REGULATORY AFFAIRS.pptx

INDUSTRIAL PHARMACY-II
Unit - III: Regulatory Affairs
Asst. Prof. Chaitali C. Dongaonkar,
M.Pharm (QA), PGDPL,
Department of Pharmaceutics,
PES Modern College of Pharmacy(For Ladies), Moshi.

Learning Objectives
To understand Introduction of Regulatory affairs, Historical Background
and Current scenario.
To be aware about Different regulatory authorities with their Roles and
Responsibilities.
To study Various Regulatory Requirements for Drug Approval.
To know Data required for FDA submission.

Introduction
Dynamic and challenging profession
Developed by government
Acts as interface between Pharmaceutical companies and regulatory
agencies
To ensure the public health controlling safety and efficacy
Pharmaceuticals, Veterinary medicines, Medical devices, Pesticides,
Agrochemicals, Cosmetics etc

Importance of Laws and Regulation

Elixir Sulfanilamide
Improperly prepared sulfonamide antibiotic
Mass Poisoning in the United States in 1937
Caused death of 100 people

S.E.Massengil Company, Pharmaceutical manufacturer
Oral preparation - Sulfonamide + Diethylene Glycol
DEG = Poisonous to humans and mammals
Harold Watkin - chief Pharmacist and Chemist not aware

Watkins - Raspberry flavor + Powdered drug + DEG
Animal testing not required by law at that time
So, Messengill performed none
Because No regulations required premarket testing of drugs

Company started selling and distributing medication in September
1937 and in October
American Medical Association received report of several deaths
caused by the medication

Thalidomide Tragedy
Thalidomide - Cancer Treatment, Leprosy
But in 1957, West Germany was available for OTC
Initially thought to be safe in pregnancy but concerns related birth
defects arise in 1961
So drug removed from the market

Thalidomide Tragedy
10000 embryos affected during pregnancy out of which about 40%
died around the time of birth
Survived had limb(Phocomelia), eye, urinary tract and heart problems

Historical Aspects
Multiple tragedies increased legislation for drug products Quality,
Safety and efficacy
This leads to the strictest norms for Marketing Authorisation and GMPs
The drug industries in India was at a very primitive stage till the 20th
century as most of drugs imported from foreign countries

Regulatory Authorities
Rules and regulations based upon Global, Regional and National trade
Necessity of drugs based on population
Development and Market Authorization applications of Drug based upon Global/Regional Harmonized
guidelines
Representative in each country in the world
ICH(International Council for Harmonization) = USA, EU, Japan
Requirements for manufacturer = MAA (Market Authorization Application)

Examples of Regulatory Authorities

FDA Recalls
(Ref:https://www.fda.gov/drugs/drug-safety-and-availability/drug-recalls)

TGA Overview
(Ref: https://www.tga.gov.au/hubs/advertising-therapeutic-goods)

CDSCO Alerts
(Ref : https://www.cdsco.gov.in/opencms/opencms/system/modules/CDSCO.WEB/elements/download_file_division.jsp?num_id=NzU3Ng==)

Zolgensma Injection
Novartis = Zolgensma Gene Therapy
Treat Spinal Muscular Atrophy ( SMA)
2.1 million US Dollar = 15.24 Cr Indian Rupees
Import from US = If prescribed

Health Authority (HA)
Prepare drug regulatory guidelines and guidance documents
Compliant and conformity to existing laws as well as regulations
Coordinate with Global and regional regulatory body
Process for Marketing Authorization Approval

Pharmaceutical Industry
Manufacturer develops drugs
According to regulatory necessity of Quality, Safety, Efficacy
Applies for Marketing Authorization

Role of Regulatory Affairs
Department
Interface between the pharmaceutical industry and Drug Regulatory authorities
Registration of the drug products in respective countries prior to their marketing
Contact between the Ministry of Health/Government departments and the
company
Pharmaceutical business regulated = designing appropriate laws (rules) and
enforcing the same to attain
Highest standard of quality into the Global Trade

Department
1.To bring a new drug into the market, it takes many years
2.Process should be managed effectively from the starting of the
process to the end
3.Drugs can meet the regulatory requirements
4. Allow evaluation of quality, efficacy and safety to meet the shortest possible timeline.

Drug Regulatory Affairs
DRA
Domestic
Regulatory Affair
- DRA
Country of origin
International
Drug Regulatory
Affair - IRA
Other than
Country of origin

Global Market
Regulated Market
Semi-Regulated Market

Regulated Market
Well defined procedures for marketing & distribution of pharmaceuticals.
Human and Veterinary use.
US, EU (UK, Germany, France, Ireland, Sweden etc.), Japan, Canada, Australia,
New Zealand, South Africa.

Semi – Regulated Market (ROW)
NOT having any specific Authorities for supply of Medicines
Small countries, New countries
Depend upon other countries

ROW Countries
Asia (Sri Lanka, India, Bangladesh ASEAN: 10 Countries group -Philippines, Vietnam Singapore, Malaysia,
Thailand, Indonesia, Laos, Cambodia, Brunei Darussalam, Myanmar)
African countries (Algeria, Zambia, Ethiopia, Ghana, Kenya, Malawi, Mozambique, Namibia, Nigeria,
Sierra Leone, Tanzania, Zimbabwe etc
Middle East countries (Gulf Co-operation Council countries i.e. Bahrain, Kuwait, Oman, Qatar, Saudi
Arabia, UAE)
Latin America (Mexico, Brazil, Panama, Peru, Guatemala, Argentina, Chile, Dominican Republic)
CIS (common wealth of independent states): Russia, Ukraine, OFSUs (Armenia, Azerbaijan, Belarus,
Georgia, Kazakhstan, Kirghizstan, Moldova, Tajikistan, Turkmenistan, Uzbekistan etc.)

Department
crucial role in each phase of drug development and post marketing
activities
accumulate all the date pertains to drug discovery and development
stages and uses the same for the purpose of registration and
marketing of drug.
Follow arrangement of strict and guidelines throughout the drug
development process = to ensure the drug and efficacy of drugs in the
humans

Department
takes part in the drug development, marketing concepts
requirement to approve the packaging and advertising of drug/product
before it is used commercially

Responsibility of Regulatory Affairs
Professionals
to ensure that their companies are complying with all of the system policy and laws
pertaining to their business
Working with federal, state, and local regulatory agencies and staff
on specific issues distressing their commerce i.e. working with Government agencies
advice their companies on the various aspects of regulatory affairs

Responsibility of Regulatory Affairs
Professionals
to keep an eye on the ever-changing legislation in all the countries = company have an interest to register
their products
advice legally and technically at all stage
help companies to save a lot of resources, time and money in drug development and its marketing
the preparation and presentation of registration documents to regulatory agencies
follow up all the process and discussion
obtain and maintain marketing authorization (MA) for the concerned products.

Regulatory requirements for Drug
Approval
different nations = different requirements for the regulatory approval of
novel or new drug
difficult for every country to have the same regulatory approach for the
Marketing Authorization Application (MAA)
necessary to have knowledge = regulatory requirements for MAA of each
country

Different phases of clinical trials

Example:
an application submitted to the respective regulatory authority
permission to market a new drug
To obtain this permission a sponsor submits:
1. Preclinical and clinical test data (analyzing the drug information)
2. Description of manufacturing procedures.

Agency’s Action on NDA
a technical screening
To ensure that the sufficient data
The required information Submitted in each area
Justifying the “filling” application form

Possible action after the review of NDA
Approvable
Drug can be approved
Minor Deficiencies can be
corrected by applicant
Like Labelling Changes
Commitment to do Post
approval changes
Approval
Drug
approved
NOT
Approvable
List of deficiencies
Reasons with Explanation

Conclusion
There are three possible action send to sponsor after reviewing of NDA
If action taken is either NOT Approvable or Approvable
Regulatory body = Opportunity to applicant for meeting with agency
For discussing deficiencies

Drug development teams
The process of bringing a new pharmaceutical drug to the market
A lead compound = identified through the process of drug discovery
It includes
1.pre-clinical research on microorganisms and animals, filing for regulatory status
2. Investigational new drug to initiate clinical trials on humans,
3.Obtaining regulatory approval with a new drug application to market the drug.

Drug development teams
Process of drug discovery and development = very long (10-12 years)
Includes the close interaction of large number of scientific disciplines.
Biotechnology and pharmaceutical companies employ teams:
1.To mentor the process of various stages of drug development
2.Making the drug candidate into therapeutic products.

The Responsibilities of Project
Teams

NON-CLINICAL DRUG DEVELOPMENT
Pre-clinical trial: A laboratory test for a novel drug or a new medical
device
Animal subjects, to see if the hoped-for treatment really works and if it
is safe to test on humans.

The primary aims of the non-clinical (or pre-clinical) development
phase is to analyze, determine candidate = the greatest probability of
success
Assess its safety, and raise firm scientific foundations
Before transition to the clinical development phase

Process of non-clinical development of medicine:
1. very complex,
2. time consuming and
3. regulatory driven.
• The selected candidate compound should also meet non-medical
objectives, also
• include defining the IPR
• making enough medicinal products available for clinical trials.

Once identification of candidate compound
completed…..
Assessment of Efficacy
Profiling
Toxicology/safety
continue throughout the life-cycle of the product

Various Pharmacological approaches
to Drug Discovery

study of effects of chemical substances on living systems
all the aspects of drug discovery
details of interaction between drug molecule
consequences of placing the drug in the market.

Component of pharmacological
evaluation
Components of
Pharmacological
Evaluation
Selectivity Testing
Screening for
Selectivity Binding Assay
Pharmacological
Profiling
In Vitro
Models
In Vivo
Models
Safety
Pharmacology

Selectivity Testing
screening for selectivity and Binding assay
To determine the potency of drug
the selectivity of a compound for a chosen
molecular target needs to be assessed.

Pharmacological Profiling
determination of pharmacodynamics effect of new compound
in-vitro models = cell lines or isolated tissues
in-vivo models = normal animals, animal models of disease

Safety Pharmacology
the scientific evaluation and study of potentially life threatening
pharmacological effects of a potential drug
unrelated to the desired therapeutic effect
therefore may present a hazard

conducted at doses not too much in excess of the intended clinical dose
to identify unanticipated effects of new drugs on major organ function (i.e.
secondary pharmacological effects)
detecting possible undesirable or dangerous effects of the drug in
therapeutic doses.
acute effects produced by single-dose administration = effects on chronic
exposure as in toxicological studies

Toxicological approaches to Drug Discovery
Toxicology
Acute
Toxicity
- at least two species
- e.g. mice and Rats
- same route = intended for humans
- two more routes = ensure systemic absorption(nature of the drug)
- Mortality: Parenteral administration = 72 hours
Oral administration = 7 Days
- The symptoms, signs and mode of death should be reported
- Appropriate macroscopic and microscopic findings where necessary
Long Term
Toxicity
- at least two mammalian species
- two mammalian species one should be a non-rodent
- Duration: application is for
marketing permission, clinical trial, phases of trials
- If a species metabolize the drug in the same way as humans preferred
- administered 7 days = the route intended for clinical use in humans
- control group = vehicle
- the highest dose = produce observable toxicity,
- the lowest dose = not cause observable toxicity , comparable to the intended
therapeutic dose in humans or a multiple of it.

Clinical Phases in New Drug
Development

Investigational New Drug (IND)
Application

Introduction
Any pharmaceutical company can approach to obtain permission for
the initiation of human clinical trials
To ship an experimental drug across (usually to clinical investigators)
before a marketing
Application for the drug has been approved
To provide the data showing = tests of a new drug on humans

Current Federal law = A drug be the subject of an approved marketing
application before it is transported or distributed
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 application = the sponsor technically obtains this exemption
from the FDA

During a new drug’s early preclinical development:
1. The sponsor's primary goal = if the product is reasonably safe for
initial use in humans
2. if the compound exhibits pharmacological activity = justifies
commercial development
3. Identified as a viable candidate for development = focuses on
collecting the data and information
4. Establish that the product = NOT expose humans to unreasonable
risks when used in limited

FDA's role in the development of a new drug begins when the drug's sponsor
(usually the manufacturer or potential marketer)
Screened the new molecule for pharmacological activity and acute toxicity
potential in animals
wants to test its diagnostic or therapeutic potential in humans
At that point, the molecule changes in legal status under the Federal Food,
Drug, and Cosmetic Act
Becomes a new drug subject to specific requirements of the drug regulatory
system.

IND Classification
IND
Commercial
- Permits Sponsors = Collect data on clinical safety &
Effectiveness
- Needed for application = Marketing i.e. IND Application
Research(Non – Commercial)
- Permits Sponsors = use drug in research
- Obtain advanced Scientific knowledge of new drug
- No plan to Market the product

Types of IND Applications
Investigator
Emergency
Treatment
Screening
Four Types

Investigator IND Applications
Physician = initiates and conducts an investigation
Immediate direction = administered or dispensed
Purpose: Unapproved drug
Approved products = new indications
Approved products = new patient population

Emergency Use IND Application
Allows FDA = authorise use of experimental drug
Emergency situation = NOT allowed time for submission of IND application
(21CFR Sec.312.23 or Sec.312.20)
Patients = Not meet the criteria of existing study protocol
Approved study protocol = Not exist
Authorise shipment of drug for specified use in advance

Treatment IND application
Experimental drugs = for serious or life-threatening conditions
Final clinical work conducted and FDA review takes place
Drug not approved for marketing, under clinical investigation for
serious or life-threatening diseases

Patients for whom no alternative drug or therapy is available
Serious diseases = drug made available during phase III investigations
or after all clinical trials completed
Immediately life-threatening disease = Drug made available earlier
than Phase III not earlier than Phase II

Screening IND application
Multiple, closely related compounds screening for better compounds or
formulations
Preferred = developed under separate IND
Screening = different salts, esters and other derivatives
Chemically different = Pharmacodynamically similar

IND Review and Report
FDA = opportunity to review the IND application for safety
Assure research subjects = No unreasonable risk
Report evaluates = Medical review, chemistry review, pharmacology
and toxicology review, statistical analysis, safety review

Meaning of Symbols in Flowchart

Investigator's Brochure
Compilation of clinical and nonclinical data on investigational product
Relevant to the study of the product in human

Purpose
Provide information to the investigators and others involved in the trial
Dose, Dose frequency or interval, Mode of administration, safety
monitoring procedures
Clinical management of study subjects during clinical trials
Information presented in concise and simple manner

Clinician or potential investigator = Appropriateness of proposed trial,
medically qualified person participate in a editing

Contents
Table of contents
Summary
Introduction
Description Of investigational product
Non-clinical studies includes non-clinical pharmacology, toxicology, pharmacokinetics
Effects in humans
Summary of data and guidance for the investigator

Sr. No. Contents Description
1. Summary
- NMT = 2 pages
Highlight = the significant physical, chemical, pharmaceutical, pharmacological, toxicological,
pharmacokinetic, metabolic, and clinical information.
2. Introduction
- Chemical name,
- active ingredients,
- pharmacological class,
- anticipated therapeutic/diagnostic indication(s).
- General approach to be followed in evaluation
3.
Description of I.P.
(Investigational Product)
- Physical, chemical and pharmaceutical properties of I.P.
- Storage and handling of I.P.
- Any structural similarity = known compound given.
4. Non-clinical studies
- The results = non-clinical pharmacology, toxicology, pharmacokinetic and investigational product
metabolism studies should be provided in summary form.
- The information provided may include: 1.Species tested
2.Number of sex in each group,
3.Unit dose (e.g., milligram/kilogram (mg/kg),
4. Dose interval,
5. Route of administration
6. Duration of dosing.

Sr. No. Contents Description
4.1 Non-clinical Pharmacology A summary of the pharmacological aspects = in animals should be included.
4.2
Pharmacokinetics and
Product Metabolism in
Animals
A summary of:
- pharmacokinetics (ADME) and biological transformation
- disposition (getting a drug into its appropriate position in the body and in an appropriate
concentration)
- in all species studied should be given.
4.3
Toxicology
(The study of the adverse
effects of chemicals on
animals)
A summary of: the toxicological effects = in different animal species.
- Single dose,
- Repeated dose,
- Carcinogenicity,
- Special studies (irritancy, sensitization),
- Reproductive toxicity
5 Effects in Humans:
- Thorough discussion of the known effects of the investigational product(s) in humans should be
provided,
- Information = pharmacokinetics, metabolism, Pharmacodynamics, dose response, safety,
efficacy and other pharmacological activities.
- Pharmacokinetics and Product Metabolism in Humans.
6
Summary of Data and
Guidance for the
Investigator
- Section = non-clinical and clinical data of IP.
- IB = a clear understanding of the possible risks, adverse reactions, observations
precautions needed for the clinical trial.

Drug
Approval
Process
Preclinical Studies
Phase I
Phase II
Phase III
FDA Approval
Phase IV
IND
- NDA
- Advisory
Committee
Meeting

New Drug Application (NDA)
The vehicle through which drug sponsors formally propose to the
regulatory body
to approve a new pharmaceutical for sale and marketing
the data gathered during the animal studies and human clinical trials
an investigational new product becomes a part of the NDA.

Aim of NDA
The aims of NDA include providing adequate information to permit FDA
reviewers to establish the following:
1. Safety and effectiveness of drug,
2. Benefits overweigh risks,
3. Is the drug’s proposed labeling (package insert) appropriate, and what should
it contain?
4. Are the methods used in manufacturing (Good Manufacturing Practice, GMP)
5. The drug and the controls used to maintain the drug’s quality adequate to
preserve the drug’s identity, strength, quality, and purity? Risk Benefit.

NDA Requirements
- 12 Sections
- 8 Items (Supporting Documents whichever applicable)

NDA Review Process
Once the application is submitted, the FDA has 60 days = preliminary review
The NDA is "sufficiently complete to permit a substantive review“.
If everything is found to be acceptable, the FDA will decide if the NDA will get
a standard or accelerated review.
Communicate the acceptance of the application
Their review choice in another communication known as the 74-day letter.

BA & BE
Bioavailability: Bioavailability means the rate and extent to which the
active ingredient or active moiety is absorbed from a drug product and
becomes available at the site of action.
Equivalence: compares drug products with respect to a specific
characteristic or function or to a defined set of standards.

BE studies are very essential to ensure uniformity in standards of
quality, efficacy and safety of pharmaceutical products.
Reasonable assurance can be provide for the various products
containing same active ingredient
Marketed by different licensees are clinically equivalent and
interchangeable.
Both Bioavailability and Bioequivalence focus on release of drug
substance from its dosage form and subsequent absorption in
circulation.
Similar approaches to measure bioavailability should be followed in
demonstrating bioequivalence.

BE study methods
Study Methods
P’Kinetics
- Use of P’kinetics parameters
- Release of drug = product
- Measurement of Drug conc. At
site of action not possible
- Relationship: drug conc at site
of action & systemic circulation
P’Dynamics
- Local site of actions = exert
primary clinical effects
- Measures systemic approach
- Dose response relationship
Comparative clinical Trials
- PK & PD = NOT available
- FDA gives guidance on this
studies
- Eg. Dermatopharmacokinetics
In-Vitro Dissolution studies
- Highly soluble drug
formulations
- Rapidly dissolving drug
products
- Reduce No. of in-vivo studies

Clinical Research Protocols
It is a complete written description of and scientific rationale for a
research activity = involving human subjects
Sufficient information is to be gathered on the quality of the non-clinical
safety to conduct the protocol
Health authority/ethics committee approval is granted in the country
where approval of the drug or device is sought.

The clinical trial design and objectives = clinical trial protocol.
States the background, objectives, rationale, design, methodology
(including the methods for dealing with AEs, withdrawals etc.)
Statistical considerations of the study.
States the conditions = the study shall be performed and managed.
Better ways:
- prevent disease in people who never had the disease
- prevent a disease from reoccurring.

The protocols used To…..
clarify the research question.
compile existing knowledge.
formulate a hypothesis and objectives.
decide about a study design.
clarify ethical considerations.
apply for funding.
have a guideline and tool for the research team.

Parts of the Protocol
1. Title Page.
2. Signature Page.
3. Content Page.
4. List of Abbreviations.
5. Introduction/Abstract.
6. Objectives.
7. Background/Rationale.
8. Eligibility Criteria.
9. Study Design/Methods (Including Drug/Device Info).
10. Safety/Adverse Events.
11. Regulatory Guidance.
12. Statistical Section (Including Analysis and Monitoring).
13. Human Subjects Protection/Informed Consent.

DATA PRESENTATION FOR FDA SUBMISSIONS
Study data standards = a standard way to exchange clinical and non-
clinical study data
a consistent general framework for organizing study data
including templates = datasets, standard names for variables
identify appropriate controlled terminology and standard ways of doing
calculations with common variables
Data standards = help FDA receive, process, review, and archive
submissions more efficiently and effectively

FDA = working towards a standardized approach to capture, receive
and analyze study data.
Standardization of study data is vital:
to integrate pre-marketing study data
post-marketing safety data to improve public health and patient safety
central to this vision is the creation of an enterprise data infrastructure
(Janus) within FDA to improve the management of all structured
scientific data

Data Standards
Data Standards
Exchange
- Consistent way to exchange information
- ensure that the sending and the receiving Systems
- understand unambiguously what information is being
exchanged
Terminology
- Consistent way to describe concepts
Eg. Unique Ingredient Identifiers (UNII) = FDA
- Describe substances in foods and drugs
- National Institute of Cancer (NIC)
terminology = cancer

BIOSTATISTICS IN
PHARMACEUTICAL PRODUCT
DEVELOPMENT

BIOSTATISTICS
Science
Professionals = collect + analyse + interpret conclusions
Statistics + Biological Sciences = Biostatistics
Statistical theories and applications
Analyse genetic data and disease rates
To design clinical trials = evaluation of new drugs

MANAGEMENT OF CLINICAL
STUDIES

Clinical trial management = the process that an organization follows to
ensure that quality (defined as minimized risks and clean data) is delivered
efficiently and punctually.
a project manager initiates and follows in order to successfully manage
clinical trial sites, clinical research associates and workflow.
using clinical trial management tools or software prolonged timelines
heavy costs related to large trials have been prompted a new focus on more
efficient clinical trial management.
It is possible to dramatically reduce the total cost of a clinical trial by 60% -
90% without compromising the scientific validity of the results.

Life Cycle of Clinical Trial Project
A more accurate control, regardless of the therapeutic area or trial
stages (all the way through from ‘preclinical’ phase 1 to ‘post approval’
phase 4 studies)
ensured by typically breaking down the life cycle of each clinical trial
project into 4 phases: Conceptual, Planning, Implementation and
Analysis

Clinical Trial Protocol
A protocol is a document that describes the purpose, design,
methodology, statistical considerations and organization of a study,
and provides basic information and rationale for the clinical study.
The contents that should be present in the protocol are described by
the GCP. The protocol writing is a task for one person, usually the
principal investigator, not a committee.
There are various challenges of Project management in clinical trials.
Clinical trials all need the same coordinated processes and systems,
irrespective of the size, scope, costs, or period.
The key challenge is then to implement and maintain effective
management systems and techniques in response to the needs of the
trial project.

REGULATORY AFFAIRS.pptx

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