1. DEVELOPMENT&
REGULATION OF DRUGS
Dr. Mahmoud Naga
JANUARY 1, 2018
ST. HIND ALSHANKITI
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2. Development& Regulation of Drugs
The development of a drug from an initial idea to its entry into the
market is a very complex process which can take around 5-10 years
and cost billions. The idea for a new development can come from a
variety of sources which include the current necessities of the market,
new emerging diseases, academic and clinical research, etc... Once a
target for discovery has been chosen, the pharmaceutical industries or
the associated academic centers work on the early processes to
identify the chemical molecules with suitable characteristics to make
the targeted drugs
1. DRUG DISCOVERY
The discovery of a new chemical entity that modifies a cell or tissue
function is but the first step in the drug development process. Once
shown to be effective and selective, a compound which is to be
discovered must be completely free of toxicity, should have good
bioavailability and marketable before it can be considered to be a
therapeutic entity
Figure 1 the development of drugs

3. IDEA
Typically, researchers discover new drugs through:
(1) identification or elucidation of a new drug target. (2) rational design of a
new molecule based on an understanding of biologic mechanisms and drug
receptor structure. (3) screening for biologic activity of large numbers of natural
products, banks of previously. discovered chemical entities, or large libraries of
peptides, nucleic acids, and other organic molecules. (4) chemical modification
of a known active molecule, resulting in a me-too analog. (Muntha, 2016)
Once a new drug target or promising molecule has been identified, the process
of moving from the basic science laboratory to the clinic begins. This
translational research involves the preclinical and clinical steps.
2. DEVOLEPMENT
Drug development takes place in many stages and these stages are under
management of FDA
what is FDA
The FDA is the administrative body that oversees the drug evaluation process in
the USA and grants approval for marketing of new drug products.
To receive FDA approval for marketing, the originating institution or company
(almost always the latter) must submit evidence of safety and effectiveness.
Outside the USA, the regulatory and drug approval process is generally similar
to that in the USA. The FDA’s authority to regulate drugs derives from specific
legislation. If a drug has not been shown through adequately controlled testing
to be “safe and effective” for a specific use, it cannot be marketed in interstate
commerce for this use. (FDA, 2018 )
IND: The United States Food and Drug Administration's Investigational New
Drug
NDA: The NDA application is the vehicle through which drug sponsors
formally propose that the FDA approve a new pharmaceutical for sale and
marketing in the U.S.

4. DRUG SCREENING
Drug screening is the process by which potential drugs are identified and
optimized before selection of a candidate drug to progress to marketing. It can
involve screening large libraries of chemicals for a particular biological activity
in high-throughput screening assays. And it’s divided into 2 types: in-vitro which is
proceed in lab and in-vivo which is preclinical and then clinical test (trails)
1. PRECLINICAL SAFETY & TOXICITY TESTING
Drugs are always toxic at some dose. the process which seeks to define the
toxicities of drugs and the therapeutic index of it comparing to its benefits and
risks is an essential part of the new drug discovery. The goals of preclinical
toxicity studies include identifying potential human toxicities, designing tests to
further define the toxic mechanisms, and predicting the most relevant toxicities
to be monitored in clinical trials.
Acute toxicity
testing
Acute toxicity testing is carried out to determine the effect of a
single dose on a particular animal species. In general, it is
recommended that acute toxicity testing be carried out with two
different animal species (one rodent and one no rodent). In acute
toxicological testing, the investigational product is administered at
different dose levels, and the effect is observed for 14 days. All
mortalities caused by the investigational product during the
experimental period are recorded and morphological, biochemical,
pathological, and histological changes in the dead animals are
investigated. (Parasuraman, 2011 )
Mutagenicity
testing
is used to assess submicroscopic changes in the base sequence of
DNA, chromosomal aberrations, and structural aberrations in DNA
including duplications, insertions, inversions, and translocations.
(Parasuraman, 2011 )
Effect on
reproductive
performance
Two species, usually one rodent and rabbits. Test effects on animal
mating behavior, reproduction, parturition, progeny, birth defects,
postnatal development. (Bertram G. Katzung, 2012)
Chronic
toxicity testing
Chronic toxicity studies are conducted with a minimum of one
rodent and one no rodent species. The test compound is
administered over more than 90 days, and the animals are observed
periodically. A chronic toxicology study provides inferences about
the long-term effect of a test substance in animals, and it may be
extrapolated to the human safety of the test substance.
(Parasuraman, 2011 )

5. approximately 50% of the animals. Presently, the LD50 is estimated from the
smallest number of animals possible. These doses are used to calculate the
initial dose to be tried in humans, usually taken as one hundredth to one tenth of
the no-effect dose in animals. (Bertram G. Katzung, 2012)
2. Clinical Trials.
In a clinical trial, participants receive specific interventions according to the
research plan or protocol created by the investigators. Clinical trials used in
drug development are sometimes described by phase. These phases are defined
by the Food and Drug Administration (FDA).
Once a new drug is judged ready to be studied in humans, a Notice of Claimed
Investigational Exemption for a New Drug (IND) must be filed with the FDA
The IND includes (1) information on the composition and source of the drug,
Carcinogenicity
testing
Both rodents and no rodent animal species may be used in
carcinogenicity testing. The tests are carried out over the greater
portion of an animal's lifespan. During and after exposure to test
substances, the experimental animals are observed for signs of
toxicity and development of tumors. If these are not found, a test
may be terminated after 18 months in the case of mice and hamsters
and after 24 months with rats. If the animals are healthy,
hematological analysis is performed after the 12 months and the 18
months, respectively, and the study is terminated. The animals are
sacrificed, and gross pathological changes are noted, and
histopathological studies are carried out on all the tissues.
(Parasuraman, 2011 )
Table 1 Toxicity testes

6. (2) chemical and manufacturing information, (3) all data from animal studies,
(4) proposed plans for clinical trials, (5) the names and credentials of physicians
who will conduct the clinical trials, and (6) a compilation of the key data
relevant to study of the drug in humans that has been made available to
investigators and their institutional review boards.
It must pass 4 phases, 3 to get the approval from FDA and the 4th is
post-marketing
Phase I
studies assess the safety of a drug or device. This initial phase of testing, which
can take several months to complete, usually includes a small number of healthy
volunteers (20 to 100), who are generally paid for participating in the study. The
study is designed to determine the effects of the drug or device on humans
including how it is absorbed, metabolized, and excreted. This phase also
investigates the side effects that occur as dosage levels are increased. About
70% of experimental drugs pass this phase of testing. (Overview of Clinical
Trials, 2014-2015)
Phase II
studies test the efficacy of a drug or device. This second phase of
testing can last from several months to two years and involves up to
several hundred patients. Most phase II studies are randomized trials
where one group of patients receives the experimental drug, while a
second "control" group receives a standard treatment or placebo. Often

7. these studies are "blinded" which means that neither the patients nor the
researchers know who has received the experimental drug. This allows
investigators to provide the pharmaceutical company and the FDA with
comparative information about the relative safety and effectiveness of the new
drug. About one-third of experimental drugs successfully complete both Phase I
and Phase II studies. (Overview of Clinical Trials, 2014-2015)
Phase III
studies involve randomized and blind testing in several hundred to several
thousand patients. This large-scale testing, which can last several years,
provides the pharmaceutical company and the FDA with a more thorough
understanding of the effectiveness of the drug or device, the benefits and the
range of possible adverse reactions. 70% to 90% of drugs that enter Phase III
studies successfully complete this phase of testing. Once Phase III is complete,
a pharmaceutical company can request FDA approval for marketing the drug.
(Overview of Clinical Trials, 2014-2015)
3- MARKETING
After marketing, the drug is still in monitoring to either complete phase IV
or to pulled from the market if it fails.
Phase IV
studies, often called Post Marketing Surveillance Trials, are conducted after a
drug or device has been approved for consumer sale. Pharmaceutical companies
have several objectives at this stage: (1) to compare a drug with other drugs
already in the market; (2) to monitor a drug's long-term effectiveness and
impact on a patient's quality of life; and (3) to determine the cost-effectiveness
of a drug therapy relative to other traditional and new therapies. Phase IV
studies can result in a drug or device being taken off the market or restrictions
of use could be placed on the product depending on the findings in the study.
(Overview of Clinical Trials, 2014-2015)
Reasons for Pulling a Drug from the Market
Risk of Health Problems - Sometimes further study reveals a connection
between taking a drug and a potential health problem. Some pharmaceutical

8. drugs have been linked to an increased risk of heart attack, stroke, kidney
failure, and other serious complications.
Risk of Health Problems - Sometimes further study reveals a connection
between taking a drug and a potential health problem. Some pharmaceutical
drugs have been linked to an increased risk of heart attack, stroke, kidney
failure, and other serious complications.
Previously Unknown Drug Interactions - Mixing drugs can cause health
problems. Sometimes a drug may be discovered to cause problems when taken
with another drug, a certain type of vitamin, or certain foods.
Manufacturing and Packaging Errors - Sometimes a problem at the factory
will require a recall. A contamination problem may make a drug unsafe for
consumption, or a packaging error may unseal a drug before it reaches the
patient.
Patent application
The time from the filing of a patent application to approval for marketing of a
new drug may be 5 years or considerably longer. Since the lifetime of a patent is
20 years in the USA, the owner of the patent (usually a pharmaceutical
company) has exclusive rights for marketing the product for only a limited time
after approval of the new drug application. Because the FDA review process
can be lengthy, the time consumed by the review is sometimes added to the
patent life. However, the extension (up to 5 years) cannot increase the total life
of the patent to more than 14 years after approval of a new drug application. As
of 2005, the average effective patent life for major pharmaceuticals was 11
years. After expiration of the patent, any company may produce the drug, file an
abbreviated new drug application (ANDA), demonstrate required equivalence,
and, with FDA approval, market the drug as a generic product without paying
license fees to the original patent owner. (Bertram G. Katzung, 2012)
REFERENCES
Bertram G. Katzung, S. B. (2012). Basic & Clinical Pharmacology Twelfth Edition. McGraw-
Hill.
FDA. (2018 , 03 16). Retrieved from FDA.
Muntha, P. (2016, 06 04). Drug Discovery & Development. Retrieved from Research &
Reviews in Pharmacy and Pharmaceutical Sciences.
Overview of Clinical Trials. (2014-2015). Retrieved from CenterWatch.
Parasuraman, S. (2011 ). Toxicological screening. J Pharmacol Pharmacother, 74–79.