “adulteration” or “misbranding” was
given to Wiley’s USDA Bureau of Chemistry

• Wiley used these new regulatory powers to pursue an aggressive
campaign against the manufacturers of foods with chemical additives, but
the Chemistry Bureau’s authority was soon checked by judicial decisions,
as well as by the creation of the Board of Food and Drug Inspection and
the Referee Board of Consulting Scientific Experts as separate
organizations within the USDA in 1907 and 1908 respectively 6



• A 1911 Supreme Court decision ruled that the 1906 act did not
apply to false claims of therapeutic efficacy in response to
which a 1912 amendment added “false and fraudulent” claims
of “curative or therapeutic effect” to the Act’s definition of

• However, these powers continued to be narrowly defined by the
courts, which set high standards for proof of fraudulent intent.

• In 1927, the Bureau of Chemistry’s regulatory powers were
reorganized under a new USDA body, the Food, Drug, and
Insecticide organization.

• This name was shortened to the Food and Drug
Administration (FDA) three years later. 7



• Protecting the public health by assuring that foods are safe,
wholesome, sanitary and properly labeled; human and veterinary
drugs, and vaccines and other biological products and medical
devices intended for human use are safe and effective.

• Protecting the public from electronic product radiation.

• Assuring cosmetics and dietary supplements are safe and properly

• Regulating tobacco products.

• Helping the public get the accurate science-based information
they need to use medicines, devices, and foods to improve their

• FDA’s responsibilities extend to the 50 United States, the
District of Columbia, Puerto Rico, Guam, the Virgin Islands,
American Samoa, and other U.S. territories and possessions. 8



• The FDA is led by the Commissioner of Food and Drugs, appointed by
the President with the advice and consent of the Senate.

• The Commissioner reports to the Secretary of Health and Human

• The 21st and current Commissioner is Dr. Margaret A. Hamburg.
She has
served as Commissioner since February 2009.

• FDA consists of six product centers, one research center, and two
offices –

• Center for Biologics Evaluation and Research – which regulates
products such as vaccines, blood, and gene therapy.

• Center for Devices and Radiological Health – which regulates
medical devices ranging from thermometers to kidney dialysis machines,
and mproducts that give off radiation, such as microwave ove9ns.



• Center for Drug Evaluation and Research – which regulates over-the-
counter and prescription medications.

• Center for Food Safety and Applied Nutrition- which regulates most
foods (except meat and poultry, which are regulated by the U.S. Department of
Agriculture), food additives, infant formulas, dietary supplements, and cosmetics.

• Center for Tobacco Products – which regulates cigarettes,cigarette tobacco,
roll-your-own tobacco, and smokeless tobacco.

• Center for Veterinary Medicine _which regulates feed and drugs and devices
used in pets, farm animals, and other animals.

• National Center for Toxicological Research- which supports FDA’s
product centers by providing innovative scientific technology, training, and
technical expertise.

• Office Of Regulatory Affairs- which conducts inspections and enforces
FDA regulations.

• Office of the Commissioner-which provides leadership and direction to
FDA’s wpwrwo.DdulouMcixt.c ocmenters, research center, and Office of Regulatory Affairs10



• USFDA has over 11516 employees, located in 167 U.S. cities.
Among its staff, FDA has chemists, microbiologist, and other
scientists, as well as investigators and inspectors who visit 16000
facilities a year as part of their oversight of the business that FDA

• The FDA has its headquarters at Silver Spring, Maryland and has
223 field offices and 13 laboratories located throughout the 50
states, the United States Virgin Islands, and Puerto Rico

• In 2008, the FDA started opening offices in foreign countries,
including China, India, Costa Rica, Chile, Belgium, and the United

• . Kingdom 11


As of Oct. 1, 2009, FDA employs the following numbers of
people in its centers/offices:

Office Employees

Center for Biologics Evaluation and Research (CBER) 946

Center for Drug Evaluation and Research (CDER) 2889

Center for Devices and Radiological Health (CDRH) 1203

Center for Food Safety and Applied Nutrition (CFSAN) 877

Center for Tobacco Products (CTP) 194 12



• Advisory committees provide FDA with independent advice from
outside experts on issues related to human and veterinary drugs,
vaccines and other biological products, medical devices, and food.

• In general, advisory committees include a chair, several members,
plus a consumer, industry, and sometimes a patient representative.

• Additional experts with special knowledge may be added for
individual committee meetings as needed.

• Although the committees provide advice to the agency, FDA
makes the final decisions. 13



• The FDA regulates more than $1 trillion worth of consumer
goods, about 25% of consumer expenditures in the United

• This includes $466 billion in food sales, $275 billion in drugs,
$60 billion in cosmetics and $18 billion in vitamin supplements.

• Much of the expenditures is for goods imported into the United
States; the FDA is responsible for monitoring a third of all imports. 14



• Most federal laws concerning the FDA are part of the Food, Drug
and Cosmetic Act,(first passed in 1938 and extensively amended
since) and are codified in Title 21, Chapter 9 of the United States

• Other significant laws enforced by the FDA include the Public
Health Service Act, parts of the Controlled Substances Act, the
Federal Anti-Tampering Act, as well as many others. In many
cases these responsibilities are shared with other federal agencies 15



Important enabling legislation of the FDA includes :

Act Year

Biologics Control Act 1902

Pure Food and Drug Act 1906

Federal Food, Drug, and Cosmetic Act 1938

Public Health Service Act 1944

Food Drug and Cosmetic Act 1945

Food, Drug, and Cosmetics ActAmendments 1962

Fair Packaging and Labeling Act 1966

Medical Device RegulationAct 1976

Prescription Drug MarketingAct 1987

Anti–drug Abuse Act 1988

Nutrition Labeling and EducationAct 1990

Prewswcw.rDiuplotMiiox.nco mDrug User FeeAct 1992 16



Important enabling legislation of the FDA includes :

Act Year

Dietary Supplement Health and Education Act 1994

Food and Drug Administration Modernization Act 1997

Bioterrorism Act 2002

Medical Device User Fee and Modernization Act 2002

Animal Drug User Fee Act 2003

Food and Drug Administration Amendments Act of 2007

Family Smoking Prevention and Tobacco Control 2009
Act 17


CFR Title 21

C.F. R – Code of federal Regulaion is a codification of general rules
and regulations also known as administrative law published in the
federal register by the executive department and agencies of federal
government of united states

Title 21 of the CFR is reserved for rules of the Food and Drug

CFR 21 was received from the Government Printing Office
(GPO) and contains the most recently received revision.

Food and Drugs: Parts 1 to 1499 different types of parts to food,
drug, cosmetic and medical devices and etc 18


CFR Title 21

21 CFR part 11- Electronic submission and Electronic

21 CFR part 50- Protection of human subjects

21 CFR part 54- Financial Disclosure by Clinical

21 CFR part 56- Institutional Review Board

21 CFR part 101-Food Labelling.

21 CFR part 104-Nutritional quality guidelines for foods

21 CFR part 106- Infant Formula Quality Control

21 CFR part 110- Cgmp Practices in manufacturing
packing or holding human food. 19


FDA Guidelines to conduct cGMP in
Pharma Industry

• 21 CFR part 210- cGMP Practices in
manufacturing, packing or holding of
Drugs: General

• 21 CFR part 211- cGMP Practices for
finished pharmaceuticals 20


21 CFR 210

• 210.1- Status of cGMP regulation.
• 210.2- Applicability of cGMP regulation.
• 210.3- Definitions 21


21 CFR 211

➢ Subpart A – General provision
• 211.1 – Scope

➢ Subpart B- Organization and Personnel
• 211.22-Responsibility of quality control unit
• 211.25-Personnel qualification
• 211.28-Personnel responsibility
• 211.34-Consultants 22


21 CFR 211

➢ Subpart C – General provision
• 211.42-Design and construction features.

• 211.46-Ventilation, air filtration, air heating and

• 211.48-Plumbing
• 211.50-Sewage and refuse
• 211.52- Washing and toilet facilities
• 211.56-Sanitization
• 211.58-Maintenance 23


21 CFR 211

➢ Subpart D – Equipment
• 211.63- Equip. design,size and location.

211.65- Equip. constrution
• 211.67- Equip. cleaning and maintenance
• 211.68- Automatic,machanical and electonic

• 211.72- Filters 24


21 CFR 211

➢ Subpart E – Control of components, drug
product container and closures
• 211.80- General requirement
• 211.82- Receipt & storage of untested

• 211.84-Testing of approval or rejection of

• 211.86-Use of approved components
• 211.87- Retesting of approved components

211.89- Rejected components
• 2ww1w.D1ulo.M9ix.4com- Drug product container and closures 25


21 CFR 211

➢ Subpart F – F-Prodution and process controls
• 211.100- Written procedure and deviation
• 211.101- Charge in of components
• 211.103- Calculation of yield
• 211.105- Equip. identification
• 211.110- Sampling and testing of in-process drug

• 211.111- Time limitation on prodution
• 211.113-Control on microbiological

• 2ww1w.D1ul.oM1ix1.com5- Reprocessing 26


21 CFR 211

➢ Subpart G – Packing and labelling control
• 211.122- Material examination and usage

• 211.125-Labelling issuance
• 211.130-Packing and labelling operation
• 211.132-Tamper evident packing required for

OTC Drug product
• 211.134-Drug product inspection. 211.137-

Expiration dating 27


21 CFR 211

➢ Subpart H-Holding &Distribution
• 211.142- Ware house procedure
• 211.150- Distribution procedure

➢ Subpart I- Laboratory control
• 211.160- General requirement
• 211.165-Testing and release for distribution

211.166-Stability testing
• 211.167- Special testing requirement 211.170-

Reserve samples
• 211.173- Laboratory animals 28


21 CFR 211

➢ Subpart J –Record and reports
• 211.180- General requirement
• 211.182- Equip. cleaning and use log
• 211.184- Component, drug product container &

labelling records
• 211.186- Master prodution and control records

211.188- Batch prodution and control records
211.192- Prodution record review

• 211.194- Laboratory records
• 211.196- Distribution records
• 2ww1w.D1ulo.M1ix.9com8- Complaint files 29


Hatch Waxman Act

• Also known as “The Drug Price Competition and
Patent Term Restoration Act”

• Enacted in 1984
▪Amended the Patent laws

▪Amended the Federal Food, Drug, and Cosmetic Act

• Before 1962- new drug approved based on o n l y safety

• 1962- Proof of efficacy made compulsory for
marketing approval of a new drug (Kefauver-Harris



Hatch Waxman Act

• There was no provision for patent term extension
prior to enactment of the Hatch Waxman Act, to
make up for the time lost out of the total patent term
during the marketing approval process

• Generic companies required to submit their own
comprehensive NDA
▪ Costly
▪ Time consuming

• If drug was covered by patent
▪ Testing could not begin until patent expired

• To overcome the above problems an act was needed
• to promote generic companies



Objectives of the Act

• Reducing the cost associated with the approval of a
generic drug

• Allowing Early-Experimental-Use
• Compensating the branded drugs manufacturers

for the time lost from the patent term because of the
regulatory approval formality

• Motivating the generic drug manufacturers

“HWA strives to strike a balance between the interests of
branded drug manufacturers, generic drug

manufacturers and the consumers”



Provisions of the Act

• Creation of section 505(j)
• Section 505(j) established the ANDA approval

• The timing of an ANDA approval depends in part on

patent protections for the innovator drug
• NDA must include any patent that claims the “drug“

or a “method of using [the] drug” for which a claim of
patent infringement could reasonably be asserted

• On approval of NDA, FDA publishes patent
information for drug in Orange Book (“Approved
Drug Products with Therapeutic Equivalence




• FDA publishes patent information on approved drug
products in the Orange Book

• An NDA applicant must submit the following
information for each patent:
▪ Patent no and date on which the patent will expire
▪ Type of patent, i.e. drug, drug product, or method

of use
▪ Name of patent owner
▪ The name of an agent of the patent owner or

• Brand drugs listed for generics to compare with their

proposed products



Four Types of Patent Certifications

• When an applicant submits an ANDA to the FDA, the
applicant must certify one of four things under section
▪ that the required patent information relating to

such patent has not been filed (Para I);
▪ that such patent has expired (Para II);
▪ that the patent will expire on a particular date

(Para III);
▪ that such patent is invalid or will not be infringed

by the drug, for which approval is being sought
(Para IV – Patent Challenge)



ANDA Filing Para IV







ANDA Filing Para IV



ANDA Filing Para IV

• 180 Day Market exclusivity
▪ First applicant to submit a substantially complete

ANDA (first-to-file)
▪ May be shared by multiple applicants
▪ Subject to forfeiture

• 30-month stay of FDA approval
▪ If patent owner or NDA holder sues the ANDA

applicant for patent infringement within 45 days
of receiving notice of the Paragraph IV

▪ Runs from date of notification or expiration of
NCE exclusivity

▪ May be lengthened or shortened by the court 38


ANDA Filing Para IV

• Notification Letter: 20 Days
▪ Upon ANDA acceptance for filing, the applicant

must notify the NDA holder and patent owner of
the ANDA within 20 days. The notice must
include a detailed statement of the factual and
legal basis of the opinion of the applicant that the
patent is invalid or will not be infringed

• Lawsuit: 45 Days
▪ Upon notification, the NDA holder and patent

owners have 45 days in which to initiate an action
for patent infringement. If such an action is
brought within 45 days, the ANDA is subject to a
30-month stay of FDA approval beginning on the 39

date the notification letter was received


ANDA Filing vs Approvals



Exempt Acts of Patent

• The manufacture, use, or sale of a patented drug is
not an act of infringement, to the extent it is necessary
for the preparation and submission of an ANDA

• The Hatch-Waxman Act provides under 35 U.S.C.
271(e)(1), generally that:

“It shall not be an act of infringement to make, use, or
sell a patented invention … solely for uses reasonably
related to the development and submission of
information under a Federal law which regulates the
manufacture, use, or sale of drugs.”



Hatch Waxman Trade Off



• Automatic Injunction 1st successful Para IV filer

• Notice of generic competition A big head start on others

• Can be worth $$ mn per day



Benefits for branded manufacturers

• Orange Book provides public notice of patents
• Allows for resolution of patent disputes prior to

generic entry
• 30-month stay of FDA approval of generic drugs
• Patent Term Restoration
• Allows for Several Market Exclusivities:
• Data Exclusivity

▪ 5 years for New Chemical Entity (NCE) Drug
▪ 3 years for non-NCE Drug
▪ Orphan Drug (7 years)
▪ Pediatric (PEDS) (6 months)



Benefits for generic manufacturers

• 180-day market exclusivity for first successful
challenger to Orange Book patent

• Allows generics to challenge Orange Book patents
without risk of damages

• “Safe Harbor” rule allows generics to perform
bioequivalence and other testing relating to regulatory
approval without risk of patent infringement

“Dr. Reddy’s was the first Indian company to
get the 180-day exclusivity for marketing

Fluoxetine (Eli Lilly’s Prozac) 40 mg capsule
in August 2001”



Non Patent Exclusivity

Types Term
New chemical entity 5 years

New Clinical study 3 years

Orphan drug 7 years

Pediatric exclusivity 6 months

180-day generic market exclusivity 180 days



New Chemical Entity

• New Chemical Entity (NCE): “a drug that contains
no active moiety that has been approved by FDA in
any other application submitted under section 505(b)
of the act”

• Active Moiety: “the molecule or ion, excluding those
appended portions of the molecule that cause the drug
to be an ester, salt (including a salt with hydrogen or
coordination bonds), or other noncovalent derivative
(such as a complex, chelate, or clathrate) of the
molecule, responsible for the physiological or
pharmacological action of the drug substance”



NCE Exclusivity for Enantiomers

• Federal Drug Administration Amendments Act,

• Under strict conditions, an enantiomer can qualify as
a NCE:
• The single enantiomer has not been previously

approved except in the approved racemic drug
• The NDA includes full new clinical investigations
• The clinical studies were not used for the racemate
• The enantiomer indication is not in the same

therapeutic category as the racemate
• Three-year exclusivity available:

• e.g., Lexapro(escitalopram);
Nexium (esomeprazole)



Orphan Drug Exclusivity

• Orphan Drug Act, 1983
• Granted: to drugs intended for treatment of a “rare

disease or condition”
• Affects < 200,000 people in the U.S., or
• No reasonable expectation of recouping dev. costs

• Blocks: approval of 505(b)(1), (b)(2), or ANDA
directed to the same drug, for same disease

• Length: seven years
• Additional rewards: tax credits; grants; fees waived



Pediatric Exclusivity

• Food and Drug Administration Modernization Act,
1997 (“FDAMA”)

• Granted: to applicants who successfully complete
FDA-requested clinical trials of a drug in a pediatric

• Blocks: approval of 505(b)(2) or ANDA
• Length: six months beyond any existing marketing or

patent exclusivity
• Gov’t funding of pediatric studies if no exclusivity



Generic Drug Exclusivity

• Hatch-Waxman Act, 1984
• Granted: to first ANDA applicant who submits a

“substantially complete” ANDA containing a
paragraph IV certification

• Substantially complete = sufficient to permit review
• Blocks: approval of subsequently-filed ANDA

containing a paragraph IV certification
• Length: 180 days, from commercial marketing



180 Day Exclusivity Forfeiture

• Medicare Modernization Act, 2003 (“MMA”)
• Six ways to forfeit:

1. failure to market
2. withdrawal of application
3. amendment of certification
4. failure to obtain tentative approval within 30

5. improper agreement with another applicant, the

listed drug application holder, or a patent owner
6. expiration of all patents



USFDA (Drug Product Approval

Investigational New Drug Applications (INDA)

• Definition: The investigational new drug (IND) application is
the result of a successful preclinical development program.

• The IND is also the vehicle through which a sponsor advances
to the next stage of drug development known as clinical trials
(human trials)

• Current Federal law requires that a drug be the subject of an
approved marketing application before it is transported or
distributed across state lines. Because a sponsor will probably
want to ship the investigational drug to clinical investigators in
many states, it must seek an exemption from that legal
requirement. The IND is the means through which the sponsor
technically obtains this exemption from the FDA



USFDA (Drug Product Approval

Investigational New Drug Applications (INDA)
• Types of INDs:
1. Investigator INDs: An Investigator IND is submitted by a

physician who both initiates and conducts an investigation, and
under whose immediate direction the investigational drug is
administered or dispensed. A physician might submit a research
IND to propose studying an unapproved drug, or an approved
product for a new indication or in a new patient population

2. Commercial INDs: They are applications that are submitted
primarily by companies whose ultimate goal is to obtain
marketing approval for a new product. However, there is another
class of filings broadly known as “noncommercial” INDs. The
vast majority of INDs are, in fact, filed for noncommercial
research. These types of INDs include “Investigator INDs,”
“Emergency Use INDs,” and “Treatment INDs



USFDA (Drug Product Approval

Investigational New Drug Applications (INDA)
• Types of INDs:
3. Emergency Used IND: This IND allows the FDA to authorize

use of an experimental drug in an emergency situation that does
not allow time for submission of an IND in accordance with
21CFR Sec.312.23 or Sec.312.34. It is also used for patients who
do not meet the criteria of an existing study protocol, or if an
approved study protocol does not exist

4. Treatment IND: Other name is Expanded Access IND, this IND
may be submitted for experimental drugs showing promise in
clinical testing of serious or immediately life-threatening
conditions while the final clinical work is conducted and the FDA
review takes place (21 CFR 312.34)



USFDA (Drug Product Approval

Investigational New Drug Applications (INDA)



USFDA (Drug Product Approval

Investigational New Drug Applications (INDA)

➢ Criteria for application:
• A clinical study is required for an IND if it is intended to

support a:
✓ New indication
✓ Change in the approved route of administration or dosage level
✓ Change in the approved patient population (e.g. pediatric) or a

population at greater or increase of risk (elderly, HIV positive,

✓ Significant change in the promotion of an approved drug
• Application submission:
✓ Most INDs are paper submissions. While only 12% of INDs are

submitted electronically, 28% of IND Amendments are
submitted electronically a result of maintaining a growing

number of INDs submitted electronically to date


USFDA (Drug Product Approval

Investigational New Drug Applications (INDA)

➢ Criteria for application:
• A clinical study is required for an IND if it is intended to

support a:
✓ New indication
✓ Change in the approved route of administration or dosage level
✓ Change in the approved patient population (e.g. pediatric) or a population at

greater or increase of risk (elderly, HIV positive, immunocompromised)
✓ Significant change in the promotion of an approved drug

• Application submission:
✓ Most INDs are paper submissions. While only 12% of INDs are submitted

electronically, 28% of IND Amendments are submitted electronically a result
of maintaining a growing number of INDs submitted electronically to date

• Additional regulation:
✓ Experimental drugs under an IND must be labeled, “Caution: New Drug–

Limited by Federal (or United States) law to investigational use.”


USFDA (Drug Product Approval

Investigational New Drug Applications (INDA)
• Noteworthy examples:
The FDA closed its medical marijuana IND program (the

Compassionate Investigational New Drug program) in 1991, facing
an influx of AIDS patients seeking access to the drug. Seven

patients continue to receive cannabis from the government under
the program



USFDA (Drug Product Approval

Investigational New Drug Applications (INDA)
• Requirement for an IND:
a) A sponsor shall submit an IND to FDA if the sponsor intends to

conduct a clinical investigation with an investigational new drug
that is subject to 312.2(a)

b) A sponsor shall not begin a clinical investigation subject to
312.2(a) until the investigation is subject to an IND which is in
effect in accordance with 312.40

c) A sponsor shall submit a separate IND for any clinical
investigation involving an exception from informed consent under
50.24 of this chapter. Such a clinical investigation is not permitted
to proceed without the prior written authorization from FDA.
FDA shall provide a written determination 30 days after FDA
receives the IND or earlier



USFDA (Drug Product Approval

Investigational New Drug Applications (INDA)
• Phases of an investigation:
An IND may be submitted for one or more phases of an investigation.
The clinical investigation of a previously untested drug is generally
divided into three phases. Although in general the phases are
conducted sequentially, they may overlap. These phases of an
investigation are a follows:
✓ Phase I studies assess the safety of a drug or device
✓ Phase II studies test the efficacy of a drug or device
✓ Phase III studies involve randomized and blind testing in several

hundred to several thousand patients
✓ Phase IV studies continues testing the drug or treatment to collect

additional short-term safety information



USFDA (Drug Product Approval

Investigational New Drug Applications (INDA)
• Format and Content of IND
1. Cover Sheet (Form FDA 1571)
2. Table of Contents
3. Introductory Statement & General investigational plan
4. Investigator’s Brochure
5. Protocols
6. Chemistry, Manufacturing & Control Information
7. Previous Human Experience with the Investigational Drug
8. Additional Information




(HC) 62


CTD Triangle 63



Electronic Common Technical Document (eCTD) is a topic of increasing
interest in the pharmaceutical environment. Electronic Common Technical
Document (eCTD) is an interface for the pharmaceutical industry to agency
transfer of regulatory information. 64



• The Canadian health ministry (Health Canada)’s Therapeutic
Products Directorate is the federal authority that regulates the
market for pharmaceutical drugs and medical devices for
human use. At a federal level, pharmaceuticals are classified
into prescription and non-prescription, with provinces further
dividing medicines into general sales and Schedule I to III (I
being prescription, II being pharmacist-assistance drugs and III
being pharmacy self-selection). Unscheduled medicines can be
sold through all retail outlets as general sale items.

• Canada has a Bolar-style provision which allows generic firms
to begin producing a generic version of a drug before the
patent protecting that drug has expired, but they may not
launch the generic until after the patent has expired. 65



Regulatory Authority Health Canada

Website of regulatory https://www.canad

Fees for Drug Registration CAD 49,811 –

Normal time taken for 06-24 Months
Registration Requirement eCTD
[Dossier Format]
Whether plant inspection is Yes
mandatory 66



• Health Canada is the Federal department responsible for helping
Canadians maintain and improve their health. It ensures that
high-quality health services are accessible, and works to reduce
health risks.

• Health Canada is engaged in various activities and has
numerous responsibilities related to health. Health Canada
supports activities that:

✓ Preserve and modernize Canada’s health care system: Health
Canada manages health care costs by communicating health
risks and promoting healthy lifestyles.

✓ Enhance and protect the health of Canadians: Health Canada
provides surveillance, prevention, control and research of
disease outbreaks across Canada and around the world.

✓ Work in partnership with others: Health Canada partners closely
with other federal departments, agencies, provincial/territorial
goverwnwwm.DuelonMixt.sco mand health organizations. 67


How new drugs are authorized for sale in Canada

• New drugs are regulated under Part C, Division 8 of the Food and Drug
Regulations. Companies are granted market authorization by Health
Canada in several ways. Regardless of the method of authorization, a
manufacturer receives a Notice of Compliance (NOC) when it has met
Health Canada’s regulatory requirements for the safety, efficacy and
quality of a product. The following provides a brief overview of three of
the most common routes by which new drugs are authorized for sale in

✓ Innovator drugs (“brand name drugs”): Manufacturers receive
authorization to sell these products in Canada by submitting a New
Drug Submission (NDS) pursuant to section C.08.002 of the Food
and Drugs Regulations.

✓ Subsequent entry drugs (“generic drugs”): Health Canada often
authorizes manufacturers to market these drugs by requiring them to
submit an Abbreviated New Drug Submission (ANDS) pursuant to
section C.08.002.1 of the Food and Drug Regulations. These products
will receive a declaration of bioequivalence to a Canadian Reference 68
Product (pursuant to Section C.08.004 (4)), which will be stated on
the NOC.


How new drugs are authorized for sale in Canada

✓ The Health Canada Changes in Manufacturer’s Name and/or Product
Name Policy outlines another option for manufacturers wishing to
receive authorization through an NOC to market brand name and
generic drug products. This policy applies to eligible drug
submissions submitted to Health Canada for a change in the
manufacturer’s name and/or product name subsequent to a merger,
buy-out or other corporate restructuring or the establishment of a
licensing agreement.

• Products that receive an NOC according to one of these
mechanisms have met Health Canada’s regulatory requirements
for safety, efficacy and quality. 69


The type of submission being presented to Health

1. CTA (Clinical Trial Application)

2. CTA-A (Clinical Trial Application Amendment)

3. NDS (New Drug Submission)

4. SNDS (Supplemental New Drug Submission)

5. ANDS (Abbreviated New Drug Submission)

6. SANDS (Supplemental Abbreviated New Drug Submission)

7. NC (Notifiable Change)

8. DIN (Drug Identification Number submission)

9. PDC (Post-Authorization Division 1 Change) 70


The type of submission being presented to Health

CTA (Clinical Trial Application):
• The Canadian CTA dossier is simple and consists of the following documents

(exceptions are possible): administrative form, protocol, protocol summary
(Health Canada’s template), Informed Consent Form, Investigator’s Brochure
and quality dossier summary (Health Canada’s template per study phase).

• Health Canada reviews the CTA and notifies the sponsor within 30 calendar
days from the date that the application is considered complete. Questions may
be issued during the review, and the sponsor will have 2 calendar days to
provide the response (exceptions can apply). Note that CTAs are required for
phases I to III clinical trials. The authorization (No Objection Letter) is
mandatory prior to initiating the trial and importing the investigational
product(s) in Canada.

• If the HPFB provides authorization, the study can be underway with human
subjects that are informed and have given their consent to be administered the
drug for their participation. Note that a Canadian Ethic Committee must also
approve the study material (protocol, Investigator’s Brochure and Informed
Consent Form). Tests are conducted in a controlled environment where drug 71
administration procedures and results are closely tracked, monitored and


The type of submission being presented to Health

New Drug Submission (NDS):

✓ If results of all the preclinical studies and the clinical trials
show that a drug’s potential therapeutic benefit outweighs its
risks (side effects, toxicity, etc.), and the chemistry and
manufacturing dossier is complete, then the sponsor may
decide to file an NDS with the appropriate HPFB Directorate
in order to be granted authorization to sell the drug in Canada.
A sponsor can submit an NDS whether the clinical trials were
done in Canada or in other countries. The NDS must include
the results of the quality (Chemistry and manufacturing),
preclinical and clinical studies, whether done in Canada or in
other countries.

✓ The information requested as part of an NDS application must
be detailed enough that Health Canada can make an assessment
on the safety and effectiveness of the new drug. All
submissions must be provided to Health Canada in an 72

electronic Common Technical Document (eCTD) format.


The type of submission being presented to Health

Abbreviated New Drug Submission (ANDS):

The ANDS regulation was created to make the approval process
for generic drugs simpler and more cost effective. Under an
ANDS, the manufacturer of a drug has to prove that its product is
pharmaceutically equivalent and/and bioequivalent with the
innovator’s drug. For the purpose of an ANDS the sponsor may
need to perform a bioequivalence study or a physico-chemical
comparison (parenteral drugs or drugs for which it is not ethical to
conduct the study on healthy volunteer). 73


Steps in the review process for a drug

1. When a sponsor decides that it would like to market a drug in
Canada, it files a “New Drug Submission” with HPFB. This
contains information and data about the drug’s safety,
effectiveness and quality. It includes the results of the
preclinical and clinical studies, whether done in Canada or
elsewhere, details regarding the production of the drug,
packaging and labelling details, and information regarding
therapeutic claims and side effects.

2. HPFB performs a thorough review of the submitted
information, sometimes using external consultants and advisory

3. HPFB evaluates the safety, efficacy and quality data to assess
the potential benefits and risks of the drug. 74


Steps in the review process for a drug

4. HPFB reviews the information that the sponsor proposes to
provide to health care practitioners and consumers about the
drug (e.g. the label, product brochure).

5. If, at the completion of the review, the conclusion is that the
benefits outweigh the risks and that the risks can be mitigated, t

he drug is issued a Notice of Compliance (NOC) confirming the
dossier’s compliance with the Food and Drugs Act and its
Regulations, as well as a Drug Identification Number (DIN)
which permits the sponsor to market the drug in Canada and
indicates the drug’s official approval in Canada.

6. In addition, Health Canada laboratories may test certain
biological products before and after authorization to sell in
Canada has been issued. This is done through its Lot Release 75

Process, in order to monitor safety, efficacy and quality.


Important Points for HC Registration

What happens if a Drug receives a Notice of Non-Compliance?
Upon the completion of the review process, if the HPFB finds that
there is insufficient evidence to support the safety, efficacy or
quality claims of the drug, HPFB will not grant a marketing
authorization for that drug. At this point, the sponsor typically has
3 options: to supply additional information to the HPFB, to re-
submit a submission at a later date with additional supporting data
(without prejudice), or to ask that HPFB to reconsider its decision.

Marketing authorization:
A legal document issued by Health Canada authorizing the sale of
a drug or a device based on the health and safety requirements of
the Food and Drugs Act and its Regulations. The marketing
authorization may be in the form of a Drug Identification Number
(DIN), a device licence for classes II, III and IV medical devices,
or a nawtwuwr.Daullo Mhixe.coamlth product licence (NPN or DIN-HM). 76


Important Points for HC Registration

Drug Identification Number (DIN):

A computer-generated eight digit number assigned by Health
Canada to a drug product prior to being marketed in Canada. It
uniquely identifies all drug products sold in a dosage form in
Canada and is located on the label of prescription and over-the
counter drug products that have been evaluated and authorized for
sale in Canada. A DIN uniquely identifies the following product
characteristics: manufacturer; product name; active ingredient(s);
strength(s) of active ingredient(s); pharmaceutical form; and route
of administration. 77


Accelerated Review Process:

For health conditions that are serious, life-threatening or for a
severely debilitating disease (such as Alzheimer’s disease,
cancer, AIDS, or Parkinson’s disease), the HPFB can provide
faster authorization of a drug as follows:

1. Priority Review (PR): Applies to drugs that shows substantial
evidence of clinical effectiveness at the end of the clinical trial

2. Notice of Compliance with conditions (NOC/c): Applies to
drugs with promising evidence of clinical effectiveness
throughout the clinical trial phases. Approval would be
granted to a manufacturer to market and sell that drug in
Canada with the condition that the manufacturer execute
additional studies to confirm the drug’s benefit and safety. 78


For Quality

GUIDANCE DOCUMENT Quality (Chemistry and Manufacturing) Guidance: New Drug
Submissions (NDSs) and Abbreviated New Drug Submissions (ANDSs) can be identified at
abbreviated-new-drug-submissions.pdf 79