Basic Notes On Clinical Trials Phase I-IV

New chemical entities (NCEs) are discovered through screening existing compounds or
designing new molecules. Once synthesized, they go through a rigorous testing process. Their
pharmacological activity, therapeutic promise, and toxicity are tested using isolated cell cultures
and animals, as well as computer models. A promising NCE is then modified to optimize its
pharmacological activity with fewer undesirable biological properties.
Once pre-clinical studies are completed and the NCE has been proven safe on animals, the drug
sponsor applies for Investigational New Drug (IND) status. If it receives approval, Phase I
clinical trials are started to establish the tolerance of healthy human subjects at different doses
and to study the effects on humans of anticipated dosage levels. The firm also studies the NCE's
absorption, distribution, metabolism, and excretion patterns. This stage requires careful
supervision, as it is not yet certain if the drug is safe for humans. Phase 1 primarily determines
how a medicine works in humans and helps to predict the dosage range for the medicine, and
involves healthy volunteers. This initial phase of testing in humans is done in a small number of
healthy volunteers (20 to 100), who are usually paid for participating in the study.
If phase I results are favorable, Phase II is authorized. A relatively small number of patients
participate in controlled trials to establish the compound's potential usefulness and short-term
risks. Most phase II studies are randomized trials. One group of patients will receive the
experimental drug, while a second "control" group will receive a standard treatment or placebo.
Often these studies are "blinded"--neither the patients nor the researchers know who is getting
the experimental drug. In this manner, the study can provide the pharmaceutical company and
the FDA comparative information about the relative safety of the new drug, and its effectiveness.
Only about one-third of experimental drugs successfully complete both phase I and phase II
studies. Depending on these results, phase III trials are approved. The firm gathers precise
information on the drug's effectiveness for specific indications and to determine whether it
produces a broader range of adverse effects than those exhibited in the smaller phase I and II
trials. Phase 2 tests efficacy as well as safety among a small group of patients (100-300) with the
condition for which the medicine has been developed.
Phase III can involve several hundred to several thousand subjects, and is extremely expensive.
Reviews occur before and during each phase, and drug development may be terminated at any
point if the risk of failure and the added cost needed to prove effectiveness outweigh the
probability of success. In a phase III study, a drug is tested in several hundred to several
thousand patients. This large-scale testing provides the pharmaceutical company and the FDA
with a more thorough understanding of the drug's effectiveness, benefits, and the range of
possible adverse reactions. Most phase III studies are randomized and blinded trials.Phase III
studies typically last several years. Seventy to 90 percent of drugs that enter phase III studies
successfully complete this phase of testing. Once a phase III study is successfully completed, a
pharmaceutical company can request FDA approval for marketing the drug.
There is a data and safety monitoring board in the United States under the Food and Drug
Administration (FDA). This group of experts in given therapeutic areas has access to "unblinded
data" throughout the conduct of a trial, but does not let anyone else know what the data show
until it is necessary. For example, the board will not divulge efficacy data unless a point is
reached where it seems appropriate to recommend stopping the trial because the drug's basic
efficacy has been either accepted or rejected. The FDA usually insists on the drug proving its
efficacy with respect to ameliorating a disease before giving approval to sell it.
Post-Marketing -- Late Phase Three/Phase IV Studies
If clinical trials are successful, the sponsor seeks FDA marketing approval by submitting a new
drug application (NDA). If approved, the drug can be marketed immediately, although the FDA
often requires some amendments before marketing can proceed. The amendments are based on
recommendations from the FDA's outside advisory panels.
In late phase III/phase IV studies, pharmaceutical companies have several objectives: (1) studies
often compare a drug with other drugs already in the market; (2) studies are often designed to
monitor a drug's long-term effectiveness and impact on a patient's quality of life; and (3) many
studies are designed to determine the cost-effectiveness of a drug therapy relative to other
traditional and new therapies. Phase 4 trials are conducted after a medicine has been granted a
licence. In these studies a medicine is prescribed in an everyday healthcare environment which
allows results to be developed using a much larger group of participants.
Phase 4 trials are performed to:
• Know more about the side effects and safety of the drug
• What are the long term risk and benefits?
• How well the drug works when it’s used more widely than in clinical trials.
• Develop new treatment uses for the medicine.
• Compare with other treatments for the condition.
• Determine the clinical effectiveness of the medicine in a much wider variety of patient types in
conditions of “real life”.
• How is it being marketed?
• How good are the orders?
• Feedback of the doctors?
• How frequently are the orders being placed?
A drug's manufacturing process must meet stringent best-practice standards. Scaling up from
making a drug in the research phase to producing it in large quantities is difficult. In the lab,
processing is done in small batches. In commercial production, significantly greater quantities
are being produced, so ingredients generally go into a flow process that produces output
continuously. (These are still batches in the sense that after the desired quantity is produced, the
run stops, the equipment is cleaned, and a different drug is made.) Variations from the mean in a
dose's chemical make-up must be very small (the FDA constant-dosage requirement). Such
uniformity of output is difficult in continuous processing because many parameters and
conditions have to be kept constant. This requires a good understanding of optimizing the
chemical process and maintaining safeguards against abnormal conditions.
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New chemical entities (NCEs) are discovered through screening existing compounds or

Post-Marketing -- Late Phase Three/Phase IV Studies

Phase 4 trials are performed to:

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