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About Drug Development

Bringing one new drug to the public typically costs a pharmaceutical or biotechnology company on
average more than $1 billion and takes an average of 10 to 15 years. PPD's comprehensive portfolio
of services, spanning preclinical through post-approval, features integrated laboratory, Phase I-IV
and consulting services to provide end-to-end solutions.

Download the .pdf version of the drug development process info graphic(Adobe Acrobat file, 194
Kb).

Expand all FAQs

Drug Discovery and Development

How are new drugs discovered?

New drugs begin in the laboratory with scientists, including chemists and pharmacologists, who
identify cellular and genetic factors that play a role in specific diseases. They search for chemical
and biological substances that target these biological markers and are likely to have drug-like
effects. Out of every 5,000 new compounds identified during the discovery process, approximately
five are considered safe for testing in human volunteers after preclinical evaluations. After three to
six years of further clinical testing in patients, only one of these compounds on average is ultimately
 approved as a marketed drug for treatment. The following sequence of research activities begins the
process that results in development of new medicines:

 Target Identification. Drugs usually act on either cellular or genetic chemicals in the body, known
as targets, which are believed to be associated with disease. Scientists use a variety of techniques
to identify and isolate individual targets to learn more about their functions and how they influence
disease. Compounds are then identified that have various interactions with the drug targets that
might be helpful in treatment of a specific disease.
 Target Prioritization/Validation. To select targets most likely to be useful in the development of
new treatments for disease, researchers analyze and compare each drug target to others based
on their association with a specific disease and their ability to regulate biological and chemical
compounds in the body. Tests are conducted to confirm that interactions with the drug target are
associated with a desired change in the behavior of diseased cells. Research scientists can then
identify compounds that have an effect on the target selected.
 Lead Identification. A lead compound or substance is one that is believed to have potential to
treat disease. Laboratory scientists can compare known substances with new compounds to
determine their likelihood of success. Leads are sometimes developed as collections, or libraries,
of individual molecules that possess properties needed in a new drug. Testing is then done on
each of these molecules to confirm its effect on the drug target.
 Lead Optimization. Lead optimization compares the properties of various lead compounds and
provides information to help biopharmaceutical companies select the compound or compounds
with the greatest potential to be developed into safe and effective medicines. Often during this
same stage of development, lead prioritization studies are conducted in living organisms (in vivo)
and in cells in the test tube (in vitro) to compare various lead compounds and how they are
metabolized and affect the body.
What is required before an investigational drug can be tested in human volunteers?

In the preclinical stage of drug development, an investigational drug must be tested extensively in
the laboratory to ensure it will be safe to administer to humans. Testing at this stage can take from
one to five years and must provide information about the pharmaceutical composition of the drug, its
safety, how the drug will be formulated and manufactured, and how it will be administered to the first
human subjects.

 Preclinical Technology. During the preclinical development of a drug, laboratory tests document
the effect of the investigational drug in living organisms (in vivo) and in cells in the test tube (in
vitro).
 Chemistry Manufacturing and Controls (CMC)/Pharmaceutics. The results of preclinical
testing are used by experts in pharmaceutical methods to determine how to best formulate the
drug for its intended clinical use. For example, a drug that is intended to act on the sinuses may be
formulated as a time-release capsule or as a nasal spray. Regulatory agencies require testing that
documents the characteristics -- chemical composition, purity, quality and potency -- of the drug's
active ingredient and of the formulated drug.
 Pharmacology/Toxicology. Pharmacological testing determines effects of the candidate drug on
the body. Toxicology studies are conducted to identify potential risks to humans.
 In the United States, results of all testing must be provided to the U.S. Food and Drug Administration
(FDA) and/or other appropriate regulatory agencies to obtain permission to begin clinical testing in
humans. Regulatory agencies review the specific tests and documentation required to proceed to
the next stage of development.

How are investigational drugs tested in humans?

Testing of an investigational new drug begins with submission of information about the drug and
application for permission to begin administration to healthy volunteers or patients.

 Investigational New Drug (IND)/Clinical Trial Exception (CTX)/Clinical Trial Authorization

(CTA) Applications. INDs (in the U.S.), CTXs (in the U.K.) and CTAs (in Australia) are examples
of requests submitted to appropriate regulatory authorities for permission to conduct
investigational research. This research can include testing of a new dosage form or new use of a
drug already approved to be marketed.

In addition to obtaining permission from appropriate regulatory authorities, an institutional or

independent review board (IRB) or ethical advisory board must approve the protocol for testing, as
well as the informed consent documents that volunteers sign prior to participating in a clinical study.
An IRB is an independent committee of physicians, community advocates and others that ensures a
clinical trial is ethical and the rights of study participants are protected.

Clinical testing is usually described as consisting of Phase I, Phase II and Phase III clinical studies.
In each successive phase, increasing numbers of patients are tested.

 Phase I Clinical Studies. Phase I studies are designed to verify safety and tolerability of the
candidate drug in humans and typically take six to nine months. These are the first studies
conducted in humans. A small number of subjects, usually from 20 to 100 healthy volunteers, take
the investigational drug for short periods of time. Testing includes observation and careful
documentation of how the drug acts in the body -- how it is absorbed, distributed, metabolized and
excreted.
 Phase II Clinical Studies. Phase II studies are designed to determine effectiveness and further
study the safety of the candidate drug in humans. Depending upon the type of investigational drug
and the condition it treats, this phase of development generally takes from six months to three
years. Testing is conducted with up to several hundred patients suffering from the condition the
investigational drug is designed to treat. This testing determines safety and effectiveness of the
drug in treating the condition and establishes the minimum and maximum effective dose. Most
Phase II clinical trials are randomized, or randomly divided into groups, one of which receives the
investigational drug, one of which gets a placebo containing no medication and sometimes a third
group that receives a current standard treatment to which the new investigational drug will be
compared. In addition, most Phase II studies are double-blinded, meaning that neither patients nor
researchers evaluating the compound know who is receiving the investigational drug or placebo.
 Phase III Clinical Studies. Phase III studies provide expanded testing of effectiveness and safety
of an investigational drug, usually in randomized and blinded clinical trials. Depending on the type
of drug candidate and the condition it treats, this phase usually requires one to four years of
testing. In Phase III, safety and efficacy testing is conducted with several hundred to thousands of
volunteer patients suffering from the condition the investigational drug treats.
 New Drug Application (NDA)/Marketing Authorization Application (MAA)NDAs (in the U.S.)
and MAAs (in the U.K.) are examples of applications to market a new drug. Such applications
document safety and efficacy of the investigational drug and contain all the information collected
during the drug development process. At the conclusion of successful preclinical and clinical
testing, this series of documents is submitted to the FDA in the U.S. or to the applicable regulatory
authorities in other countries. The application must present substantial evidence that the drug will
have the effect it is represented to have when people use it or under the conditions for which it is
prescribed, recommended or suggested in the labeling. Obtaining approval to market a new drug
frequently takes six months to two years.

About Drug Development

Bringing one new drug to the public typically costs a pharmaceutical or biotechnology company on
average more than $1 billion and takes an average of 10 to 15 years. PPD's comprehensive portfolio
of services, spanning preclinical through post-approval, features integrated laboratory, Phase I-IV
and consulting services to provide end-to-end solutions.

Download the .pdf version of the drug development process info graphic(Adobe Acrobat file, 194
Kb).

Expand all FAQs

Drug Discovery and Development

How are new drugs discovered?
 New drugs begin in the laboratory with scientists, including chemists and pharmacologists, who
identify cellular and genetic factors that play a role in specific diseases. They search for chemical
and biological substances that target these biological markers and are likely to have drug-like
effects. Out of every 5,000 new compounds identified during the discovery process, approximately
five are considered safe for testing in human volunteers after preclinical evaluations. After three to
six years of further clinical testing in patients, only one of these compounds on average is ultimately
approved as a marketed drug for treatment. The following sequence of research activities begins the
process that results in development of new medicines:

 Target Identification. Drugs usually act on either cellular or genetic chemicals in the body, known
as targets, which are believed to be associated with disease. Scientists use a variety of techniques
to identify and isolate individual targets to learn more about their functions and how they influence
disease. Compounds are then identified that have various interactions with the drug targets that
might be helpful in treatment of a specific disease.
 Target Prioritization/Validation. To select targets most likely to be useful in the development of
new treatments for disease, researchers analyze and compare each drug target to others based
on their association with a specific disease and their ability to regulate biological and chemical
compounds in the body. Tests are conducted to confirm that interactions with the drug target are
associated with a desired change in the behavior of diseased cells. Research scientists can then
identify compounds that have an effect on the target selected.
 Lead Identification. A lead compound or substance is one that is believed to have potential to
treat disease. Laboratory scientists can compare known substances with new compounds to
determine their likelihood of success. Leads are sometimes developed as collections, or libraries,
of individual molecules that possess properties needed in a new drug. Testing is then done on
each of these molecules to confirm its effect on the drug target.
 Lead Optimization. Lead optimization compares the properties of various lead compounds and
provides information to help biopharmaceutical companies select the compound or compounds
with the greatest potential to be developed into safe and effective medicines. Often during this
same stage of development, lead prioritization studies are conducted in living organisms (in vivo)
and in cells in the test tube (in vitro) to compare various lead compounds and how they are
metabolized and affect the body.
What is required before an investigational drug can be tested in human volunteers?

In the preclinical stage of drug development, an investigational drug must be tested extensively in
the laboratory to ensure it will be safe to administer to humans. Testing at this stage can take from
one to five years and must provide information about the pharmaceutical composition of the drug, its
safety, how the drug will be formulated and manufactured, and how it will be administered to the first
human subjects.

 Preclinical Technology. During the preclinical development of a drug, laboratory tests document
the effect of the investigational drug in living organisms (in vivo) and in cells in the test tube (in
vitro).
 Chemistry Manufacturing and Controls (CMC)/Pharmaceutics. The results of preclinical
testing are used by experts in pharmaceutical methods to determine how to best formulate the
drug for its intended clinical use. For example, a drug that is intended to act on the sinuses may be
formulated as a time-release capsule or as a nasal spray. Regulatory agencies require testing that
 documents the characteristics -- chemical composition, purity, quality and potency -- of the drug's
active ingredient and of the formulated drug.
 Pharmacology/Toxicology. Pharmacological testing determines effects of the candidate drug on
the body. Toxicology studies are conducted to identify potential risks to humans.

In the United States, results of all testing must be provided to the U.S. Food and Drug Administration
(FDA) and/or other appropriate regulatory agencies to obtain permission to begin clinical testing in
humans. Regulatory agencies review the specific tests and documentation required to proceed to
the next stage of development.

How are investigational drugs tested in humans?

Testing of an investigational new drug begins with submission of information about the drug and
application for permission to begin administration to healthy volunteers or patients.

 Investigational New Drug (IND)/Clinical Trial Exception (CTX)/Clinical Trial Authorization

(CTA) Applications. INDs (in the U.S.), CTXs (in the U.K.) and CTAs (in Australia) are examples
of requests submitted to appropriate regulatory authorities for permission to conduct
investigational research. This research can include testing of a new dosage form or new use of a
drug already approved to be marketed.

In addition to obtaining permission from appropriate regulatory authorities, an institutional or

independent review board (IRB) or ethical advisory board must approve the protocol for testing, as
well as the informed consent documents that volunteers sign prior to participating in a clinical study.
An IRB is an independent committee of physicians, community advocates and others that ensures a
clinical trial is ethical and the rights of study participants are protected.

Clinical testing is usually described as consisting of Phase I, Phase II and Phase III clinical studies.
In each successive phase, increasing numbers of patients are tested.

 Phase I Clinical Studies. Phase I studies are designed to verify safety and tolerability of the
candidate drug in humans and typically take six to nine months. These are the first studies
conducted in humans. A small number of subjects, usually from 20 to 100 healthy volunteers, take
the investigational drug for short periods of time. Testing includes observation and careful
documentation of how the drug acts in the body -- how it is absorbed, distributed, metabolized and
excreted.
 Phase II Clinical Studies. Phase II studies are designed to determine effectiveness and further
study the safety of the candidate drug in humans. Depending upon the type of investigational drug
and the condition it treats, this phase of development generally takes from six months to three
years. Testing is conducted with up to several hundred patients suffering from the condition the
investigational drug is designed to treat. This testing determines safety and effectiveness of the
drug in treating the condition and establishes the minimum and maximum effective dose. Most
Phase II clinical trials are randomized, or randomly divided into groups, one of which receives the
investigational drug, one of which gets a placebo containing no medication and sometimes a third
group that receives a current standard treatment to which the new investigational drug will be
compared. In addition, most Phase II studies are double-blinded, meaning that neither patients nor
researchers evaluating the compound know who is receiving the investigational drug or placebo.
 Phase III Clinical Studies. Phase III studies provide expanded testing of effectiveness and safety
of an investigational drug, usually in randomized and blinded clinical trials. Depending on the type
of drug candidate and the condition it treats, this phase usually requires one to four years of
testing. In Phase III, safety and efficacy testing is conducted with several hundred to thousands of
volunteer patients suffering from the condition the investigational drug treats.
 New Drug Application (NDA)/Marketing Authorization Application (MAA)NDAs (in the U.S.)
and MAAs (in the U.K.) are examples of applications to market a new drug. Such applications
document safety and efficacy of the investigational drug and contain all the information collected
during the drug development process. At the conclusion of successful preclinical and clinical
testing, this series of documents is submitted to the FDA in the U.S. or to the applicable regulatory
authorities in other countries. The application must present substantial evidence that the drug will
have the effect it is represented to have when people use it or under the conditions for which it is
prescribed, recommended or suggested in the labeling. Obtaining approval to market a new drug
frequently takes six months to two years.
Does testing continue after a new drug is approved?

After the FDA (or other regulatory agency for drugs marketed outside the U.S.) approves a new
drug, pharmaceutical companies may conduct additional studies, including Phase IIIb and Phase IV
studies. Late-stage drug development studies of approved, marketed drugs may continue for several
months to several years.

 Phase IIIb/IV Studies. Phase IIIb trials, which often begin before approval, may supplement or
complete earlier trials by providing additional safety data or they may test the approved drug for
additional conditions for which it may prove useful. Phase IV studies expand testing of a proven
drug to broader patient populations and compare the long-term effectiveness and/or cost of the
drug to other marketed drugs available to treat the same condition.
 Post-Approval Studies. Post-approval studies test a marketed drug in new age groups or patient
types. Some studies focus on previously unknown side effects or related risk factors. As with all
stages of drug development testing, the purpose is to ensure the safety and effectiveness of
marketed drugs.
https://www.fda.gov/patients/drug-development-process/step-1-discovery-and-development

The Drug Development Process

Step 1: Discovery and Development
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Discovery

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:

 How it is absorbed, distributed, metabolized, and excreted.

 Its potential benefits and mechanisms of action.
 The best dosage.
 The best way to give the drug (such as by mouth or injection).
 Side effects or adverse events that can often be referred to as toxicity.
 How it affects different groups of people (such as by gender, race, or ethnicity) differently.
 How it interacts with other drugs and treatments.
 Its effectiveness as compared with similar drugs.

Step 2: Preclinical Research

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Before testing a drug in people, researchers must find out whether it has the potential to cause
serious harm, also called toxicity. The two types of preclinical research are:

 In Vitro

 In Vivo

FDA requires researchers to use good laboratory practices (GLP), defined in medical product
development regulations, for preclinical laboratory studies. The GLP regulations are found in 21
CFR Part 58.1: Good Laboratory Practice for Nonclinical Laboratory Studies. These regulations set
the minimum basic requirements for:

 study conduct
 personnel
 facilities
 equipment
 written protocols
 operating procedures
 study reports
 and a system of quality assurance oversight for each study to help assure the safety of FDA-
regulated product

Usually, preclinical studies are not very large. However, these studies must provide detailed
information on dosing and toxicity levels. After preclinical testing, researchers review their findings
and decide whether the drug should be tested in people.

Step 3: Clinical Research

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While preclinical research answers basic questions about a drug’s safety, it is not a substitute for
studies of ways the drug will interact with the human body. “Clinical research” refers to studies, or
trials, that are done in people. As the developers design the clinical study, they will consider what
they want to accomplish for each of the different Clinical Research Phases and begin the
Investigational New Drug Process (IND), a process they must go through before clinical research
begins.

On this page you will find information on:

 Designing Clinical Trials

 Clinical Research Phase Studies
 The Investigational New Drug Process
 Asking for FDA Assistance
 FDA IND Review Team
 Approval

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:

 Who qualifies to participate (selection criteria)

 How many people will be part of the study
 How long the study will last
 Whether there will be a control group and other ways to limit research bias
 How the drug will be given to patients and at what dosage
 What assessments will be conducted, when, and what data will be collected
 How the data will be reviewed and analyzed

Clinical trials follow a typical series from early, small-scale, Phase 1 studies to late-stage, large scale,
Phase 3 studies.

Clinical Research Phase Studies

The Investigational New Drug Process

Drug developers, or sponsors, must submit an Investigational New Drug (IND)

application to FDA before beginning clinical research.

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 investigator

Asking for FDA Assistance

 Phase 1

Study Participants: 20 to 100 healthy volunteers or people with the

disease/condition.

Length of Study: Several months

Purpose: Safety and dosage

Approximately 70% of drugs move to the next phase

Phase 2

Study Participants: Up to several hundred people with the

disease/condition.

Length of Study: Several months to 2 years

Purpose: Efficacy and side effects

Approximately 33% of drugs move to the next phase

 Phase 3

Study Participants: 300 to 3,000 volunteers who have the disease or

condition

Length of Study: 1 to 4 years

Purpose: Efficacy and monitoring of adverse reactions

Approximately 25-30% of drugs move to the next phase

Phase 4

Study Participants: Several thousand volunteers who have the

disease/condition

Purpose: Safety and efficacy

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.

Approval

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. 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:
o Participants are exposed to unreasonable or significant risk.
o Investigators are not qualified.
o Materials for the volunteer participants are misleading.
o The IND application does not include enough information about the trial’s
risks.

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.
The developer is responsible for informing the review team about new protocols, as well
as serious side effects seen during the trial. This information ensures that the team can
monitor the trials carefully for signs of any problems. After the trial ends, researchers
must submit study reports.

This process continues until the developer decides to end clinical trials or files a
marketing application. Before filing a marketing application, a developer must have
adequate data from two large, controlled clinical trials.

Step 4: FDA Drug Review

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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 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:

 Proposed labeling
 Safety updates
 Drug abuse information
 Patent information
 Any data from studies that may have been conducted outside the United States
 Institutional review board compliance information
 Directions for use

FDA Review
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 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.

Step 5: FDA Post-Market Drug Safety

Monitoring
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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.

On this page you will find information on:

 Supplemental Applications
 INDs for Marketed Drugs
 Manufacturer Inspections
 Drug Advertising
 Generic Drugs
 Reporting Problems
 Active Surveillance

Supplemental Applications

Developers must file a supplemental application if they wish to make any significant changes from
the original NDA. Generally, any changes in formulation, labeling, or dosage strength must be
approved by FDA before they can be made.

INDs for Marketed Drugs

If sponsors want to further develop an approved drug for a new use, dosage strength, new form, or
different form (such as an injectable or oral liquid, as opposed to tablet form), or if they want to
conduct other clinical research or a post-market safety study, they would do so under an IND.

Manufacturer Inspections

FDA officials conduct routine inspections of drug manufacturing facilities across the United States,
and abroad if approved products are manufactured overseas. Manufacturers may be informed of
inspections in advance, or the inspections may be unannounced. Inspections may be routine or
caused by a particular problem or concern. The purpose of these inspections is to make sure that
developers are following good manufacturer practice. FDA can shut down a facility if minimum
standards are not met.

Drug Advertising

FDA regulates prescription drug advertisements and promotional labeling. By law, a developer is
prohibited from advertising unapproved uses of their product.

All advertisements, such as product claims or reminder ads, cannot be false or misleading. They
must contain truthful information about a drug’s effectiveness, side effects, and prescribing
information. These advertisements can be found in medical journals, newspapers, and magazines,
and on the Internet, television, or radio.

Promotional labeling differs from drug advertisements in the way it is distributed. Pharmaceutical
companies give out brochures or other promotional materials to physicians or consumers. The drug’s
prescribing information must accompany promotional labeling. Learn more at Prescription Drug
Advertising.
Generic Drugs

New drugs are patent protected when they are approved for marketing. This means that only the
sponsor has the right to market the drug exclusively. Once the patent expires, other drug
manufacturers can develop the drug, which will be known as a generic version of the drug. Generic
drugs are comparable to brand name drugs and must have the same:

 Dosage form
 Strength
 Safety
 Quality
 Performance characteristics
 Intended use

Because generic drugs are comparable to drugs already on the market, generic drug manufacturers
do not have to conduct clinical trials to demonstrate that their product is safe and effective. Instead,
they conduct bio-equivalence studies and file an Abbreviated New Drug Application. Learn more
at Generic Drugs: Questions and Answers.

Reporting Problems

FDA has several programs that allow manufacturers, health professionals, and consumers to report
problems associated with approved drugs.

 MedWatch is a gateway for reporting problems with medical products (drugs and devices)
and learning about new safety information. You can subscribe to regular MedWatch safety
alerts.
 Medical Product Safety Network (MedSun) monitors the safety and effectiveness of medical
devices. FDA recruits 350 healthcare providers throughout the United States to report any
medical device problems that result in serious injury or death. Each month, FDA publishes
the MedSun newsletter. The newsletter gives consumers important information about
medical device safety.

Active Surveillance

Under the Sentinel Initiative, FDA is developing a new national system to more quickly spot possible
safety issues. The system will use very large existing electronic health databases—like electronic
health records systems, administrative and insurance claims databases, and registries—to keep an
eye on the safety of approved medical products in real time. This tool will add to, but not replace,
FDA's existing postmarket safety assessment tools. Learn more about the Sentinel Initiative and its
major activities.
 https://pacificbiolabs.com/stages-of-drug-development

Stages of Drug Development

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.
Pacific BioLabs can assist you through all stages of drug developoment. Our scientists can
help you to determine your testing needs, and our experienced staff can perform the
critical tests and studies that are necessary to win FDA approval.
To get you started, below we have provided an in-depth overview of many stages in the
drug development process and necessary studies. Keep in mind this is just a guide; if you
have any specific questions call Pacific BioLabs at 510-964-9000 to speak to a
knowledgeable resource who can help you identify what testing you may need to perform.
Detailed Stages of Drug Development

1. Discovery
2. Product Characterization
3. Formulation, Delivery, Packaging Development
4. Pharmacokinetics And Drug Disposition
5. Preclinical Toxicology Testing And IND Application
6. Bioanalytical Testing
7. Clinical Trials

Discovery

Discovery often begins with target identification – choosing a biochemical mechanism

involved in a disease condition. Drug candidates, discovered in academic and
pharmaceutical/biotech research labs, are tested for their interaction with the drug target.
Up to 5,000 to 10,000 molecules for each potential drug candidate are subjected to a
rigorous screening process which can include functional genomics and/or proteomics as
well as other screening methods. Once scientists confirm interaction with the drug target,
they typically validate that target by checking for activity versus the disease condition for
which the drug is being developed. After careful review, one or more lead compounds are
chosen.
Product Characterization

When the candidate molecule shows 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 determined. Characterization
studies will undergo analytical method development and validation. Early stage
pharmacology studies help to characterize the underlying mechanism of action of the
compound.
Formulation, Delivery, Packaging Development

Drug developers must devise a formulation that ensures the proper drug delivery
parameters. It is critical to begin looking ahead to clinical trials at this phase of the drug
development process. Drug formulation and delivery may be refined continuously until,
and even after, the drug’s final approval. Scientists determine the drug’s stability—in the
formulation itself, and for all the parameters involved with storage and shipment, such as
heat, light, and time. The formulation must remain potent and sterile; and it must also
remain safe (nontoxic). It may also be necessary to perform leachables and extractables
studies on containers or packaging.
Pharmacokinetics And Drug Disposition

Pharmacokinetic (PK) and ADME (Absorption/Distribution/Metabolism/Excretion)

studies provide useful feedback for formulation scientists. PK studies yield parameters
such as AUC (area under the curve), Cmax (maximum concentration of the drug in blood),
and Tmax (time at which Cmax is reached). Later on, this data from animal PK studies is
compared to data from early stage clinical trials to check the predictive power of animal
models.
Preclinical Toxicology Testing and IND Application

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 stages of preclinical toxicology testing are:

Acute Studies
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 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.

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
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.

Toxicokinetic Studies
These are typically similar in design to PK/ADME studies except that they use much higher
dose levels. They examine the effects of toxic doses of the drug and help estimate the
clinical margin of safety. There are numerous FDA and ICH guidelines that give a wealth of
detail on the different types of preclinical toxicology studies and the appropriate timing for
them relative to IND and NDA or BLA filings. (See Regulatory/Animal Welfare and at FDA
Guidances.)
Bioanalytical Testing

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.
Clinical Trials

The Bioanalytical Team at PBL can support clinical trials. Clinical studies are grouped
according to their objective into three types or phases:

Phase I Clinical Development (Human Pharmacology)

Thirty days after a biopharmaceutical company has filed its IND, it may begin a small-scale
Phase I clinical trial unless the FDA places a hold on the study. 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.

Phase II 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.

Phase III 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). BLAs are
currently reviewed by the FDA’s Center for Biologics Evaluation and Research
(CBER). NDAs are reviewed by the Center for Drug Evaluation and Research (CDER).