DEVELOPMENT OF NEW DRUGS

Dosen Pengampu : Novia Sinata, M.Si, Apt

Kelompok 3
1. Fazri perdana (1501071)

2. Ira Fazira (1801056

3. Nurul Latifah (1801064)

4. Putri Zahra (1801066)

5. Syalshabillah (1801074)

SEKOLAH TINGGI ILMU FARMASI RIAU

DEVELOPMENT OF NEW
DRUGS
New drugs have revolutionized the practice of
medicine, converting many once fatal or
debilitating diseases into manageable therapeutic
exercises.
 Among the first steps in the development of
a new drug is the discovery of synthesis of a
potensial new drug molecule and seeking and
understanding of its interaction (mechanism)
with the appropriate biologic target. Repeated
application of this approach leads to compounds
with increased potency and selectivity (figure 5-
1).
 By law, the safety and efficacy of drug must
be defined before marketing. In addition to in
vitro studies, relevant biologic effects, drug
metabolism, and pharmacokinetic profiles and
particulary and assessment of the relative safety
of the drug must be characterized in animals
before human drug trial can be started.
 With regulatory approval, human testing
can then go forward in three phases before the drug
can be considered for approval for general use. A
fourth phase of data gathering and safety
monitoring is becoming increasingly important and
follows after approval for general use.
DRUG DISCOVERY
Most new drugs or drug products are discovered
or developed through one or more of six
approaches:

1. Identification or elucidation of a
new drug target

2. Rational drug design of a new drug based

on an understanding of biologic mechanisms,
drug receptor structure, and drug structure

3. Chemical modification of a known

molecule
 4. Screening for biologic activity of large
numbers of natural products, banks of
previously discovered chemical entities, and
large libraries of peptides, nucleic acids, and
other organic molecules

5.Biotechnology and cloning using genes to

produce peptides and proteins. Efforts
continue to focus on the discovery of new
targets and approaches, from studies with
genomics, proteomics, nucleic acids and
molecular pharmacology for drug therapy.
Significantly increasing the number of
useful disease targets should be a positive
driver for new and improved drugs.

6. Combinations of known drugs to

obtain additive or synergistic effects
or a repositioning of a known drug for
a new therapeutic use.
DRUG SCREENING

Regardless of the source or the key idea

leading to a drug candidate molecule, testing it
involves a sequence of iterative experimentation
and characterization called drug screening. A
variety of biologic assays at the molecular,
cellular, organ system, and whole animal levels
are used to define the activity and selectivity of
the drug (Table 5–1).
 The type and number of initial screening
tests depend on the pharmacologic and
therapeutic goal. Anti-infective drugs may be
tested against a variety of infectious organisms
some of which are resistant to standard agents,
hypoglycemic drugs for their ability to lower
blood sugar, etc. In addition, the molecule will
also be studied for a broad array of other actions
to establish the mechanism of action and
selectivity of the drug. This has the advantage of
demonstrating both suspected and unsuspected
toxic effects.
 Occasionally, an unsuspected therapeutic
action is serendipitously discovered by the careful
observer. The selection of molecules for further
study is most efficiently conducted in animal
models of human disease. Where good predictive
preclinical models exist (eg, antibacterials,
hypertension or thrombotic disease), we generally
have adequate drugs. Good drugs or breakthough
improvements are conspicuously lacking and
slow for diseases for which pre-clinical models
are poor, or not yet available, eg, Alzheimer's
disease.
PRECLINICAL SAFETY & TOXICITY
TESTING

All drugs are toxic at some dose . Seeking to

correctly define the limiting toxicities of drugs
and the therapeutic index comparing benefits
and risks of a new drug might be argued as the
most essential part of the new drug development
process. Most drug candidates fail to reach the
market, but the art of drug discovery and
development is the effective assessment and
management of risk and not total risk avoidance.
 Candidate drugs that survive the initial
screening and profiling procedures must be
carefully evaluated for potential risks before and
during clinical testing. Although no chemical can
be certified as completely "safe" (free of risk), the
objective is to estimate the risk associated with
exposure to the drug candidate and to consider
this in the context of therapeutic needs and
duration of likely drug use.
IT IS IMPORTANT TO RECOGNIZE THE
LIMITATIONS OF PRECLINICAL TESTING.
THESE INCLUDE THE FOLLOWING:
1. Toxicity testing is time-consuming and
expensive. Two to 6 years may be required to
collect and analyze data on toxicity and estimates
of therapeutic index (a comparison of the amount
that causes the desired therapeutic effect to the
amount that causes toxic effects, see Chapter 2)
before the drug can be considered ready for
testing in humans.
2. Large numbers of animals may be needed to
obtain valid preclinical data. Scientists are
properly concerned about this situation, and
progress has been made toward reducing the
numbers required while still obtaining valid
data. Cell and tissue culture in vitro methods are
increasingly being used, but their predictive
value is still severely limited. Nevertheless, some
segments of the public attempt to halt all animal
testing in the unfounded belief that it has become
unnecessary.
3. Extrapolations of therapeutic index and
toxicity data from animals to humans are
reasonably predictive for many but not for all
toxicities. Seeking an improved process, a
Predictive Safety Testing Consortium of five of
America's largest pharmaceutical companies with
an advisory role by the Food and Drug
Administration (FDA) has been formed to share
internally developed laboratory methods to
predict the safety of new treatments before they
are tested in humans.
4. For statistical reasons, rare adverse effects are
unlikely to be detected.
EVALUATION IN HUMANS
Less than one third of the drugs tested in clinical
trials reach the marketplace. Federal law in the
USA and ethical considerations require that the
study of new drugs in humans be conducted in
accordance with stringent guidelines.
Scientifically valid results are not guaranteed
simply by conforming to government regulations,
however, and the design and execution of a good
clinical trial require interdisciplinary personnel
including basic scientists, clinical pharmacologists,
clinician specialists, statisticians, and frequently
others. The need for careful design and execution is
based on three major confounding factors inherent
in the study of any drug in humans
Confounding Factors in Clinical Trials
 THE VARIABLE NATURAL HISTORY OF MOST
DISEASES
Many diseases tend to wax and wane in severity;
some disappear spontaneously, even, on occasion,
malignant neoplasms. Further protection against
errors of interpretation caused by disease fluctuations
is provided by using a crossover design, which consists
of alternating periods of administration of test drug,
placebo preparation (the control), and the standard
treatment (positive control), if any, in each subject.
These sequences are systematically varied, so that
different subsets of patients receive each of the
possible sequences of treatment
 THE PRESENCE OF OTHER DISEASES AND RISK
FACTORS
Known and unknown diseases and risk factors
(including lifestyles of subjects) may influence the
results ofa clinical study. For example, some diseases
alter the pharmacokinetics of drugs (see Chapters 3
and 4). Concentrations of a blood or tissue component
being monitored as a measure of the effect of the new
agent may be influenced by other diseases or other
drugs.
 Attempts to avoid this hazard usually involve the
crossover technique (when feasible) and proper
selection and assignment of patients to each of the
study groups. This requires obtaining accurate medical
and pharmacologic histories (including use of
recreational drugs) and the use of statistically valid
methods of randomization in assigning subjects to
particular study groups.
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.
Clinical Trials: The IND & NDA
Once a 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, (2) chemical and manufacturing
information, (3) all data from animal studies, (4)
proposed clinical plans and protocols, (5) the names
and credentials of physicians who will conduct the
clinical trials, and (6) a compilation of the key data
relevant to study the drug in man made available to
investigators and their institutional review boards.
It often requires 4–6 years of clinical testing to
accumulate and analyze all required data.
Testing in humans is begun after sufficient
acute and subacute animal toxicity studies
have been completed. Chronic safety testing in
animals, including carcinogenicity studies, is
usually done concurrently with clinical trials.
In each of the three formal phases of clinical
trials, volunteers or patients must be informed
of the investigational status of the drug as well
as the possible risks and must be allowed to
decline or to consent to participate and receive
the drug.
 Phase 1 :
 the effects of the drug as a function of dosage are
established in a small number (25–50) of healthy
volunteers.
 Although a goal is to find the maximum tolerated dose,
the study is designed to avoid severe toxicity.
 These trials are nonblind or "open“
Phase 2
 is studied in patients with the target disease to
determine its efficacy.
 A single-blind design is often used, with an
inert placebo medication and an established
active drug (positive control) in addition to the
investigational agent.
 Phase 2 trials are usually done in special
clinical centers (eg, university hospitals).
 A broader range of toxicities may be detected
in this phase.
Phase 3
 the drug is evaluated in much larger numbers of patients
with the target disease sometimes thousands to further
establish safety and efficacy.
 phase 3 trials are designed to minimize errors caused by
placebo effects, variable course of the disease.
 double-blind and crossover techniques are frequently
used.
 Phase 3 studies can be difficult to design and execute and
are usually expensive because of the large numbers of
patients involved and the masses of data that must be
collected and analyzed.
 If phase 3 results meet expectations, application is made
for permission to market the new agent. Marketing
approval requires submission of a New Drug Application
(NDA) to the FDA.
Phase 4
 Once approval to market a drug has been obtained,
phase 4 begins.
 This constitutes monitoring the safety of the new drug
under actual conditions of use in large numbers of
patients.
THANK YOU