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1. Introduction
2. How are new drugs discovered?
3. What is required before an investigational
drug can be tested in human volunteers?
4. How are investigational drugs
tested in humans?
5. Does testing continue after a
new drug is approved?
Discovering and bringing one new drug to the public typically costs a pharmaceutical
or biotechnology company nearly $900 million and takes an average of 10 to 12
years. In special circumstances, such as the search for effective drugs to treat
AIDS, the Food and Drug Administration (FDA) has encouraged an abbreviated process
for drug testing and approval called fast-tracking. The drug discovery and drug development
process is designed to ensure that only those pharmaceutical products that are
both safe and effective are brought to market. PPD provides a broad array of
drug discovery and drug development services and products
to pharmaceutical, biotechnology and medical device companies to expedite drug
development, from drug discovery through clinical studies and post-approval
support.
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New drugs begin in the laboratory with chemists, scientists 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, only 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
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:
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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 a target and learn more about its functions and how
these influence disease. Compounds are then identified that have various
interactions with drug targets helpful in treatment of a specific disease.
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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.
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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.
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Lead optimization. Lead optimization compares
the properties of various lead compounds and provides information to help
pharmaceutical and biotechnology 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.
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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.
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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).
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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.
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Pharmacology/Toxicology. Pharmacological testing
determines effects of the candidate drug on the body. Toxicology studies
are conducted to identify potential risks to humans.
Results of all testing must be provided to the FDA in the U.S. and/or other
appropriate regulatory agencies in order to obtain permission to begin clinical
testing in humans. Regulatory agencies review the specific tests and documentation
that are required to proceed to the next stage of development.
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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.
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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.
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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.
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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 up 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 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.
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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 upon
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.
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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 between
six months and two years.
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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.
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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.
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