Regulatory affairs
Contents
• Introduction
• Historical overview of regulatory affairs
• Regulatory authorities
• Role of regulatory affairs department
• Responsibility of regulatory affairs professionals
Learning
objectives
• At the end of this lecture, student will be able to:
– Explain the role/significance of regulatory affairs in
pharmaceutical industry
– Explain the various regulatory authorities
– Explain the responsibility of regulatory affairs professional
What is
Regulatory affairs?
• As a discipline, regulatory affairs covers a broad range
of specific skills and occupations.
• Under the best of circumstances, it is composed of a group
of people who act as a liaison between the potentially conflicting worlds of
government, industry, and consumers to help make sure that marketed products
are safe and effective when used as advertised.
• People who work in regulatory affairs negotiate the
interaction between the regulators (the government), the regulated (industry),
and the market (consumers) to get good products to the market and to keep them
there while preventing bad products from being sold.
• The range of products covered is enormous, including foods
and agricultural products, veterinary products, surgical equipment and medical
devices, in vitro and in vivo diagnostic tools and tests, and drugs (which
range from small molecules to proteins).
• The range of issues addressed is huge, such as
manufacturing and analytical testing, preliminary safety and efficacy testing,
clinical trials, and post-marketing follow-up.
• Advertising issues, with a healthy dose of data
management, document preparation, project management, budgeting, issue
negotiation, and conflict resolution, are thrown in the mix.
• On the industry side, people in regulatory affairs work
with research scientists, clinicians, manufacturing groups, and sales and
marketing groups to make sure that the government has the information it needs
to judge a product.
• On the government side, people in regulatory affairs work
to interpret and implement laws that Congress establishes to help protect the
public. Evaluate a given drug, biologic, and/or device with respect to safety
and efficacy. Decide whether the product should be on the market—and if so, how
it should be marketed and sold.
• On the consumer side, people in regulatory affairs help
keep the other two groups honest, and provide stimulus for Congress to enact
laws
• Regulatory Affairs (RA), also called Government Affairs,
is a profession within regulated industries, such as pharmaceuticals, medical
devices, energy, and banking.
• A regulatory affair (RA) also has a very specific meaning
within the healthcare industries (pharmaceuticals, medical devices, Biologics
and functional foods). Most companies,
whether they are major multinational pharmaceutical corporations or small,
innovative biotechnology companies, have specialist departments of regulatory
affairs (RA) professionals. The success of regulatory strategy is less
dependent on the regulations than on how they are interpreted, applied, and
communicated within companies and to outside constituents
HISTORICAL
OVERVIEW OF REGULATORY AFFAIRS
• During 1950s, multiple tragedies i.e. Sulfanilamide elixir, vaccine tragedy and
thalidomide tragedy have resulted in substantial increase of legislations for
drug products quality, safety and efficacy. This has also resulted into
stricter norms for Marketing Authorization (MA) and Good Manufacturing
Practices (GMPs).
HISTORICAL OVERVIEW
OF REGULATORY AFFAIRS (USA)
• The early 18th century, chemical manufacturing factories
had started the first large scale manufacturing of glycerine during 1818-1840.
• Medicines - compounded by Pharmacists and Doctors at
Pharmacy laboratories. Crude drugs i.e. opium were extracted from natural
plants by pharmacists and progressed further for identifying isolating active
ingredients from the crude drug.
• In USA, the root of modern pharmaceutical industry was borne
during Mexican- American war (1846-1848) American troops had suffered due to
import of spurious medication for Malaria, Cholera, Dysentery, and Yellow Fever
- federal government into action for creation of Custom Laboratories.
• The first law which controlled import of medicines was
Import Drugs Act of 1848. It was
mandatory to inspect imported drugs for quality and purity at the entry of
port.
• To define the quality and purity of drug, federal
government recognized United States Pharmacopoeia (USP) as an official
compendium. Note that though United States Pharmacopoeia Committee (USPC) was
established in 1820, it was non-government body till Import Drugs Act of 1848.
• The objective - creating system for standards, quality control
and national formulary.
• At the start of 19th century, new legislations for
medicines control started due to multiple tragedies worldwide.
• This was the era when ancient traditions of manufacturing and
distribution of drugs evolved into the modern highly organized pharmaceutical
industry and controlled system of Drug Regulatory Affairs (DRA).
• Almost five decades after issuance of Import Drugs Act of 1848, vaccines tragedy happened in 1901. During this era, City and State Health Departments use to maintain stables and vaccine preparation facilities unlike the private industry today
• Legislations mandating exclusive manufacturing facility
for vaccines enacted post two events of death due to immunization failure.
• Diphtheria antitoxin developed by City Health Department
of St. Louis was contaminated by tetanus
causing bacteria - death of 14 children in November 1901. Simultaneously,
smallpox vaccine administered was found contaminated and resulted into 9 more
death in New Jersey.
• The Biologics Control Act of 1902 was the result of the
vaccine tragedy. This legislation mandated manufacturing and distribution
licensing of biological products i.e. Serum, vaccine, toxin, viruses as well as
defined labeling in terms of manufacturer’s name, address, license number,
identification of product and expiry date.
• Further federal government took steps for controlling adulteration/misbranding of foods, drugs, medicines, liquors - prohibited interstate transport of adulterated food/drugs.
• Toxic colors and preservatives like borax, sulphuric acid,
formaldehyde, copper and sulphate were banned for usage in food and drugs.
• The Food and Drugs Act of 1906 is best known as Wiley Act,
named by Dr. Harvey W. Wiley. This law made mandatory labelling of ingredients
and its content for drugs i.e. alcohol, cocaine, heroin, morphine, opium. This
was the first wide ranging, national legislation on food and medicines safety.
• The Federal Food and Drugs Act 1906 was starting point for
eventual creation of Food and Drug Administration (FDA).
• Earlier the Bureau of Chemistry was used to regulate food
safety, however in 1927, it was reorganized into the Bureau of Chemistry and
Soils and Food, Drug and Insecticide Administration.
• In 1930, the current Food and Drug Administration (FDA) came
into effect after shortening of earlier organization.
• Since the root of FDA was born in 1906, FDA still
celebrates 1906 as its establishment year.
• In 1938, Sulfanilamide Elixir tragedy raised concern about
the safety of drug products - more than 100 people died due to diethylene
glycol (highly toxic solvent) utilised for mixing Sulfanilamide drug.
Consequently, the law was enacted as Food, Drug and Cosmetic Act of 1938 to
oversee safety of medicine.
• Pre-marketing approval of all new drugs was made mandatory
and proof for scientific safety study was asked by FDA, directions for safe
use.
• Categorising medicines as Over-The-Counter (OTC) drugs and
Prescription drugs which was not in place earlier.
• Medicines for minor ailments i.e. indigestion, headache
can be fall under OTC drugs and freely sold at pharmacy store without
prescription. Major ailments drugs are “Prescription Only (RX)” and unsafe for self-medication.
• It was mandated to put statement a labeling as “Caution-
Federal Law prohibits dispensing without a prescription”. This law was known as
Durham-Humphrey Amendment of 1951, best known as Prescription Amendment Act of
1951
• Milestone changes happened on the basis of Kefauver-Harris
Drug Amendments 1962. This was the after effect of Thalidomide tragedy in
Western Europe. As per this law, new drugs were required to be supported with
efficacy as well as greater safety data, Good Manufacturing Practices (GMPs)
and prior Marketing Authorization Approval was mandated by FDA in these
amendments.
• Drug regulations evolved rampantly in last 5 decades and many laws came into effect which resulted into organized regulatory structure of FDA. The agency grew from single chemist from United Stated Agriculture Department (USAD) to approximately 9100 employees of varied category i.e. physicians, pharmacologists, chemists, microbiologists, pharmacists, veterinarian and lawyers.
HISTORICAL
OVERVIEW OF REGULATORY AFFAIRS (INDIA)
• The drug industry in India was at very primitive stage
till 20th Century.
• Drugs were imported from foreign countries.
• Post First World War, the demand for drugs increased which
led to the cheap & substandard drugs into the market, as like in USA post
Mexican American war.
a) 1900-1960:
• To control cheap drugs in market – The Poisons Act 1919 was passed -regulated possession of substance/sale
of substances as specified as poison, specifies the safe custody of the
poisons, labeling/packaging of poisons, maximum quantity to be sold and
inspection/examination of the poison sold.
• It was followed by The
Dangerous Drugs Act 1930 regulated opium plant
cultivation/manufacture/possession of opium, its import, export, tranship and
sell of opium.
• The Narcotics and
Psychotropic Substances Act in 1985 revoked the Dangerous Drugs Act 1930
and Opium Act, 1878. Following acts & rules were passed during this era:
• Drugs and Cosmetics
Act, 1940: Regulate the import, manufacture, distribute and sale of drugs.
This act covers allopathic, homeopathic, Unani and Sidha drugs.
• Drugs and Cosmetics
Rules, 1945: The rules under the Drugs and Cosmetics Act regulate only manufacture
of Ayurvedic
• Pharmacy Act, 1948:
This law was amended lastly in 1986 and it regulates the pharmacy profession of
India.
• Drugs and Magic
Remedies (Objectionable Advertisements) Rules, 1955: This rules control the
drug advertisement in India.
• Drugs Prices
Control Order, 1955 (DPCO) (under the essential commodities Act): DPCO was
further amended in 1995. Under this rule, government may review and fix maximum
sale price for bulk drugs as well as formulation.
b) 1960-1970:
• The market share was dominated by multinational companies
and very few indian manufacturers were present.
• The Indian Pharmaceutical industry was in a growth.
• Focus for pure research and development was very little
due to lack of patent protection. Due to very high import dependency on drugs,
the cost of drugs was very high as well as market availability was
comparatively low.
c) 1970-1980:
Government took control for the medicines regulation and
issued few acts and rules.
• Indian Patent Act
1970: It serves as the basis for patent protection in India. Based on this,
only process and method of manufacture of Drug substance was allowed to get the
patent. Product patent was not allowed under this act. Indian Patent Act of
1970 came into force from April 20, 1972. This new act replaced the Indian
Patents and Designs Act of 1911.
• Drug prices capped:
Drug Prices Control Order (DPCO) was
introduced to control the high price against consumers.
• Local companies
begin to make an impact: manufacturing products/drugs using different
manufacturing process by reverse engineering.
Due to this new drugs were available cheaply as well as many more
substitute drugs were available in the market against costly imported new
drugs.
• This has resulted in
1) Increase the exports to countries like Russia, Africa,
China, and South America.
2) Export of Bulk drug post patent expiry
d) 1980-1990:
The industry has started investing in API process
development and created production infrastructure. Government has also issued
export incentives.
The Narcotic Drugs and Psychotropic Substances Act, 1985 was
issued which regulates the operation of narcotic drugs and substances.
e) 1990-2000:
• The pharmaceutical industry has observed a rapid expansion
of domestic market and during same era globalisation happened.
• The companies have entered into research activity. India
joined Paris Cooperation Treaty (PCT) in 1999 and implemented product
patent effective from Jan 1, 2005.
f) 2000-2010:
This period is considered to be the Innovation and Research
era. During these years, innovative research activity, patenting of the drugs
formula, process, indication as well as merger of companies was started.
• Patent Amendment
Act 2005: With this act, provision for Black Box Application made, as per
that if patent application is filed before Jan 1, 2005, then under TRIPS,
manufacturer can market this product post 2005 without infringing product
patent.
• Compulsory Licenses: Such licenses can be granted for manufacture
and export of the drug products “to any country having insufficient or no
manufacturing capacity, for the said product, to address public health
problems”
Herbal preparations having medicinal values can be patented
under new amended law.
Major regulatory changes in terms of marketing authorization
process as well guidelines have come into effect.
Drugs and Cosmetics
(First Amendment) Rules, 2011: It mandates registration of Clinical
Research Organization (CRO) for conducting Clinical Trials (CT). Schedule Y1
suggests requirements and guidelines for registration of Clinical Research
Organizations.
Clinical Trial
Registry- India (CTRI): It has been
set up by
the ICMR’s (Indian
Council of Medical
Research) National Institute of Medical Statistics (NIMS).
• India has developed on-line registry system and mandated registration
of CRO before the enrolment of first patient for clinical trials.
• CRO needs to disclose mandatory items as mentioned under
WHO International Clinical Trials Registry Platform (ICTRP) dataset.
• Pharmacovigilance
Programme of India (PvPI): The Central Drugs Standard Control Organization
(CDSCO) has launched Pharmacovigilance programme to assure drugs safety to
indian patients. This will help monitoring adverse drug reactions to indian
patients, as well as monitoring of benefit- risk ratio.
• Guidance documents:
CDSCO has issued guidance for Industry for Fixed Dose Combinations (FDCs)
registration as well as Guidance for preparation of Common Technical Document
for Import/manufacture and Marketing Approval of New drugs for Human Use (New
Drug Application-NDA). With this CDSCO has implemented system for preliminary
scrutiny at the time of application receipt for marketing approval of Fixed
Dose Combinations (FDCs).
HISTORICAL
OVERVIEW OF REGULATORY AFFAIRS (Europe)
• Main objective of keeping unsafe products out of
marketplace in addition to ensuring Quality, Safety and Efficacy,
• Ethical
considerations: To avoid unethical and unsafe clinical trials - the
Helsinki Declaration has been set in 1964.
• Economic issues:
First health insurance system was developed in later half of 20th century. This
has resulted in to pricing transparency
due to the
fact that cost
of medicines was transferred from
customer to private
and public health insurance system.
• Unsafe products
usage: Major revolution of drug regulations started post Thalidomide
tragedy. In late 1950s, a German company was marketing new sedative pills
reduced nausea in pregnant women- created teratogenic effect which resulted
into birth defects in almost 10000 children. The babies born to women in
Germany and England were without hands, feet, toes or fingers like flippers growing
out of their shoulders and trunk.
• However, this changed with formation of European Economic Commission
(EEC) in 1957 (Currently European Union-EU)
• The first directive passed by European Economic Commission
was 65/65/EEC mandating that no medicines can be marketed in European
Communities until and unless it is not approved by at least one competent
authority within Europe.
• The objective of this legislation was to have standard
common marketing approval for medicines process within European Economic
Commission.
• At the same time, few more directives specific to the
category of products i.e. radiopharmaceuticals, immunological and homeopathic
medicines as well as classification, labeling and promotion directives were
came into effect
• Early 1990s in UK, Creuthfeldt-Jacob disease cases were
started increasing. Bovine Spongiform Encephalopathy (BSE), commonly known as
“mad cow disease”.
• It was applicable to all ingredients derived from bovine
materials i.e. lactose, magnesium stearate, gelatin.
• Free availability of information: Any information about medicine
is available almost to everyone due to wide spread use of media and internet.
To ensure public’s confidence in healthcare system, regulations pertaining to
quality, safety, efficacy and clear instructions for use came into effect.
• Products and technology innovation: Development of new
products such as biologics, blood and blood related products, and in vitro
diagnostics needed new legislations. Assess
common Marketing Authorization Application (MAA).
• Demands for products safety: Regulatory authority demands safety
data to support Marketing Authorization (MA) as well as monitoring of safety
data throughout the products post authorization cycle.
• Changes in market structure: Healthcare regulations were required
due to creation of single EU market by removing trade barrier. A common
regulatory framework was required. Since the market was open, the quality
concern for imported products led to the development of new regulations.
Pharmaceutical
legislation
• Currently, the EU legislation on medicinal products
consists basically of
• Directives must be transferred into national law by the
member countries prior to becoming effectives.
• Regulations apply directly in all member states.
• Decisions & Recommendations.
• Notice to applicants: Under this section, detailed requirements
and understanding about marketing authorisation procedure (Evaluation process,
query response and timeline) as well as dossier preparation and its content
(CTD and eCTD) and related guidelines are available. This is non-binding texts
to help applicants fulfils regulatory approval obligations to place drug
products in market.
• Regulatory guidelines: Under this section, regulatory guidelines
i.e. Quality and Biotechnology, Safety, environment and information, as well as
efficacy guidelines to support product development are available.
• Detailed drug monitoring guide: Under this section,
guidelines pertaining to drug monitoring (pharmacovigilance) for the medicinal
products already approved are available.
Regulatory
authorities
Country
Regulatory body
USA
Food and Drug Administration (FDA)
UK
Medicines and Healthcare Products Regulatory Agency (MHRA)
Australia
Therapeutic Goods Administration (TGA)
India Central Drug Standard Control
Organization (CDSCO)
Canada
Health Canada
Japan
Ministry of Health, Labour & Welfare (MHLW)
Country
wise Regulatory agency
India
www.cdsco.nic.in
http://www.cdsco.nic.in/CDSCO-GuidanceForIndustry.pdf
USA
http://www.fda.gov/drugs/default.htm
Orange book:
http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm
European
Home page: www.emea.europa.eu Guidelines page:
http://www.emea.europa.eu/htms/human/humanguidelines/quality.htm
UK
Home page: www.mhra.gov.uk Guidelines page:
http://www.mhra.gov.uk/Publications/Regulatoryguidance/index.htm
Australia
www.tga.gov.au http://www.tga.gov.au/pmeds/pmeds.htm
International
conference on harmonization (ICH)
www.ich.orgGuidelines page: http://www.ich.org/cache/compo/276-254-1.html
Canada
www.hc-sc.gc.cah
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-
ld/index-eng.php
Role of
Regulatory affairs Department
• Keep in touch with international legislation, guidelines
and customer practices
• Keep up to the date with a company’s product range
• Ensure that a company’s products comply with the current
regulations.
• The Regulatory Affairs professional’s job is to keep track
of the ever-changing legislation in all the regions in which the company wishes
to distribute its products.
• They also
advise on the
legal and scientific
restraints and requirements, and
collect, collate, and evaluate the scientific data that their research and
development colleagues are generating.
• Formulate regulatory strategy for all appropriate
regulatory submissions for domestic, international and/or contract projects.
• Coordinate, prepare and review all appropriate documents
for example dossier and submit them to regulatory authorities within a
specified time frame in conjugation with the organization.
• Prepare and review of SOPs related to RA. Review of BMR,
MFR, change control and other relevant documents.
• Monitor the progress of all registration submission.
• Maintain approved applications and the record of
registration fees paid against submission of DMF’s and other documents.
• Respond to queries
as they arise,
and ensure that registration/ approvalare granted
without delay.
• Impart training to R&D, Pilot plant, ADl and RA. Team
members on current regulatory requirements.
• Advising their companies on the regulatory aspects and climate
that would affect proposed activities. I.e. describing the "regulatory
climate" around issues such as the promotion of prescription drugs and Sarbanes-Oxley
compliance.
• Manage review audit reports and compliance, regulatory and
customer inspections.
• Regulatory Affairs professionals help the company avoid
problems caused by badly kept records, inappropriate scientific thinking or
poor presentation of data. In most product areas where regulatory requirements
are imposed, restrictions are also placed upon the claims which can be made for
the product on labelling or in advertising.
• Have a duty to provide physicians and other healthcare
professionals with accurate and complete information about the quality, safety
and effectiveness of the product.
Responsibility
of Regulatory Affairs Professional
• The Regulatory Affairs professional’s job is to keep track
of the ever-changing legislation in all the regions in which the company wishes
to distribute its products.
• They also advise on the legal and scientific restraints
and requirements, and collect, collate, and evaluate the scientific data that their
research and development colleagues are generating.
• They are responsible for the presentation of registration documents
to regulatory agencies, and carry out all the subsequent negotiations necessary
to maintain marketing authorization for the products concerned.
• They give strategic and technical advice at the highest
level in their companies, right from the beginning of the development of a
product, making an important contribution both commercially and scientifically to
the success of a development program and the company as a whole.
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