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xxxiv Cobert’s Manual of Drug Safety and Pharmacovigilance
A brief note on spelling. Just as pharmacovigilance
is not totally harmonized (harmonised), the English
language suffers similarly. We have used both US and
UK spelling inconsistently throughout this book. In
particular, we did not change spelling in URLs which,
of course, would not allow you to reach the website.
A note on URLS: We learned in the past editions of
this Manual, that URLs may have very short half-lives!
Organizations merge, reorganize, get new or updated
databases, etc. Thus, URLs which were correct at the
time of writing often change or disappear by the time
the book is published. When we do list URLs, try them.
With luck, they’ll still work. Otherwise, a Google search
should be done.
Good luck!
CHAPTER
1
1
The History and Theory
of Drug Safety and
Pharmacovigilance
W
hy does a biopharmaceuti-
cal or device company need
a drug/device safety group?
What is the mission of such a drug
safety group and how is it organized?
The Why
This is a question often asked and then taught in pro-
grams around the world. Why does a company need
a drug/device/product safety group? National laws in
many countries require manufacturers, biopharma-
ceutical companies, and others to comply with certain
requirements that are designed to ultimately protect the
human patient and recipient of products developed to
improve or mitigate a known health outcome. Why do
you need a safety group? Because the law requires it,
and our ethical obligations to the public and patients
lend to the necessity of such a group. Additionally, as
a result of inspection findings, outcomes of poor plan-
ning, manufacturing, labeling/communication, and
other unsavory events, it is in a company’s best interest
to accurately and diligently study, monitor, and evaluate
a product’s effect in humans and its safe use in order to
avoid legal and financial penalties and burdens.... and
to best protect the public health. Put simply, if you don’t
“do safety” right, you’ll pay for it later, quite literally.
In this chapter we review the background and pur-
pose of some of the regulatory agencies as well as nota-
ble historical events that led to the development of key
principles that make up what we now call good “safety
and pharmacovigilance” practices, or GVP.
A Brief History, Focusing on
the US FDA
The history of balancing benefits and risks of pharma-
cologically active substances has a very extensive his-
tory. Some of the earliest work can be traced back many
2 Cobert’s Manual of Drug Safety and Pharmacovigilance
centuries to Chinese and other Asian herbalists. Written
documentation exists to support the preparation and
safe and effective use of herbal preparations and herbal
combinations to improve human health. However, up
until a century or two ago, the requirements for the
safety and efficacy of drug products were either non-
existent or poorly defined at best. And unregulated. In
the US, the Pure Food and Drugs Act (FDA), adopted
into law in 1906, prohibited interstate commerce of
mislabeled and adulterated drugs and food within the
United States. This covered some safety aspects of drugs
but not efficacy. The FDA had, at that time, no juris-
diction or control of efficacy claims made for drugs. In
1912, the law was changed to cover false and fraudulent
claims made for drugs. However, the law did not man-
date safety and, in effect, unsafe products could be and
were marketed. The FDA could not seize unsafe drugs
and was limited only to issuing public warnings.
Much of FDA’s oversight and enforcement author-
ity have emerged because of misbehavior and disas-
ters. In 1937, a company in the United States marketed
elixir of sulfanilamide, which contained diethylene
glycol (similar to antifreeze) as a solvent. More than
100 people (including many children) died from this
product due to kidney failure caused by the solvent.
Because the law did not require safety testing for drugs,
the company had done none. As a result of this, the
Federal Food, Drug and Cosmetic Act was passed into
law in 1938. This law required safety testing to be
performed and submitted to the FDA in a New Drug
Application (NDA). Additional laws were passed in the
1940s requiring testing for purity, strength, and quality
of many drugs.
The next major event was the thalidomide disas-
ter of the early 1960s, when the NDA for thalidomide
was valiantly opposed by Dr. Frances Kelsey at the FDA
because of insufficient safety information despite strong
pressure to approve it. The product was intended for
use in pregnant women to prevent morning sickness
and was widely available for this use in Europe and was
even sold OTC in Germany. Though never marketed in
the US, thalidomide was used in the investigational set-
ting in the US. By 1962, the terrible teratogenic (birth
defect) aspect of the drug became known as babies were
born, mostly in Europe, with severely deformed arms
and legs (phocomelia).
In 1962, the Kefauver-Harris Amendment became
law and introduced the modern era of drug regulation.
Drug manufacturers now had to demonstrate to the FDA
both safety and efficacy before marketing a new drug. In
1971, the National Drug Experience Reporting System
was begun as was the publication of “The FDA Drug
Bulletin” to alert physicians and pharmacists to drug
issues. In 1985, the regulations on AE reporting for mar-
keted drugs were strengthened, and new requirements
for Investigational New Drug Applications (INDs) were
introduced. Over the years, the FDA has had multi-
ple reorganizations and alterations in its structure and
function as the overseer of drug safety and efficacy in
the US. The result is the complex system of AE collec-
tion, analysis, and reporting that we know today.
Regulations, Laws, and
Guidances
The regulations, laws, guidances, guidelines, and other
relevant documents covering drug safety and pharma-
covigilance are scattered throughout multiple places in
the Code of Federal Regulations (CFR) for the US, in
various venues for European Union (EU) and member
state documents, and now in many other regions such
as Canada, India, Australia, the Asian Pacific and other
regions worldwide.
Their ultimate goal remains the same in all coun-
tries: ensure the best use of medicines in the interest of
any subject/patient.
The EU PV requirements are designed at the EMA
level (Regulations, Directives, and Guidances) and then
implemented in each EU country; nevertheless, some
countries can be more (but never less) demanding.
Most of the EU documents are updated fairly frequently.
Most other countries in the world have their own set of
local laws, regulations, and guidances (often available
only in the local language).
Requirements in most countries are fairly simi-
lar in their intent of protecting patient safety (includ-
ing subjects in clinical trials). Some countries, such as
Australia, even refer back to EU GVP guidelines. Most
local regulations require nearly all SAEs and some
non-serious AEs to be reported quickly if there appears
The History and Theory of Drug Safety and Pharmacovigilance 3
to be a potential impact on public health. The defini-
tions of “serious” and “non-serious” AEs are more or
less standardized, although there are nuances that apply
in various jurisdictions.
More “routine” individual AEs are analyzed and
reported at periodic intervals. Most countries also
require some form of aggregate reporting of serious
and non-serious AEs at periodic intervals (e.g., every
3 months, 6 months, yearly, every 3 years), depend-
ing upon whether the drug is in clinical trials or on
the market and whether it is new or old. Although the
rules are similar throughout the world, they are suffi-
ciently different in detail (“the devil is in the details”)
they can be very difficult to track and keep up to date.
The major documents for the US and the EU are listed
below. These should be read and digested by anyone
doing drug safety for a living. The contents of these
documents are topics of this book. In the US, FDA’s
regulation-making authority derives from legislation
passed by the US Congress and signed into law by the
US President. Most of the FDA-directed legislation
gives FDA broad ability to introduce regulations and to
enforce the related requirements. The FDA regulations
do not explicitly state that a department or group must
exist to deal with drug safety. Rather, sponsor/applicant
obligations are spelled out. A “sponsor” is responsible
for clinical trials and an “applicant” is responsible for
meeting requirements associated with a marketing
application and in the post-marketing phase. To do
this adequately, an organized system or department is
necessary.
The EU PV requirements are designed at the EMA
level (Regulations, Directives, and Guidances) and then
implemented in each EU country, with some countries
being more (but never less) demanding. The EU regu-
lations are more specific and require that a formal phar-
macovigilance (PV) system be put in place and that it
is fit-for-purpose: Good Pharmacovigilance Practices
(GVPs) Module I — Pharmacovigilance systems and
their quality systems. In addition, the EU regulations
require an EU Qualified Person for Pharmacovigilance”
(EU QPPV) be nominated by the pharmaceutical com-
pany: this EU QPPV is legally responsible for ensuring a
company meets its legal obligations for the safety moni-
toring of all registered products and is a significant role
within any company.
The United States and
EU Laws, Regulations,
Guidances, Guidelines,
Directives and Practices
Drug safety in the US is covered under several sections
of the Code of Federal Regulations (CFR). FDA regula-
tions are consolidated in Title 21 of the CFR or 21 CFR
(a searchable version of 21CFR is available at www.reg-
ulations.gov).
21CFR312 covers INDs: 21CFR312.32 covers IND
safety reports, including expedited 7- and 15-day
reports. 21CFR33 covers IND annual reports. The
NDA regulations for drugs are found in 21CFR314.80.
Updates to regulations are published in the Federal
Register on a daily basis and are viewable (www.regu-
lations.gov). Note that the consolidated CFR is only
updated with the final FDA regulations from the daily
Federal Register only once a year, on April 1
st
.
A summary of safety documents for the EU can
be found at the EudraVigilance website (www.eudra
vigilance.eu), the European Commission website
(www.ec.europa.eu), and the EMA website (www.ema.
europa.eu).
There are several major documents covering drug
safety: EudraLex Volume 10 is for clinical trials (amended
in 2019 with the implementation of Regulation (EU)
No 536/2014). For post-marketing, the regulations
have been completely reviewed in 2010–2012; the main
documents are as follows:
Regulations (EU) Nos. 1235/2010 and 1027/2012.
Directives 2010/84/EU and 2012/26/EU.
Good Vigilance Practices (GVP); there is a series of
12 Good Pharmacovigilance Practice (GVP) mod-
ules, numbered I to XVI (planned Modules XI, XII,
XIII, and XIV are void, as the content has been inte-
grated into other modules). The GVP modules pro-
vide guidance to marketing authorization holders
(MAHs), the EMA, and national competent author-
ities in EU member states. They cover medicines
authorized in the EEA, regardless of the route of
authorization.
4 Cobert’s Manual of Drug Safety and Pharmacovigilance
There are several subsections devoted to drug safety
also available at this website. “Volume 10 — Clinical
Trials Guidelines” includes the following:
Detailed guidance on the collection, verification,
and presentation of adverse reaction reports aris-
ing from clinical trials on medicinal products for
human use;
Detailed guidance on the European database of
suspected unexpected serious adverse reactions
(EudraVigilance — Clinical Trial Module);
Questions and answers specific to adverse reaction
reporting in clinical trials.
Pharmaceutical companies are obliged to capture
AEs, analyze them, and report them to their health
agency locally and to other health authorities, or to
companies abroad for submission to their HAs if there
are formal corporate arrangements for sales and trials
outside the home country. Thus, a company needs to
create or have full-time (24/7) access to a safety team or
department equipped to handle spontaneous and clin-
ical trial AEs (as required) or to outsource this func-
tion. If the company is based solely in one country, the
department may be relatively small and uncomplicated.
In the simple setting, AEs are reported only to the HA in
that country. If, however, AEs can come from (or need
to go to) subsidiaries or affiliates in other countries or
from business partners with which the company has
contractual relationships, the complexity of the needs
and requirements grows enormously. If a single-country
company is doing clinical trials outside its borders, it
must be able to report AEs and handle all other safety
and regulatory matters with other countries’ health
agencies.
Safety & PV Operational
Considerations
Different languages, time zones, ever-changing govern-
ment requirements, reporting due dates, documents
and formats, electronic transmission, and so forth
must be taken into account. Standard operating pro-
cedures, Medical Dictionary for Regulatory Activities
(MedDRA®), and training systems must be in place.
An electronic safety database must be built (an enor-
mous task) or purchased or leased (still a complex and
costly endeavor). Risk evaluation and management/
mitigation systems must be in place.
Healthcare personnel, including physicians, nurses,
pharmacists, and support staff, must be hired. The busi-
ness relationships with other concerned departments
within the company, such as regulatory affairs, sales
and marketing, legal, clinical research, and others, must
be established. In other words, creating a safety depart-
ment is a complex and expensive endeavor that must be
done absolutely correctly.
After an AE report is received by the safety depart-
ment, it must be entered or uploaded into the safety
database, which is used for storage, retrieval, analysis,
and reporting data. Although such transactional data-
bases may start out in small companies as spreadsheets
with the data typed onto paper forms, most companies
respond to this need by purchasing an expensive (up to
hundreds of thousands or millions of dollars, depend-
ing on the number and location of users and informa-
tion technology, IT, maintenance staff) dedicated safety
database. In addition to a transactional database, some
large organizations have developed data warehouses to
organize and store large amounts of safety data. Much
of this is now out-sourced and stored in the cloud. They
create complex departments with tight standard operat-
ing procedures to ensure that the company remains in
full compliance with all laws, regulations, and guide-
lines and will withstand inspections and audits from the
FDA, EMA, and other HAs, business partners, outside
auditing companies and others.
There is usually a senior executive (typically a vice
president for drug safety) to oversee the entire group.
Within the drug safety group, there are multiple func-
tions to handle. Depending on the size of the company,
separate people or groups may handle each of the cate-
gories below. In small companies, all functions may fall
on one or two people or are outsourced.
Case receipt, triage, and processing by data entry
personnel;
Case evaluation by medical professionals;
Coding of AEs in MedDRA (sometimes this group is
separate from drug safety);
The History and Theory of Drug Safety and Pharmacovigilance 5
Coding of drugs in WHO-Drug or another drug
dictionary;
Quality review;
Medical review by physicians;
Submission to HAs, subsidiaries, business partners,
and so on.
To support the drug safety group, there is often a
dedicated informatics (IT/computer) group, a signaling/
pharmacovigilance group, a training group, a standard
operating procedure (quality) group, an epidemiol-
ogy group, a risk management group, a quality group
and more. These groups may be within or separate
from the drug safety department. Sometimes a medical
report writing group also falls under drug safety to pre-
pare aggregate reports, such as Periodic Safety Update
Reports (PSURs, PBRERs), annual reports, NDA peri-
odic reports, IND annual reports, and so on.
Similar groups often exist within HAs. Some author-
ities (FDA, MHRA, Health Canada, ANSM, TGA, EMA,
and others) receive reports directly from healthcare
professionals and consumers. The agencies may form
departments similar to those in companies to receive,
enter, and evaluate data and make medical judgments
on the cases. The volumes in companies may run to
tens or even hundreds of thousands of cases per year.
The FDA received over 2.3 million post-marketing
ICSRs in 2022, of which 1.3 million (57%) were expe-
dited. There were 78,000 (2%) received directly from
the healthcare community or consumers (refer to the
FDA website, www.fda.gov). These reports (redacted)
are available over the Internet using a public dashboard.
This is a large task and is performed by most health
agencies throughout the world. Because serious cases
tend to be reported to all health agencies, there is enor-
mous duplication of effort in creating databases in each
agency and company. In practice, only HAs in large
countries with advanced pharmacovigilance practices
are able to maintain relatively complete databases and
conduct meaningful signal analyses.
There are four major databases with large but
not total overlap for post-marketing AEs: the FDA in
the United States, the EudraVigilance database in the
EMA (Amsterdam), the MHRA database (UK), and the
Vigibase at the Uppsala Monitoring Centre in Sweden.
There are others as well.
Clinical trial AEs tend to be more scattered and
far less transparent than AEs for marketed products
because most of the information on drugs not yet on the
market is proprietary and guarded as secret information
by both companies and HAs. In many countries, clin-
ical trials by pharmaceutical companies, universities,
consortia, health agencies, and others must be entered
into web-based registries. The largest is the clinical
trial website maintained by the US National Library
of Medicine at the National Institutes of Health (www.
clinicaltrials.gov), with more than 460,000 trials from
all over the world registered as of the middle of 2023.
The data, however, are variable, and often there is lit-
tle or no safety data and the data are not always up to
date. Various countries, including the US, have man-
dated regular posting and updating of “Basic Results”
for safety (and efficacy) data. When the database first
went into production in 2000, trial listings and data
were incomplete, but this has gradually improved over
the ensuing years.
The Mission of a Safety
Group
The mission of the safety group must be clearly defined
and made known to all employees of the company, in
particular to senior management, marketing and sales.
It is also good policy to let the general public know
of the company’s or health agency’s commitment to
patient safety. For example, see FDA’ s Sentinel Initiative
Mission Statement. Companies also explain their safety
functions to the public, see for example, Pfizer (www.
pfizer.com), Merck (www.merck.com), and Novartis
(www.novartis.com).
The mission of the drug safety group, whether in
a company or a health agency, is first and foremost
to protect the public health by maintaining accurate,
up-to-date, and complete safety information. Medical
analyses must be done with patient safety in mind, not
“product and sales protection”. It is argued that the best
product and sales protection comes from ensuring that
full, unbiased, scientific, and complete safety informa-
tion is available to all stakeholders: patients, medical
professionals, health agencies, and the company in a
6 Cobert’s Manual of Drug Safety and Pharmacovigilance
form that can be understood by the particular target
audience. Secondary goals within a company’s safety
department relate to such corporate functions as con-
sultation within the company on safety issues, legal
matters including litigation, response to patient and
healthcare professional queries, training, and support-
ing the sales force.
There is often enormous pressure on the safety
group to minimize or wait on safety issues until they
are proved beyond a shadow of a doubt. The attitude
that the “drug is innocent until proven guilty” and
those safety warnings should not be issued to the health
agency or the public until this point is reached is not at
all appropriate in the world of safety. Rather, each safety
issue must be evaluated and acted on because of its
own merit and criticality in a timely fashion to evaluate
and minimize risk. This can become quite challenging
because risk must be considered in the context of ben-
efit and alternatives. Some problems must be addressed
on Friday at 5 p.m. and over the weekend.
In the corporate world, this attitude runs contrary
to the prevailing fiduciary obligation of a corpora-
tion (“to increase stockholder value by making more
profit”). The personnel in the drug safety department
need a fairly thick skin to work in this non-glorious
field, unlike the world of clinical research or sales
where there are congratulations (and monetary rewards
and bonuses) for completing a study, getting drugs
approved, or selling more product. Rather, drug safety
personnel need strong backbones to be able to say to
management that a product has a safety problem that
must be acted on immediately or tracked until more
data are in. Sometimes expensive studies are required
and the outcome may merely strengthen the evidence
of a problem. Good and wise corporate management
understands this and welcomes “straight talk” from the
safety unit. Bad management buries or delays. This is
becoming more dangerous as the penalties (commer-
cial, regulatory, and legal) are becoming more severe
and bad behavior goes viral on the internet overnight.
It should be noted that the concept of drug safety
is often less well understood and less well developed
in small start-up companies with only a small number
of employees. Their primary task is to develop one or
a few drugs and their goal is to complete trials rap-
idly and either sell the product to another company
for further development (e.g., large phase III trials) or
get rapid FDA approval with the goal of getting pos-
itive cash flow. These companies usually do not have
a safety department and sometimes do not even have
anyone specifically handling safety or tracking regula-
tions and new requirements. They usually rely on their
partners or CROs. They often do not handle safety well
and when safety issues or crises occur, they have sig-
nificant problems often requiring external “emergency”
assistance to help resolve the issues.
It is hoped that corporate executives will realize
that a safety problem hidden in the short run may, in
the long run, appear on the front page of the New York
Times, on TV or go viral on the Internet, or the six
o’clock news. They may need to explain their actions to
governmental investigation panels and to the multiple
lawsuits — class action, civil, and criminal — that are
frequent in the US and, increasingly, now pop up else-
where in the world on any safety-related issue.
Similarly, the role of drug safety in the health
agency is difficult. The primary mission is similar to
the corporate safety role: to protect the public health.
However, the profit-making motive is not present.
Instead, there are always intense budget pressures to
save money as well as the need to answer to multiple
demanding constituencies: in the US, the FDA answers
in one way or another to the Secretary of Health and
Human Services, the US Congress, the public, the press,
patient advocacy groups, the Internet blogosphere, the
health professions, and the companies (and lobbies) the
HAregulates. Similar political pressures exist for other
agencies around the world.
Frequently Asked Questions
Q: Why would anyone want to work in drug
safety?
A: Good question. Some of us “stumbled” into research
during post-collegiate years, and then further “stumbled”
into drug safety, found their passion and stayed. Some
of us who decided not to be HCPs, but still wanted to
serve in the public health sector, found drug safety to be
a way of ensuring compliance by companies and feel it
provides a service to the public by constantly monitoring
for changes to the safety and efficacy of the product.
The History and Theory of Drug Safety and Pharmacovigilance 7
Some healthcare professionals decide to move out of
direct clinical care, either due to stress, hours, or a
combination of both, and find industrial/pharmaceuti-
cal medicine. Unlike the “glamor” of clinical research,
where new and exciting drugs are tested, drug safety
tends to have a different atmosphere, dealing with the
problems of the new and exciting (and old and dull)
drugs.
There is much more detective work and medical
analysis in working hard to obtain all the clinical facts
available, perform a defensible medical analysis, and
come to a medically sound conclusion often based on
incomplete (or even misleading) data. The work can be
quite academic when one is working up a complex sig-
nal or risk evaluation/mitigation plan. And as always
in medicine, one never has enough information. There
is always one more test or examination one could do
to get closer to the truth. Like the clinician, the drug
safety worker is usually dealing with uncertainty and
must still make rapid and often irreversible decisions.
Yet given the data available, one must come to the med-
ically proper and defensible conclusion and convey this
in a cogent way to both medical and non-medical peo-
ple. The work is challenging and fulfilling when done
well.
The ethical issues come up when clear, compel-
ling safety arguments calling for action are made and
no action is forthcoming from management. This puts
drug safety personnel in awkward and sometimes
legally risky positions.
There is also much drama and excitement. Much
can be routine, but the next e-mail or Tweet may bring
a disaster with widespread consequences if the sig-
nal bears out. The adrenaline level rises and the “cri-
sis” team mobilizes. The drug safety department is the
emergency room of the company. Those who perform
drug safety as a career are often passionate about it. Few
decide at the outset of a pharmaceutical career that they
want to “do side effects”. Rather, they want to discover
new drugs or do clinical research or study the pharma-
cology of drugs. Many come into drug safety after trying
other areas in the industry and discover they love it.
There are a few downsides that should be noted.
If one wants to move high up in a company’s hierar-
chy this is not a good path for advancement. Of course,
one can move up within the safety area with the top
job usually being the Vice President of Drug Safety and
Pharmacovigilance. However, the people who move up
to the executive levels and other high positions almost
never come from safety. These positions usually go to
marketers, sales, research, legal and other non-safety
positions. On the other hand, few people from these
areas are clamoring for your job in safety!
Within the company, some people will be wary
when they talk or interact with safety people fearing
that they might say something that can get them into a
delicate position. “Water cooler conversation” usually
stops when the PV person approaches.
There is a lot of interaction with legal and regula-
tory. Sometimes these interactions are fine, sometimes
adversarial and sometimes very guarded. People in other
sections of the company may have (unstated) agendas
that differ from what you might expect.
Finally, sometimes they do “kill the messenger”!
Q: Is there not an inherent conflict of interest
in asking a company to police itself?
A: In a sense yes, especially when money is involved.
Most regulated professions have some level of self-
policing, including aviation, banking and finance, the
food industry, medicine, and law. The results of self-
policing have not always been happy. Thus, there
must be some level of outside oversight to ensure that
self-policing is done correctly. Finding the right bal-
ance is always the trick. In practice, there is far too
much to do and oversee in the pharmaceutical indus-
try to have total outside oversight from health agen-
cies. Rather, practicalities force the system to police
itself with regulations, periodic reports, monitoring,
reviews, audits, and other mechanisms looking over
the industry’s shoulder to “keep it honest”. In recent
times, following terrible banking and investment scan-
dals, there is a strong tendency toward risk aversion
and the demand that there be more regulation and
control “to prevent another (fill in your own crisis:
Oxycontin,Vioxx, AIG, Madoff, earthquake, Covid
etc.)”. Thus, we are likely to see more regulation and
perhaps less risk-taking. Whether or not more regula-
tion will lead to better outcomes (i.e., “safer” drugs)
remains to be seen.
CHAPTER
9
2
Primary definitions
relevant to Safety &
Pharmacovigilance
W
hat is an adverse event (AE)? A
serious AE (SAE)? An adverse
drug reaction (ADR)? A sus-
pected, unexpected, serious adverse
reaction (SUSAR)? A suspected,
expected, serious adverse reaction?
What do expected, unexpected, listed
and unlisted mean?
Note: Unless otherwise noted, the words “drug”
or “drug product” or “medicinal product” should
be taken in this book to include “biologics”,
“Combination products”, and “vaccines”, too.
Introduction
Clinical research and the product development industry
contain too many terms to fully outline in this text. This
chapter intends to focus on only the primary definitions
and terms relevant to safety and pharmacovigilance that
deserve clarification and must be understood to achieve
the goals of this science. It is hard enough to explain
to “outsiders” what “clinical safety and pharmacovigi-
lance” means, so it is even more important for those of
us within this profession have a unified understanding
of the primary terms relevant to this science to function
properly. An exhaustive Glossary can be downloaded
from the EMA website. (https://www.ema.europa.eu/en/
about-us/glossaries)
The Theory
To operate consistently in any area, be it construction,
law enforcement, education, and including product
development of any kind, one must fully understand
and abide by definitions and standards to ensure unity
and understanding from person to person. Defini-
tions and standards guide individuals with a universal
understanding of any given task or function and are