The Drug Development Process

Step 1: Discovery and Development

 Research for a new drug begins in the laboratory.

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.

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  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

 Drugs undergo laboratory and animal testing to answer basic questions

about safety.

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 vitro (meaning in glass, or in the glass) studies are performed

with microorganisms, cells, or biological molecules outside their normal
biological context.

 In Vivo ;

Studies that are in vivo (Latin for "within the living") are those in which the
effects of various biological entities are tested on whole,
living organisms or cells, usually animals, including humans, and plants, as
opposed to a tissue extract or dead organism.

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In microbiology, in vivo is often used to refer to experimentation done in a whole
organism, rather than in live isolated cells, for example, cultured cells derived
from biopsies. In this situation, the more specific term is ex vivo. Once cells are
disrupted and individual parts are tested or analyzed, this is known as in vitro.

Food and Drug Administration (FDA)

The Food and Drug Administration (FDA) is a government agency established in

1906 with the passage of the Federal Food and Drugs Act. The agency is separated
into divisions that oversee a majority of the organization's obligations involving
food, drugs, cosmetics, animal food, dietary supplements, medical devices,
biological goods, and blood products.

The FDA is known for its work in regulating the development of new drugs. The
FDA has developed rules regarding the clinical trials that must be done on all new
medications. Pharmaceutical companies must test drugs through four phases of
clinical trials before they can be marketed to individuals.

FDA requires researchers to use good laboratory practices (GLP), defined in

medical product development regulations, for preclinical laboratory studies.
These regulations set the minimum basic requirements for:

 study conduct
 personnel
 facilities
 equipment
 written protocols
 operating procedures
 study reports

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  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

 Drugs are tested on people to make sure they are safe and effective.

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.

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

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  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.

Step 4: FDA Drug Review

 FDA review teams thoroughly examine all of the submitted data related to
the drug or device and make a decision to approve or not to approve it.

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.

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
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  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.

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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 New Drug Application 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

 FDA monitors all drug and device safety once products are available for
use by the public.
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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.

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 Investigational New Drug
program.

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
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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.

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
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  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.

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.

Technical English G.Ph (2023/2024) Ms.R. BENDJELLOUL