Introduction to Pharmaceutical Regulatory Affairs
WHAT IS REGULATORY AFFAIRS?
As a discipline, regulatory affairs cover 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 data management, document preparation, project management,
budgeting, issue negotiation, and conflict resolution are also part of regulatory affairs.
BRIEF HISTORY OF PHARMACEUTICAL REGULATION
Control of pharmaceutical products has been the task of authorized institutions for thousands of
years, and this was the case even in ancient Greece and Egypt.
From the Middle Ages, control of drug quality, composition purity and quantification was
achieved by reference to authoritative lists of drugs, their preparation and their uses.
These developed into official pharmacopoeias, of which the earliest was probably the New
Compound Dispensatory of 1498 issued by the Florentine guild of physicians and pharmacists.
The pharmacopoeias were local rules, applicable in a particular city or district.
During the 19th century national pharmacopoeias replaced local ones, and since the early 1960s
regional pharmacopoeias have successively replaced national ones.
Now work is ongoing to harmonize – or at least mutually recognize – interchangeable use of the
US Pharmacopeia, the European Pharmacopoeia and the Japanese Pharmacopoeia.
In the USA the fight against patent medicines led to the passing of the US Pure Food and Drugs
Act against misbranding as long ago as 1906. The Act required improved declaration of contents,
prohibited false or misleading statements, and required content and purity to comply with labeled
information. A couple of decades later, the US Food and Drug Administration (FDA) was
established to control US pharmaceutical products.
Safety regulations in the USA were, however, not enough to prevent the sale of a pediatric
sulfanilamide elixir containing the toxic solvent diethylene glycol. In 1937, 107 people, both
adults and children, died as a result of ingesting the elixir and in 1938 the Food Drug and
Cosmetics Act was passed, requiring for the first time approval by the FDA before marketing of
a new drug product.
The thalidomide disaster further demonstrated the lack of adequate drug control and the incident
became a strong driver to develop animal test methods to assess drug safety before testing
compounds in humans. Also it forced national authorities to strengthen the requirements for
control procedures before marketing of pharmaceutical products.
Another blow hit Japan between 1959 and 1971. The SMON (subacute myelo-optical
neuropathy) disaster was blamed on the frequent Japanese use of the intestinal antiseptic
clioquinol (Entero-Vioform®, Enteroform® or Vioform®).
The product had been sold without restrictions since early 1900, and it was assumed that it would
not be absorbed, but after repeated use neurological symptoms appeared, characterized by
paraesthesia, numbness and weakness of the extremities, and even blindness. SMON affected
about 10 000 Japanese, compared to some 100 cases in the rest of the world.
These tragedies had a strong impact on governmental regulatory control of pharmaceutical
products. In 1962 the FDA required evidence of efficacy as well as safety as a condition for
registration, and formal approval was required for patients to be included in clinical trials of new
drugs.
In Europe, the UK Medicines Act 1968 made safety assessment of new drug products
compulsory.
All European countries established similar controls during the 1960s.
In Japan, the Pharmaceutical Affairs Law enacted in 1943 was revised in 1961, 1979 and 2005 to
establish the current drug regulatory system, with the Ministry of Health and Welfare assessing
drugs for quality, safety and efficacy.
The 1960s and 1970s saw a rapid increase in laws, regulations and guidelines for reporting and
evaluating the risks versus the benefits of new medicinal products. At the time the industry was
becoming more international and seeking new global markets, but the registration of medicines
remained a national responsibility.
European (EEC) efforts to harmonize requirements for drug approval began 1965, and a common
European approach grew with the expansion of the European Union (EU) to 15 countries, and
then 27.
ROLES AND RESPONSIBILITIES OF REGULATORY AUTHORITY AND COMPANY
The basic division of responsibilities for drug products is that the health authority is protecting
public health and safety, and the pharmaceutical company is responsible for all aspects of the
drug product. The regulatory approval of a pharmaceutical product permits marketing and is a
contract between the regulatory authority and the pharmaceutical company. The conditions of the
approval are set out in the dossier and condensed in the prescribing information. Any change that
is planned must be forwarded to the regulatory authority for information and, in most cases, new
approval before being implemented.
The regulatory authority:
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approves clinical trial applications
gives procedural and scientific advice to companies during drug development
approves for marketing drugs that have been scientifically evaluated to provide evidence
of a satisfactory benefit/risk ratio
monitors the safety of the marketed product, based on (a) reports of adverse reactions
from healthcare providers, and (b) from compiled and evaluated safety information from
the company that owns the product
can withdraw the license for marketing in serious cases of non-compliance (e.g. failure
on inspections, failure of adequate additional warnings in prescribing information after
clinical adverse reactions are reported, or failure of the company to consider serious
findings in animal studies).
The company:
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owns the documentation that forms the basis for assessment, is responsible for its accuracy
and correctness, for keeping it up to date, and for ensuring that it complies with standards set
by current scientific development and the regulatory authorities
collects, compiles and evaluates safety data, and submits reports to the regulatory authorities
at regular intervals – and takes rapid action in serious cases. This might involve the
withdrawal of the entire product or of a product batch (e.g. tablets containing the wrong drug
or the wrong dose), or a request to the regulatory authority for a change in prescribing
information
has a right to appeal and to correct cases of non-compliance.
The Role of the Regulatory Affairs Department
The regulatory affairs (RA) department of a pharmaceutical company is responsible for
obtaining approval for new pharmaceutical products and ensuring that approval is maintained
for as long as the company wants to keep the product on the market. It serves as the interface
between the regulatory authority and the project team, and is the channel of communication
with the regulatory authority as the project proceeds, aiming to ensure that the project plan
correctly anticipates what the regulatory authority will require before approving the product.
It is the responsibility of RA to keep abreast of current legislation, guidelines and other
regulatory intelligence.
National Regulatory Authorities
NRAs are national regulatory agencies responsible for ensuring that products released for
public distribution (normally pharmaceuticals and biological products, such as vaccines) are
evaluated properly and meet international standards of quality and safety.
Pharmaceutical Regulatory Agencies and Organizations around the World
In the present scenario, pharmaceuticals are considered as the most highly regulated
industries worldwide. The regulatory body ensures compliances in various legal and
regulatory aspects of a drug. Every country has its own regulatory authority, which is
responsible to enforce the rules and regulations and issue the guidelines to regulate drug
development process, licensing, registration, manufacturing, marketing and labeling of
pharmaceutical products.
Table 1. Major Regulatory Agencies Worldwide
Country
USA
UK
Australia
India
Canada
Europe
Denmark
Costa Rica
New Zealand
Sweden
Netherlands
Ireland
Italy
Name of Regulatory Authority
Food and Drug Administration (FDA)
Medicines and Healthcare Products Regulatory Agency (MHRA)
Therapeutic Goods Administration (TGA)
Central Drug Standard Control Organization (CDSCO)
Heath Canada
European Medicines Agency (EMEA)
Danish Medicines Agency
Ministry of Health
Medsafe- Medicines and Medical Devices Safety Authority
Medical Products Agency (MPA)
Medicines Evaluation Board
Irish Medicines Board
Italian Pharmaceutical Agency
Nigeria
Ukraine
Singapore
Hong Kong
Paraguay
Thailand
China
Germany
Malaysia
Pakistan
South Africa
Sri Lanka
Switzerland
Uganda
Brazil
Japan
Bangladesh
National Agency for Food and Drug Administration and Control
(NAFDAC)
Ministry of Health
Centre for Pharmaceutical Administration Health Sciences Authority
Department of Health: Pharmaceutical Services
Ministry of Health
Ministry of Public Health
State Food and Drug Administration
Federal Institute for Drugs and Medical Devices
National Pharmaceutical Control Bureau, Ministry of Health
Drug Control Organization, Ministry of Health
Medicines Control Council
SPC, Ministry of Health
Swissmedic, Swiss Agency for Therapeutic Products
Uganda National Council for Science and Technology (UNCST)
Agencia Nacional de Vigiloncia Sanitaria (ANVISA)
Ministry of Health, Labour and Welfare (MHLW)
Directorate General of Drug Administration
Table 2. International Organizations
World Health Organization (WHO)
Pan American Health Organization (PAHO)
World Trade Organization (WTO)
International Conference on Harmonization (ICH)
World Intellectual Property Organization (WIPO)
INTERNATIONAL HARMONIZATION
The harmonization process started in 1990, when representatives of the regulatory authorities
and industry associations of Europe, Japan and the USA (representing the majority of the global
pharmaceutical industry) met, apparently to plan an International Conference on Harmonization
(ICH).
International Conference on Harmonization (ICH)
The task of ICH was ‘… increased international harmonization, aimed at ensuring that good
quality, safe and effective medicines are developed and registered in the most efficient and costeffective manner. These activities are pursued in the interest of the consumer and public health,
to prevent unnecessary duplication of clinical trials in humans and to minimize the use of animal
testing without compromising the regulatory obligations of safety and effectiveness’ (Tokyo,
October 1990).
ICH has remained a very active organization, with substantial representation at both authority
and industry level from the EU, the USA and Japan. The input of other nations is provided
through World Health Organization representatives, as well as representatives from Switzerland
and Canada.
What Is the General Agreement on Tariffs and Trade (GATT)?
The General Agreement on Tariffs and Trade (GATT), signed on October 30, 1947 by 23
countries, was a legal agreement minimizing barriers to international trade by eliminating or
reducing quotas, tariffs, and subsidies while preserving significant regulations. The GATT was
intended to boost economic recovery after World War II through reconstructing and liberalizing
global trade.
The GATT went into effect on January 1, 1948. Since that beginning it has been refined,
eventually leading to the creation of the World Trade Organization (WTO) on January 1, 1995,
which absorbed and extended it.3 By this time 125 nations were signatories to its agreements,
which covered about 90% of global trade.4
The Council for Trade in Goods (Goods Council) is responsible for the GATT and consists of
representatives from all WTO member countries. As of September 2020, the chair of the Goods
Council is Swedish Ambassador Mikael Anzén.
The council has 10 committees that address subjects including market access, agriculture,
subsidies, and anti-dumping measures.
The World Trade Organization (WTO)
The World Trade Organization (WTO) is the only global international organization dealing with
the rules of trade between nations. At its heart are the WTO agreements, negotiated and signed
by the bulk of the world’s trading nations and ratified in their parliaments. The goal is to ensure
that trade flows as smoothly, predictably and freely as possible.
All major decisions are made by the WTO's member governments: either by ministers (who
usually meet at least every two years) or by their ambassadors or delegates (who meet regularly
in Geneva).
Intellectual property rights and the TRIPS Agreement
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What are intellectual property rights?
Intellectual property rights are the rights given to people over the creations of their minds.
“The TRIPS Agreement ... is to date the most comprehensive multilateral agreement on
intellectual property ...”
Trade-Related Aspects of Intellectual Property Rights (TRIPS)
The Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) came into
force in 1995, as part of the Agreement Establishing the World Trade Organization (WTO).
TRIPS incorporates and builds upon the latest versions of the primary intellectual property
agreements administered by the World Intellectual Property Organization (WIPO), the Paris
Convention for the Protection of Industrial Property, and the Berne Convention for the Protection
of Literary and Artistic Works, agreements that go back to the 1880s.
TRIPS is unique among these IPR accords because membership in the WTO is a "package deal,"
meaning that WTO members are not free to pick and choose among agreements. They are
subject to all the WTO's multilateral agreements, including TRIPS.
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TRIPS establishes minimum standards for the availability, scope, and use of seven
forms of intellectual property:
– copyrights,
– trademarks,
– geographical indications,
– industrial designs,
– patents,
– layout designs for integrated circuits, and
– undisclosed information (trade secrets).
It spells out permissible limitations and exceptions in order to balance the interests
of intellectual property with interests in other areas, such as public health and
economic development.
According to TRIPS, developed countries were to have implemented the agreement fully by
January 1, 1996. Developing-country members and members in transition to a market
economy were entitled to delay full implementation of TRIPS obligations until January 1,
2000. Least-developed members were given until January 1, 2006, to implement their
obligations, with the possibility of further transition upon request. Developing countries that
did not provide patent protection for particular areas of technology on their date of
application were given an additional five years, until January 1, 2005, to provide such
protection. In November 2005, the 2006 transition period for least-developed countries was
extended to July 1, 2013.
At the 2001 WTO Ministerial Conference in Doha, least-developed countries were given an
additional 10 years to implement TRIPS patent and "undisclosed information" provisions as
they relate to pharmaceuticals. In July 2002, the WTO General Council agreed to waive the
obligations of least-developed countries concerning exclusive marketing rights for
pharmaceutical products until January 1, 2016.
Common Abbreviations
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EC: Ethics Committee (EU), known as Institutional Review Board (IRB) in USA
EU: European Union
FDA: Food and Drug Administration; the US Regulatory Authority
GCP: Good clinical practice
GLP: Good laboratory
GMP: Good manufacturing practice
ICH: International Conference on Harmonization
IND: Investigational New Drug application (US)
IRB: Institutional Review Board (US), equivalent to Ethics Committee in Europe
MAA: Marketing Authorization Application (EU), equivalent to NDA in USA
NDA: New Drug Application (USA)
WHO: World Health Organization
Reference
Introduction to Regulatory affairs: Chapter 20: Regulatory Affairs by I Hägglöf, Å Holmgren