Modern drug discovery is only
slightly based on looking for biologically-active compounds from
other organisms. That can be a starting point, but now,
computers can alter small parts of molecules in virtual space and
make predictions on how they will interact with known biological
An introduction to targeted drug discovery (pdf).
Virtual chemistry is not "real," so
follow-up testing needs to be done on promising compounds. But
before anything happens, the compound must be patented,
protected as a unique invention. The patent protects the
developing company, and there is no sense testing a compound you
wont have the sole right to use. In the U.S., drug patents
last 16 years, after which other companies (usually with no testing
facilities) can then produce and sell generic versions
of the compounds. A compound might take 12 years to reach
approval for sale (and the vast majority of them never prove
usable / marketable), so new drugs tend to be very expensive between
release and patent lapse. Companies are trying to underwrite
their research and development costs on both successful and
unsuccessful compounds (plus make sometimes huge profits).
More on patents and generic drugs.
Generic drugs - what are the requirements?
pay-to-view site that just tracks patents (entrance portal).
Actual activity of these new compounds must be tested. If
cell cultures are available, that may be the first
step. A culture would be cells (generally human) that are kept
alive in dishes. There are some cancer cultures and a few
other specific disease cultures, but they are just groups of cells
in dishes. Some very important information can be derived from
culture tests, but cultures have two major limitations: they
are isolated, there are no influences like what would exist in the
body; it's unclear how much the cells have changed on adapting
to a cultured existence. They may be very different from the
cells they started as. However, researchers can assess some
basic cellular responses from cultures.
Information on cancer drug screening for a type of cancer(pdf).
Basics of cell cultures.
The next step in testing involves animal models.
These models require some features: they need to be comparable
to humans and they need to be able to sustain whatever
condition the drugs are targeted against. It helps also if
they are small, hardy, cheap to keep, easy to handle, and have
relatively short lifetimes and a high reproduction rate.
Mice are very often the model of choice, so much so that
many strains of mice have been developed that support
conditions that mice typically would not get. There are, of
course, major differences between models and humans, so that there
are many instances of drugs that worked in models but not in humans,
or which produced dramatic side effects that didnt appear in the
models. Currently, the U.S. Food and Drug Administration
(FDA) requires early testing on two different animal
models to try to address those issues.
Mice "adjusted" to be prone to certain cancers.
problems with animal models.
Making the test animals comfortable-?
Human testing of chemicals involves
clinical trials in several phases, all supervised (or at
least the results are reviewed) by the FDA.
Introduction to clinical trials.
Phase 1 Clinical Trials are used to see if its even
feasible to expose humans to the chemical. A small group of
healthy humans are given the drug and checked for major side effects
while researchers try to follow how a human metabolism deals with
the chemical. This is basically to assess the safety of the
chemical, and to see if humans can easily tolerate exposure to it.
In Phase 2
Clinical Trials, a small but statistically-significant group
(if such is available - some conditions just aren't common enough to
provide good numbers) of patients with the target condition are
given the drug. Blinding varies in this stage. Now actual
curative results are being sought, as well
as side effects that might have not shown up before. This will
be a double-blind test, or possibly triple-blind. To
proceed to the next step, the FDA will review not just safety and
efficacy, but efficacy relative to drugs that are already on the
market: to move forward, your drug should outperform
More on the steps.
In Phase 3
Clinical Trials, a much larger group (if possible) is
tested. This group should be double (sometimes triple) blind,
if numbers allow. This will double-check effects, both primary and side
effects (and rarer side effects should show up in a large group),
and sometimes will reveal issues with administering the drugs and
following up with patients. If this all goes well, the drug
may be approved for sale.
Problems with Phase 3 (pdf).
Phase 4 Trials are usually an
indication that something might not be right with the released drug.
It is required for some pediatric applications but can be very
disorganized in other instances, relying on optional reporting. This is an attempt to gather information on how the drug is
affecting the broader population now exposed to it. Sometimes a very
rare (but very serious) side effect only appears at this stage.
It make take years for anecdotal reporting to suggest a problem, but
it does sometimes happen.
Some companies see Phase 4 as an opportunity.