1. STAGES OF DRUG DEVELOPMENT
(USA MODEL)
BY
DR. JOSEPH OYEPATA SIMEON
(PH.D)

2. Stages of drug development
Drug development process
Drug development: is the process of bringing a new pharmaceutical drug to the market
once a lead compound has been identified through the process of drug discovery. Any
drug development process must proceed through several stages in order to produce a
product that is safe, efficacious, and has passed all regulatory requirements.
Detailed Stages of Drug Development
1. Discovery and Development
2. Preclinical Research
3. Investigational New Drug (IND) Application Filing
4. Clinical Research/ Clinical Trial Phase Studies
Stage 1: DISCOVERY AND DEVELOPMENT

3. Discovery The first step in the drug development process involves discovery work.
Discovery often begins with target identification – choosing a biochemical mechanism
involved in a disease condition. Drug candidates, discovered in academic and
pharmaceutical or biotech research labs, are tested for their interaction with the drug
target. Typically, researchers discover new drugs through: New insights into a disease
process that allow researchers to design a product to stop or reverse the effects of the
disease. Many tests of molecular compounds to find possible beneficial effects against
any of a large number of diseases. Existing treatments that have unanticipated effects.
New technologies, such as those that provide new ways to target medical products to
specific sites within the body or to manipulate genetic material.
At this stage in the process, thousands of compounds may be potential candidates for
development as a medical treatment. After early testing, however, only a small number of
compounds look promising and call for further study.
Development Once researchers identify a promising compound for development, they
conduct experiments to gather information on: 1. How it is absorbed, distributed,
metabolized, and excreted. 2. Its potential benefits and mechanisms of action. 3. The best
dosage form. 4. The best way to give the drug (such as by mouth or injection). 5. Side
effects or adverse events that can often be referred to as toxicity. 6. How it affects
different groups of people (such as by gender, race, or ethnicity) differently. 7. How it
interacts with other drugs and treatments. 8. Its effectiveness as compared with similar
drugs.
Stage 2: PRECLINICAL RESEARCH
Preclinical research refers to the testing of a new drug, biological procedure or a
treatment in animal models before trials may be carried out in humans. Before testing a
new drug in people, researchers must find out whether it has the potential to cause serious
harm, called toxicity. Preclinical Toxicology Testing Preclinical testing analyzes the
bioactivity, safety, and efficacy of the formulated drug product. This testing is critical to
a drug’s eventual success and, as such, is scrutinized by many regulatory entities. During
the preclinical stage of the development process, plans for clinical trials and an
Investigative New Drug (IND) application are prepared. Studies taking place during the
preclinical stage should be designed to support the clinical studies that will follow. The
main purpose of preclinical toxicology testing is: 1. Evaluate acute and short term
toxicity in animals (one rodent, one non- rodent). – Dose at increasingly high levels to
induce toxicity. – Determine lethal dose. – Dose at normal levels for short and long
term. 2. Assess how drug is absorbed, distributed, metabolized, and excreted in animals
Stages of Preclinical Toxicology Testing The main stages of preclinical toxicology
testing are: Acute Studies Acute tox studies look at the effects of one or more doses

4. administered over a period of up to 24 hours. The goal is to determine toxic dose levels
and observe clinical indications of toxicity. Usually, at least two mammalian species are
tested. Data from acute tox studies helps determine doses for repeated dose studies in
animals and Phase I studies in humans. Repeated Dose Studies Depending on the
duration of the studies, repeated dose studies may be referred to as subacute, subchronic,
or chronic. The specific duration should anticipate the length of the clinical trial that will
be conducted on the new drug. Again, two species are typically required.
Genetic Toxicity Studies These studies assess the likelihood that the drug compound is
mutagenic or carcinogenic. Procedures such as the Ames test (conducted in bacteria)
detect genetic changes. DNA damage is assessed in tests using mammalian cells such as
the Mouse Micronucleus Test. The Chromosomal Aberration Test and similar procedures
detect damage at the chromosomal level.
There are two types of preclinical research: In Vitro and In Vivo. In vitro testing
examines the drug molecules' interactions in test tubes and within the lab setting. In vivo
testing involves testing the drug molecules on animal models and in other living cell
cultures. Although efficacy is beginning to be established here, safety is uncertain. This is
the stage where only 1 to 5 lead compounds are chosen between thousands of drug
molecule candidates. By the time preclinical research has been ended, many years have
often passed. However, this study provides detailed information on dosing and toxicity
levels of new drug candidate. After preclinical testing, researchers review their findings
and decide whether the drug should be tested in people. The information is gathered from
this preclinical testing, as well as information on chemistry, manufacturing, and control
(CMC), and submitted to regulatory authorities (in the US, to the FDA), as
an Investigational New Drug (IND) application. If the IND is approved, development
moves to the clinical phase.
CLINICAL RESEARCH
“Clinical research” refers to studies or trials that are done in human. This stage includes,
Designing Clinical Trials, Clinical Research Phase Studies, The Investigational New
Drug (IND) Process Asking for regulatory agent assistance e.g. FDA Assistance (for
USA)
DESIGNING CLINICAL TRIALS Researchers design clinical trials to answer specific
research questions related to a medical product. These trials follow a specific study plan,
called a protocol that is developed by the researcher or manufacturer. Before a clinical
trial begins, researchers review prior information about the drug to develop research
questions and objectives. Then, they decide: 1. Who qualifies to participate (selection
criteria) 2. How many people will be part of the study 3. How long the study will last 4.

5. Whether there will be a control group and other ways to limit research bias 5. How the
drug will be given to patients and at what dosage 6. What assessments will be conducted,
when, and what data will be collected 7. How the data will be reviewed and analyzed
Clinical trials follow a typical series from early, small-scale, Phase 1 studies to late,
large- scale, Phase 3 studies.
CLINICAL RESEARCH PHASE STUDIES Phase 1 Clinical Development (Human
Pharmacology): Phase I studies are used to evaluate pharmacokinetic parameters and
tolerance, generally in healthy volunteers. These studies include initial single-dose
studies, dose escalation and short-term repeated-dose studies.
Study Participants: 20 to 100 healthy volunteers or people with the disease/condition.
Length of Study: Several months
Purpose: Determining safety and dosage. During Phase 1 studies, researchers test a new
drug in normal volunteers (healthy people). However, if a new drug is intended for use in
cancer patients, researchers conduct Phase 1 studies in patients with that type of cancer.
Phase 1 studies are closely monitored and gather information about how a drug interacts
with the human body. Researchers adjust dosing schemes based on animal data to find
out how much of a drug the body can tolerate and what its acute side effects are. As a
Phase 1 trial continues, researchers answer research questions related to how it works in
the body, the side effects associated with increased dosage, and early information about
how effective it is to determine how best to administer the drug to limit risks and
maximize possible benefits. This is important to the design of Phase 2 studies.
Approximately 70% of drugs move to the next phase.
Phase 2 Clinical Development (Therapeutic Exploratory) Phase II clinical studies are
small-scale trials to evaluate a drug’s preliminary efficacy and side-effect profile in 100
to 250 patients. Additional safety and clinical pharmacology studies are also included in
this category.
Study Participants: 100 to 250
Length of Study: Several months to 2 years
Purpose: Evaluate Efficacy/effectiveness, look for side effects. In Phase 2 studies,
researchers administer the drug to a group of patients with the disease or condition for
which the drug is being developed. Typically involving a few hundred patients, these
studies aren't large enough to show whether the drug will be beneficial. Instead, Phase 2
studies provide researchers with additional safety data. Researchers use these data to

6. refine research questions, develop research methods, and design new Phase 3 research
protocols. Approximately 33% of drugs move to the next phase.
Phase 3 Clinical Development (Therapeutic Confirmatory) Phase III studies are large-
scale clinical trials for safety and efficacy in large patient populations. While phase III
studies are in progress, preparations are made for submitting the Biologics License
Application (BLA) or the New Drug Application (NDA).
Study Participants: 300 to 3,000 volunteers who have the disease or condition
Length of Study: 1 to 4 years.
Purpose: Confirm effectiveness, monitoring of adverse reactions for long term use.
Researchers design Phase 3 studies to demonstrate whether or not a product offers a
treatment benefit to a specific population. Phase 3 studies provide most of the safety data.
In previous studies, it is possible that less common side effects might have gone
undetected. Because these studies are larger and longer in duration, the results are more
likely to show long-term or rare side effects. Approximately 25-30% of drugs move to
the next phase.
Phase 4 Study Participants: Several thousand volunteers who have the disease/condition
Purpose: Safiety and efficacy. Phase 4 trials are carried out once the drug or device has
been approved by FDA during the Post-Market Safety Monitoring. The Investigational
New Drug (IND) Application Filing Drug developers or sponsors must submit an
Investigational New Drug (IND) application file to FDA (food and drug administration)
before beginning human clinical trials. In the IND application, developers must include:
Animal study data and toxicity (side effects that cause great harm) data, Manufacturing
information, Clinical protocols (study plans) for studies to be conducted, Data from any
prior human research, Information about the investingator.
Summary of Clinical phase
Clinical trials involve three or four steps
 Phase I trials, usually in healthy volunteers, determine safety and dosing.
 Phase II trials are used to get an initial reading of efficacy and further explore safety in small
numbers of patients having the disease targeted by the NCE.
 Phase III trials are large, pivotal trials to determine safety and efficacy in sufficiently large
numbers of patients with the targeted disease. If safety and efficacy are adequately proved,
clinical testing may stop at this step and the NCE advances to the new drug
application (NDA) stage.

7.  Phase IV trials are post-approval trials that are sometimes a condition attached by the FDA,
also called post-market surveillance studies.
The process of defining characteristics of the drug does not stop once an NCE (new
chemical entity) begins human clinical trials. In addition to the tests required to move a
novel drug into the clinic for the first time, manufacturers must ensure that any long-term
or chronic toxicities are well-defined, including effects on systems not previously
monitored (fertility, reproduction, immune system, among others). They must also test
the compound for its potential to cause cancer (carcinogenicity testing)
FDA responds to IND applications in one of two ways: 1) Approval to begin clinical
trials 2) Clinical hold to delay or stop the investigation. If FDA is satisfied that the trial
meets Federal standards, the applicant is allowed to proceed with the proposed study.
Stage 4: FDA FINAL REVIEW If a drug developer has evidence from its early tests and
preclinical and clinical research that a drug is safe and effective for its intended use, the
company can file an application to market the drug. The FDA review team thoroughly
examines all submitted data on the drug and makes a decision to approve or not to
approve it. Its purpose is to demonstrate that a drug is safe and effective for its intended
use in the population studied. A drug developer must include everything about a drug—
from preclinical data to Phase 3 trial data—in an NDA. Developers must include reports
on all studies, data, and analyses. Along with clinical results, developers must include: 1.
Proposed labeling 2. Safety updates 3. Drug abuse information 4. Patent information 5.
Any data from studies that may have been conducted outside the United States 6.
Institutional review board compliance information 7. Directions for use
FDA Post-Market Safety Monitoring: Even though clinical trials provide important
information on a drug’s efficacy and safety, it is impossible to have complete information
about the safety of a drug at the time of approval. Despite the rigorous steps in the
process of drug development, limitations exist. Therefore, the true picture of a product’s
safety actually evolves over the months and even years that make up a product’s lifetime
in the marketplace. FDA reviews reports of problems with prescription and over-the-
counter drugs, and can decide to add cautions to the dosage or usage information, as well
as other measures for more serious issues.