Unit 2 Notes DRA
Unit 2 Notes DRA
Shaheen Sultana
Unit: 2
2. A table of contents
All sections under the table of contents should be paginated.
5. Investigator’s brochure
A copy of the investigator’s brochure, containing the following information:
a) A brief description of the drug substance and the formulation, including the structural formula,
if known.
b) A summary of the pharmacological and toxicological effects of the drug in animals and, to the
extent known, in humans.
c) A summary of the pharmacokinetics and biological disposition of the drug in animals and, if
known, in humans.
d) A summary of information relating to safety and effectiveness in humans obtained from prior
clinical studies.
e) A description of possible risks and side effects to be anticipated on the basis of prior
experience with the drug under investigation or with related drugs, and of precautions or special
monitoring to be done as part of the investigational use of the drug.
6. Protocols
i. A statement of the objectives and purpose of the study.
ii. The name and address and a statement of the qualifications (curriculum vitae or other
statement of qualifications) of each investigator, and the name of each sub-investigator, and the
name and address of each reviewing Institutional Review Board (IRB).
iii. The criteria for patient selection and for exclusion of patients and an estimate of the number
of patients to be studied.
iv. A description of the design of the study, including the kind of control group to be used, if any,
and a description of methods to be used to minimize bias on the part of subjects, investigators,
and analysts.
v. The method for determining the dose(s) to be administered, the planned maximum dosage, and
the duration of individual patient exposure to the drug.
vi. A description of the observations and measurements to be made to fulfill the objectives of the
study.
vii. A description of clinical procedures, laboratory tests, or other measures to be taken to
monitor the effects of the drug in human subjects and to minimize risk.
After submission of IND to the FDA, it is assigned to the FDA for its review and evaluation. The
FDA has 30days from the receipt of IND to decide whether the proposed clinical trial should
proceed or not. If the sponsor is not contacted within 30days, the trial may proceed. Meanwhile
reviewers at FDA may put a “Clinical Hold” on the proposed Clinical trials at any time. This
prevents human testing of drug. It may be due to the following reasons
i. If there is any unreasoned threat to the safety of the trial subjects i.e. if the subjects face any
illness or injury due to treatment.
ii. Insufficient data to assess patient risks.
iii. If the investigators involved in the study do not meet the necessary requirements with respect
their qualification.
iv. Misleading or incomplete investigators brochure.
In case if all the requirements for FDA approval are satisfied an IND is granted. Once an IND is
in effect, all the proposed changes to the original IND thereafter, must be submitted as
amendments for approval.
IND categories
Commercial: These are applications that are submitted primarily by the companies to obtain
marketing approval for a new product.
Research (non-commercial): These INDs are filed for noncommercial research. These are three
types:
a. Investigator IND: It 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.
b. Emergency Use IND: It 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. 312.20. 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.
c. Treatment IND: It is submitted for experimental drugs showing promise in clinical
testing for serious or immediately life-threatening conditions while the final clinical work
is conducted and the FDA review takes place.
Preclinical data to provide information that the product is reasonably safe for initial testing in
humans. Also included are any previous experience with the drug in humans (often foreign use).
2. Manufacturing Information
Information pertaining to the composition, manufacturer, stability, and controls used for
manufacturing the drug substance and the drug product. This information is assessed to ensure
that the company can adequately produce and supply consistent batches of the drug.
3. Clinical Protocols and Investigator Information
Detailed protocols for proposed clinical studies to assess whether the initial-phase trials will
expose subjects to unnecessary risks.
4. Qualifications of clinical investigators
Professionals (generally physicians) who oversee the administration of the experimental
compound to assess whether they are qualified to fulfill their clinical trial duties. Finally,
commitments to obtain informed consent from the research subjects, to obtain review of the
study by an institutional review board (IRB), and to adhere to the investigational new drug
regulations.
2. Responsibilities of Investigators
a. Conducting the trial in accordance with the signed investigator statement, protocol, and
applicable regulations.
b. Protecting the rights, safety, and welfare of trial participants.
c. Obtaining informed consent from all trial participants.
d. Maintaining proper records.
e. Furnishing all required progress reports, safety reports, financial disclosure reports, and a
final report.
f. Complying with Institutional Review Board review and Ensuring the proper handling of
controlled substances.
g. Maintaining records of the Investigational Product (from delivery at the site to dispensing
to the participant as well as use by the participant, return by the participant, and
reconciling all product prior to destruction).
h. Ensuring that the Investigational Product is used in accordance with the approved
protocol. Explaining the correct use of the Investigational Product to each participant and
checking at intervals that each participant is following instructions properly.
The goals of the NDA are to provide enough information to permit FDA reviewer to reach
the following key decisions:
Whether the drug is safe and effective in its proposed use(s), and whether the benefits of the
drug outweigh the risks.
Whether the drug’s proposed labeling (package insert) is appropriate, and what it should
contain.
Whether the methods used in manufacturing the drug and the controls used to maintain the
drug’s quality are adequate to preserve the drug’s identity, strength, quality and purity.
NDA 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
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. At the conclusion of FDA review of an NDA, there are 3
possible actions that can send to sponsor:
a. Not approvable- in this letter list of deficiencies and explain the reason.
b. Approvable - it means that the drug can be approved but minor deficiencies that can be
corrected like-labeling changes and possible request commitment to do post-approval
studies.
c. Approval- it states that the drug isapproved. If the action taken is either an approvable or
a not approvable, then FDA provides applicant with an opportunity to meet with agency
and discuss the deficiencies.
NDA Requirements
1. Application format
The NDA regulations require the submission of Archival copy, Review copy, field copy.
i. Archival copy :
This is a complete copy of an application submission and is intended to serve as a reference
source for FDA reviewers. This contains information which not contained in the review copy.
ii. Review copy:
It is divided into five (or six) sections containing technical and scientific information required by
FDA reviewers.
iii. Field copy: This is required by FDA inspectors during pre-approval facilities inspection.
Section I: Index
Section II: labeling: it include draft labeling intended to use on container
Section III (Application Summary): It is an abbreviated version entire application which give
clear idea about drug and its application to the reviewer.
Section IX: Safety update reports: Safety update reports are submitted 120 days after the initial
application, following the receipt of an approval letter. New data related to safety is updated in
this report.
Section XI: Case reports for taulations: It include complete tabulation for each patient from
phase I to Phase III study.
Section XII: Case reports forms: It is mandatory to submit the case report form for each patient
who either hve died during the study or dropped from the study due to adverse event regardless
of whether patient was receiving drug or placebo.
If more than one ANDA has been filed on a particular drug, first filed ANDA may be given 180
days exclusivity following approval against later filed ANDAs. Therefore first generic company
will acquire a larger market share. Therefore market benefit is provided to the first ANDA
applicant in terms of 180 days market exclusivity.
FILING OF ANDA:
• In order to file ANDA all required items should be in proper order (organization). Detail
information is available under Regulation 21 CFR 314.50, 21 CFR 314.94 and 21 CFR
314.440
• Office of Generic Drug (OGD) strongly encourages submission of the bioequivalence,
chemistry and labeling portions of an application in electronic format.
• From 1977-1992, 105 Non approval letter issued by FDA due to chemistry &
manufacturing deficiencies.
• According to this guidelines information that applicant provide should prove that the
proposed product is the same as listed product with respect to its indications for use,
active ingredients(s), route of administration, dosage form, strength, bioavailability, and
labeling.
The manufacturer should assess the effect of the change on the identity, strength (eg,
assay, content uniformity), quality (eg, physical, chemical, and biological properties),
purity (eg, impurities and degradation products), or potency (eg, biological activity,
bioavailability, bioequivalence) of a product as they may relate to the safety or
effectiveness of the product.
The FDA has published several SUPAC guidances, including Changes to an Approved
NDA or ANDA for the pharmaceutical industry.
These guidances address the following issues:
1. Components and composition
2. Manufacturing sites
3. Manufacturing process
4. Specifications
5. Container closure system, and
6. Labeling, as well as
7. Miscellaneous changes and
8. Multiple related changes.
These documents describe
(1) the level of change,
(2) recommended CMC tests for each level of change,
(3) in vitro dissolution tests and/or bioequivalence tests for each level of change, and
(4) documentation that should support the change.
g. Container Closure System Changes: Reporting category for the packaging change
needs to be considered
To assess the effect of the change on the identity, strength (e.g., assay, content uniformity),
Quality (e.g., physical, chemical, and biological properties), Purity (e.g., impurities and
degradation products), or Potency (e.g., biological activity, bio-availability, bioequivalence) of a
drug product as these factors may relate to the safety or effectiveness of the drug product, CDER
has published guidance, including the SUPAC (scale-up and post approval changes) guidance,
that provide recommendations on reporting categories. Reporting categories:
A. Major change
Major change is a change that has a substantial potential to have an adverse effect on the identity,
strength, quality, purity, or potency of a drug product as these factors may relate to the safety or
effectiveness of the drug product. Examples:
1. Changes that may affect the controlled (or modified) release,
2. Changes that may affect drug product sterility assurance (eg change in sterilization method)
3. Manufacturing process or technology (eg. Dry to wet granulation)
A major change requires the submission of a supplement and approval by FDA prior to
distribution of the drug product made using the change.
B. Moderate change
Moderate change is a change that has a moderate potential to have an adverse effect on the
identity, strength, quality, purity, or potency of the drug product as these factors may relate to the
safety or effectiveness of the drug product. There are two types of moderate change:
Supplement - Changes Being Affected in 30 Days: requires the submission of a supplement to
FDA at least 30 days before the distribution of the drug product made using the change. These
changes:
a. A change in the container closure system that does not affect the quality of the drug
product
b. An increase or decrease in production scale that involves different equipment
c. Replacement of equipment with that of a different design that does not affect the process
methodology
The applicant must not distribute the drug product made using the change if within 30 days, FDA
informs the applicant that either:
(i) The change requires approval prior to distribution of the drug product
(ii) Any of the required is missing; the applicant must not distribute the drug product made using
the change until the supplement has been amended to provide the missing information
Supplement - Changes Being Affected: FDA may identify certain moderate changes for which
distribution can occur when FDA receives the supplement. Example of such changes involved:
a. Addition to a specification or changes in the methods or controls to provide increased
assurance that the drug substance or drug product will have the characteristics of identity,
strength, quality, purity, or potency that it purports or is represented to possess;
b. A change in the size and/or shape of a container for a nonsterile drug product, except for
solid dosage forms,
c. Changes in the labeling to reflect newly acquired information
d. To add or strengthen a contraindication, warning, precaution, or adverse reaction
e. To add or strengthen an instruction about dosage and administration that is intended to
increase the safe use of the drug product;
f. To delete false, misleading, or unsupported indications for use or claims for effectiveness
C. Minor change
Minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency
of the drug product as these factors may relate to the safety or effectiveness of the drug product.
Examples of changes:
a. The deletion or reduction of an ingredient intended to affect only the color of the drug product
b. Editorial changes: in previously submitted information (e.g., correction of spelling or
typographical errors, reformatting of batch records).
c. Replacement of equipment with that of the same design and operating principles
The applicant (for minor changes) is required to submit in the annual report:
(i) A statement by the holder of the approved NDA that the effects of the change have been
assessed;
(ii) A full description of the manufacturing and controls changes, including the manufacturing
site(s) or area(s) involved;
(iii) The date each change was implemented;
(iv) Data from studies and tests performed to assess the effects of the change
MAIN BODIES:-
Central Drug Standard Control Organization (CDSCO)
Ministry of Health & Family Welfare (MHFW)
Indian Council of Medical Research (ICMR)
Indian Pharmaceutical Association (IPA)
Drug Technical Advisory Board (DTAB)
Central Drug Testing Laboratory (CDTL)
Indian Pharmacopoeia Commission (IPC)
1. CDSCO In India, the Central Drugs Standard Control Organization (‘CDSCO’) is the main
regulatory body currently regulating import, sale and manufacture of medical devices which
have been notified as drugs by virtue of Section 3(b) (IV) of the D&C Act. The CDSCO lays
down standards of drugs, cosmetics, diagnostics and devices and issues licenses to drug
manufacturers and importers. It also lays down regulatory measures, amendments to Acts and
Rules and regulates market authorization of new drugs, clinical research in India and standards
of imported drugs etc. Headquartered in New Delhi, the CDSCO is India's main regulatory body
for pharmaceuticals and medical devices and Within the CDSCO, the Drug Controller General of
India (DCGI) is responsible for the regulation of pharmaceuticals and medical devices. The
DCGI is advised by the Drug Technical Advisory Board (DTAB) and the Drug Consultative
Committee (DCC). Licensing and classification of medical devices are handled by the Central
Licensing Approval Authority (CLAA). The CLAA is also responsible for setting and enforcing
safety standards, appointing notified bodies to oversee conformity assessment, conducting
postmarket surveillance and issuing warnings and recalls for adverse events.
The CDSCO establishes safety, efficacy, and quality standards for pharmaceuticals and medical
devices. It publishes and updates the Indian Pharmacopeia, a list of regulated pharmaceuticals
and devices. For all drug and device applications, the CDSCO appoints notified bodies to
perform conformity assessment procedures, including testing, in order to ensure compliance with
their standards. The CDSCO is also divided into several zonal offices which do pre-licensing and
post-licensing inspections, post-market surveillance, and recalls when necessary.
In addition to its regulatory functions, the CDSCO offers technical guidance, trains regulatory
officials and analysts, and monitors adverse events. The CDSCO works with the World Health
Organization to promote Good Manufacturing Practice (GMP) and international regulatory
harmony.
2. National Institute of Health and Family Welfare (NIHFW)-NIHFW is an Apex Technical
Institute, funded by Ministry of Health and Family Welfare, for promotion of health and family
welfare programmers in the country through education, training, research, evaluation,
consultancy and specialized services. The NIHFW was established on March 9, 1977 by a
merger of the National Institute of Health Administration and Education (NIHAE) with the
National Institute of Family Planning (NIFP).
List of Governing Body Members of NIHFW
18 members
1 Chairman (ex-officio)
1 Vice Chairman (ex-officio)
9 Member (ex-officio)
6 Member
1 Member Secretary (ex-officio)
ACTIVITIES AND RESPONSIBILITIES:
Measuring weight of children to assess the nutritional status.
Assessment of diseases like level of anaemia.
Testing of food material like cooking salt for level iodine.
To release fund on the advice of the Ministry.
It is responsible for all governmental programs relating to family planning in India.
18 Members
10 ex-officio Members
5 Nominated Members
5 Elected Members
4. CENTRAL DRUG TESTING LABORATORY (CDTL): The central drug laboratory, Kolkata
is national statutory laboratory of the government of India for quality control of drug and
cosmetic and established under the D&C act, 1940. Oldest quality control laboratory of the drug
control authorities in India. Function under the director general of Health Services in the
Ministry of Health and Family Welfare.
The Food and Drug Modernization Act states that the FDA has 4 roles:
*To promote health by reviewing research and approving new products.
*To ensure foods and drugs are safe and properly labelled.
*To work with other nations to “reduce the burden of regulation”.
*To cooperate with scientific experts and consumers to effectively carry out these obligations
The FDA is led by the Commissioner of Food and Drugs, who is appointed by the President
and confirmed by the Senate.
Type of Applications:
Investigational New Drug Application (IND): Application submitted to FDA to seek
permission to test a new drug or a biologic in human. New Drug Application (NDA):
When the sponsor of the new drug believes that enough Evidence on the drugs safety and
effectiveness has been obtained to meet FDA’s requirements for marketing approval, the
sponsor submits to FDA a New Drug Application.
Abbreviated New Drug Application (ANDA): An Abbreviated New Drug Application
(ANDA) contains data that, when submitted to FDA's Centre for Drug Evaluation and
Research, Office of Generic Drugs, provides for the review and ultimate approval of a
generic drug product. Generic drug applications are called "abbreviated” because they are
generally, not required to include preclinical (animal) and clinical (human) data to
establish safety and effectiveness
Biologic License Application (BLA): A biologics license application is a submission
that contains specific information on the manufacturing processes, chemistry
pharmacology, clinical pharmacology and the medical effects of the biologic product.
ACTIVITIES OF EMA
THE ROLE OF EMA
• EMA is responsible for the scientific evaluation, primarily of innovative and high-
technology medicines developed by pharmaceutical companies for use in the EU.
• EMA was established in 1995 to ensure the best use of scientific resources across Europe
for the evaluation, supervision and pharmacovigilance of medicines.
• Experts participate in the work of EMA as members of its scientific committees, working
parties, scientific advisory groups or as members of the national assessment teams that
evaluate medicines. The experts are chosen on the basis of their scientific expertise and
many of them are made available to EMA by the NCAs in Member States.
• Increasingly, patients and healthcare professionals are involved in the work of the
Agency including in the evaluation of medicines.
Functions of EMA
1. GUIDELINES AND SCIENTIFIC ADVICE
EMA prepares scientific guidelines in cooperation with experts from its scientific
committees and working groups.
These guidelines reflect the latest thinking on developments in biomedical science.
They are available to guide the development programmes of all medicine developers who
wish to submit an application for a marketing authorisation in the EU, and to ensure that
medicines are developed consistently and to the highest quality.
EMA also gives product-specific scientific advice to companies for the development of
medicines.
4. CLINICAL TRIALS
• The authorisation and oversight of a clinical trial is the responsibility of the Member
State in which the trial is taking place.
• The European Clinical Trials Database (EudraCT) tracks which clinical trials have been
authorised in the EU. It is used by NCAs and clinical-trial sponsors to enter information
protocols and results of clinical trials.
• A subset of this information is made publicly available by EMA via the EU clinical trials
register.
FUNCTION OF MHLW:
a. Health Policy: The MHLW is responsible for formulating and implementing policies related
to healthcare, medical services, and public health in Japan. This includes regulating
pharmaceuticals, medical devices, and food safety, as well as promoting health promotion and
disease prevention.
b. Labour Policy: The MHLW is responsible for overseeing policies related to labour and
employment in Japan. This includes regulating working conditions, minimum wage, and social
security programs.
C. Social Welfare Policy: The MHLW is responsible for formulating and implementing policies
related to social welfare, including support for the elderly, people with disabilities, and children.
d. Disaster Management: The MHLW plays a crucial role in disaster management in Japan,
including responding to natural disasters and pandemics, and providing emergency medical care
and assistance.
Organization:
Three main parts of the MHLW are:
1) Health Policy Bureau
2) Pharmaceutical and Food Safety Bureau (PFSB)
3) Pharmaceutical and Medical Device Agency (PMDA)
Health Policy Bureau: The Health policy bureau handles promotion of R&D, production,
distribution policies and drug pricing and other functions related to the pharmaceutical firms.
PFSB: The Pharmaceutical and Food Safety Bureau (PFSB) strives to protect people's life and
health through comprehensive efforts, covering clinical experiments, technical examinations for
registration and after-sales follow-ups, to secure the safety, efficacy, etc. of pharmaceuticals.
PMDA: The Pharmaceuticals and Medical Devices Agency (PMDA) was established and came
into service on April 1, 2004, under the Act on the Pharmaceuticals and Medical Devices
Agency, which consolidated the services of the Pharmaceuticals and Medical Devices Evaluation
Center of the National Institute of Health Sciences (PMDEC), the Organization for
Pharmaceutical Safety and Research (OPSR), and part of the Japan Association for the
Advancement of Medical Equipment (JAAME).
The three (03) main types of drug applications that you can submit to the PMDA are as follows:
a. Investigational New Drug (IND): You need to submit this application before conducting
clinical trials in Japan.
b. New Drug Application (NDA): You need to submit this application to get approval for
marketing a new drug in Japan.
c. Abbreviated New Drug Application (ANDA): You must submit this application to get
approval for marketing a generic drug in Japan.
Australia
Therapeutics Goods Administration is the regulatory body for therapeutic goods in Australia.
TGA is responsible for conducting assessment and monitoring activities to ensure that
therapeutic goods available in Australia are of an acceptable standard.
The objectives of Therapeutic Goods Act 1989, which came into effect on 15 Feb, 1991 is to
1) provide a national framework for the regulation of therapeutic goods in Australia to
ensure quality, safety and efficacy of the medicines and ensure quality, safety and
performance of medical devices
2) Essentially therapeutic goods must be entered on the Australian Register of Therapeutic
Goods (ARTG) before they can be supplied in Australia.
Role of TGA
The TGA carries out an overall control through five main processes:
1. Pre-market evaluation and approval of registered products intended for supply in
Australia;
2. Development, maintenance and monitoring of the systems for listing of medicines;
3. Licensing of manufacturers in accordance with international standards of GMPs
4. Post-market monitoring, through sampling, adverseevent reporting, surveillance
activities, and response to public inquiries;
5. The assessment of medicines for export.
Application category:
a. Generic product
b. New medicine requiring proof of efficacy of the product.
c. A variation to an existing approved assessed listed medicine, where the medicine
contains one of the following:
1. different active ingredient(s)
2. different strength (i.e. quantity of active ingredient(s))
3. different indication(s) (other than removing an indication)
4. different dosage form; or
5. different excipients.
Elements to Regulate
• Licensing and Audit of Manufactures Act requires each Australian manufacturer of
medicinal products for human use to hold a manufacturing license. License holders are
required to comply with the manufacturing principles of the Act, including compliance
with GMP.
• Pre-Market Assessment: This includes study of toxicity and dosage form of medicines.
The product risk is determine by side effects, inappropriate self medication, adverse
effect for prolonged use
TGA regulates therapeutic goods before the products reach the market (pre-market) and
afterwards, when they are in general use (post-market).
At the pre-market stage, TGA acquires the information necessary for a decision about whether or
not to register, list or include therapeutic goods on the ARTG. They do this through accepting
certification, actively evaluating information supplied by sponsors or manufacturers, or by direct
inspection.
Medicines containing low-risk ingredients, including most complementary medicines, receive a
lesser degree of checking than higher risk products, and are listed (AUST L) on the ARTG. The
listing process is based on the certification of claims by sponsors. For products containing low-
risk ingredients, regulation centers on the safety of the product and the consistency of the
manufacturing process; less emphasis is placed on assessing the evidence for the claims being
made.
Products carrying a higher risk, which include all prescription medicines, receive a higher degree
of scrutiny and, if found to comply, are registered (AUST R) on the ARTG. Registration
involves the evaluation of data related to safety, manufacturing and efficacy. Thus, when taking
a therapeutic good that is registered on the ARTG, Australians can be confident that the product
does not only meet safety and quality criteria, but that it has been demonstrated to have the
claimed effect.
Canada
Canada is the second largest pharmaceutical market in North America. The Health Canada is the
federal Regulatory body which is responsible to ensure the safe and effective use of drugs and
health products in Canada. Strict Regulatory regime of different bodies for Food and Veterinary,
Pharma and Biological drugs, makes it challenging for foreign manufacturers to enter the region.
Those Regulatory bodies include:
• Health Canada’s Health Products and Food Branch (HPFB) – for Food, Health and
Veterinary
• Therapeutic Product Directorate (TPD) – for Pharmaceuticals and Medical Devices
• Biologics and Genetic Therapies Directorate (BGTD) – for Biological and
Radiopharmaceutical drugs
• Health Canada's Health product and food branch (HPFB) is the national authority that
regulated, evaluates and monitor the safety, efficacy and quality of therapeutic and
diagnostic products available to Canadians
Types of Applications
1. SANDS (Supplement to Abbreviated New Drug Submission)
2. SNDS (Supplement to a New Drug Submission) are types of submission towards Health
Canada which stand as important resources to ANDS (Abbreviated New Drug
Submission) and NDS (New Drug Submission).