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DRUG DEVELOPMENT PROCESS: Stages of Drug Development
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
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
i. Clinical Trial Phase Studies
ii. The IND Process
iii. FDA IND approval
5. FDA Review
i. New Drug Application
ii. Review of The New Drug Application
iii. FDA Final Approval
6. FDA Post-Market Safety Monitoring
Stage 1: DISCOVERY AND DEVELOPMENT
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.
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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.
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
7. How it interacts with other drugs and treatments.
8. Its effectiveness as compared with similar drugs.
When the candidate molecule looks promise as a therapeutic, it must be
characterized—the molecule’s size, shape, strengths and weaknesses, preferred
conditions for maintaining function, toxicity, bioactivity, and bioavailability must be
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determined. Characterization studies undergoes analytical method development and
validation. Early stage pharmacology studies help to characterize the underlying
mechanism of action of the compound.
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-
– 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
Stages Of Preclinical Toxicology Testing
The main stages of preclinical toxicology testing are:
Acute tox studies look at the effects of one or more doses 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
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Genertic 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.
Reproductive Toxicity Studies
Segment I reproductive tox studies look at the effects of the drug on fertility. Segment
II and III studies detect effects on embryonic and post-natal development. In general,
reproductive tox studies must be completed before a drug can be administered to
women of child-bearing age.
Carcinogenicity studies are usually needed only for drugs intended for chronic or
recurring conditions. They are time consuming and expensive, and must be planned
for early in the preclinical testing process.
Bioanalytical laboratory work and bioanalytical method development supports most of
the other activities in the drug development process. The bioanalytical work is key to
proper characterization of the molecule, assay development, developing optimal
methods for cell culture or fermentation, determining process yields, and providing
quality assurance and quality control for the entire development process. It is also
critical for supporting preclinical toxicology/pharmacology testing and clinical trials.
There are two types of preclinical research:
In vitro testing examines the drug molecules' interactions in test tubes and within the
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.
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Stage 3: 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 FDA Assistance
FDA IND Review Team
DESIGNING CLINICAL TRIALS
Researchers design clinical trials to answer specific research questions related to a
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. 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
Length of Study: Several months
Purpose: Determining safety and dosage
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During Phase 1 studies, researchers test a new drug in normal volunteers (healthy
people). In most cases, 20 to 80 healthy volunteers or people with the
disease/condition participate in Phase 1. However, if a new drug is intended for use in
cancer patients, researchers conduct Phase 1 studies in patients with that type of
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
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
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: Up to several hundred people with the disease/condition.
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
Instead, Phase 2 studies provide researchers with additional safety data. Researchers
use these data to refine research questions, develop research methods, and design
new Phase 3 research protocols.
Approximately 33% of drugs move to the next phase.
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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
Researchers design Phase 3 studies to demonstrate whether or not a product offers a
treatment benefit to a specific population. Sometimes known as pivotal studies, these
studies involve 300 to 3,000 participants.
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
Approximately 25-30% of drugs move to the next phase.
Study Participants: Several thousand volunteers who have the disease/condition
Purpose: Safety 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 before beginning human clinical trials.
In the IND application, developers must include:
Animal study data and toxicity (side effects that cause great harm) data
Clinical protocols (study plans) for studies to be conducted
Data from any prior human research
Information about the investigator
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FDA will examine the results from the preclinical test report, look at side effects and
other safety features of the experimental drug and then, if approved, it can move onto
An IND approval is also the point at which a patented drugs' 20-year exclusivity period
Asking for FDA Assistance
Drug developers are free to ask for help from FDA at any point in the drug
development process, including:
Pre-IND application, to review FDA guidance documents and get answers to
questions that may help enhance their research.
After Phase 2, to obtain guidance on the design of large Phase 3 studies
Any time during the process, to obtain an assessment of the IND application
Even though FDA offers extensive technical assistance, drug developers are not
required to take FDA’s suggestions. As long as clinical trials are thoughtfully designed,
reflect what developers know about a product, safeguard participants, and otherwise
meet Federal standards, FDA allows wide latitude in clinical trial design.
FDA IND Review Team
The review team consists of a group of specialists in different scientific fields. Each
member has different responsibilities.
Project Manager: Coordinates the team’s activities throughout the review process,
and is the primary contact for the sponsor.
Medical Officer: Reviews all clinical study information and data before, during, and
after the trial is complete.
Statistician: Interprets clinical trial designs and data, and works closely with the
medical officer to evaluate protocols and safety and efficacy data.
Pharmacologist: Reviews preclinical studies.
Pharmakineticist: Focuses on the drug’s absorption, distribution, metabolism, and
excretion processes. Interprets blood-level data at different time intervals from
clinical trials, as a way to assess drug dosages and administration schedules.
Chemist: Evaluates a drug’s chemical compounds. Analyzes how a drug was made
and its stability, quality control, continuity, the presence of impurities, etc.
Microbiologist: Reviews the data submitted, if the product is an antimicrobial
product, to assess response across different classes of microbes.
The FDA review team has 30 days to review the original IND submission. The process
protects volunteers who participate in clinical trials from unreasonable and significant
risk in clinical trials.
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FDA responds to IND applications in one of two ways:
Approval to begin clinical trials.
Clinical hold to delay or stop the investigation.
FDA can place a clinical hold for specific reasons, including:
1. Participants are exposed to unreasonable or significant risk.
2. Investigators are not qualified.
3. Materials for the volunteer participants are misleading.
4. The IND application does not include enough information about the trial’s
A clinical hold is rare; instead, FDA often provides comments intended to improve the
quality of a clinical trial. In most cases, 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.
Find out how the FDA is Speeding Up the Approval Process-
New Drug Application
A New Drug Application (NDA) tells the full story of a drug. Its purpose is to
demonstrate that a drug is safe and effective for its intended use in the population
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
6. Institutional review board compliance information
7. Directions for use
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FDA Review of The New Drug Application
Once FDA receives an NDA, the review team decides if it is complete. If it is not
complete, the review team can refuse to file the NDA. If it is complete, the review team
has 6 to 10 months to make a decision on whether to approve the drug. The process
includes the following:
Each member of the review team conducts a full review of his or her section of the
application. For example, the medical officer and the statistician review clinical data,
while a pharmacologist reviews the data from animal studies. Within each technical
discipline represented on the team, there is also a supervisory review.
FDA inspectors travel to clinical study sites to conduct a routine inspection. The
Agency looks for evidence of fabrication, manipulation, or withholding of data.
The project manager assembles all individual reviews and other documents, such as
the inspection report, into an “action package.” This document becomes the record for
FDA review. The review team issues a recommendation, and a senior FDA official
makes a decision.
FDA Final Approval
In cases where FDA determines that a drug has been shown to be safe and effective for
its intended use, it is then necessary to work with the applicant to develop and refine
prescribing information. This is referred to as “labeling.” Labeling accurately and
objectively describes the basis for approval and how best to use the drug.
Often, though, remaining issues need to be resolved before the drug can be approved
for marketing. Sometimes FDA requires the developer to address questions based on
existing data. In other cases, FDA requires additional studies. At this point, the
developer can decide whether or not to continue further development. If a developer
disagrees with an FDA decision, there are mechanisms for formal appeal.
FDA Advisory Committees
Often, the NDA contains sufficient data for FDA to determine the safety and
effectiveness of a drug. Sometimes, though, questions arise that require additional
consideration. In these cases, FDA may organize a meeting of one of its Advisory
Committees to get independent, expert advice and to permit the public to make
comments. These Advisory Committees include a Patient Representative that provides
input from the patient perspective. Learn more about FDA Advisory Committees.
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Stage 5: 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,
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.
U.S. Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993