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Subject: Drugs: From Compound to Pharmacy
 
In the United States drugs, from compound to pharmacy, are regulated
by the Food & Drug Administration (FDA).
 
 The chance that a particular compound will reduce suffering
or cure a significant disease offers substantial financial rewards for
drug companies. The role of the FDA, is that of an over-seer to insure
that financial interests do not over shadow safety and efficacy
in order to "fast track" a compound into the market place and medicine
chest without thorough or complete testing.
 
 The FDA does not have authority to insure the safety and efficacy of
surgical procedures.
 
 Drug companies have access to vast numbers of compounds extracted from
species around the world which may have been used in native remedies or
enzymes extracted from disease resistant fish and animals. Some
compounds may have already shown their safety and efficacy in treating
other diseases.
 
 GM1 for example, was a compound that has been used to treat other
conditions with mixed success. It's use was thought to be connected with
the appearance of another condition which was later disproved in another
follow-up study.
 
 Agnati LF.  Fuxe K.  Calza L.  Goldstein M.  Toffano G.  Giardino L.
Zoli M., in their study titled; Further studies on the effects of the
GM1 ganglioside on the degenerative and regenerative features of
mesostriatal dopamine neurons, concluded, "These results indicate that
chronic GM-1 treatment may be beneficial in the treatment of neurons
undergoing degeneration, which takes place e.g. in Parkinson's disease
and after mechanical injury to the brain due to accidents or
neurosurgical operations." Acta Physiologica Scandinavia.
Supplementum.  532:37-44, 1984.
 
 Schneider JS.  Yuwiler A., in their study titled, GM1 ganglioside
treatment promotes recovery of striatal dopamine concentrations in
the mouse model of MPTP-induced parkinsonism, reported, "On the basis
of these observations, GM1 appears to increase the dopamine content
of the striatum by promoting or stimulating regenerative sprouting of
dopaminergic terminals and perhaps collateral sprouting from remaining
intact fibers in the MPTP model of Parkinsonism in the young mouse.
We suggest that GM1 ganglioside may hold some promise as a potential
adjunct in the treatment of Parkinson's Disease." Experimental Neurology
105(2):177-83, 1989 Aug.
 
 In the FDA process, the toxicity question was satisfied, the compound
was not toxic to tissue and was tolerated without significant side effects
in animals.
 
INITIAL NEW DRUG APPLICATION
 
 Drug companies with documentation in hand on the results of the in
vivo and in vitro studies on tissues and animals, file an Initial New
Drug application with the FDA.
 
 The IND sets in motion a 17 year patent on any results, permits use
of the compound in limited quantities for clinical trials, outlines
how the compound will be manufactured to insure quality and stability,
and outlines the clinical testing protocols.
 
 If there have significant adverse effects associated with the compound
in the past, the FDA may require changes in the clinical testing protocols
to allow for additional tests. Additional blood or urine tests or MRI/PET
scans may be required.
 
 For compounds tested for Parkinson's, Schwab and England Activities of
Daily Living. Hoehn & Yahr rating scale, Unified Parkinson Disease Rating
Scale (UPDRS), and or MMSE is used to determine efficacy. What can be called
significant improvement is documented before hand.
 
When the FDA finally approves the IND, clinical trials can begin.
 
There are three phases of clinical trials.
 
Phase 1 Clinical Trial
 
 Phase 1 consists of administering the compound to a small number of
"healthy" subjects and perhaps some minimal before and after testing
to determine efficacy. This is sometimes called an open label safety
and efficacy trial. Some companies have used the results of a Phase 1
clinical trial and wide spread public relations to encourage investment
and add value to their stock. The FDA is kept apprised of any adverse
reactions that were reported during phase 1. The length of time need
to complete phase 1 is approximately 6 months.
 
Phase 2 Clinical Trial
 
 Phase 2 is where 200 to 300 Parkinson's patients are tested in a
double-blind, randomized, placebo-controlled, cross-over study. Large
numbers of patients are used because some will not be able to tolerate
the compound, some will drop out due to perceived lack of improvement,
or perhaps their diagnosis of Parkinson's is incorrect. Enough
patients must be enrolled to overcome the loss in numbers.
 
 Patient A, may receive either a placebo or the real compound (neither
the patient nor the doctor know which) for a period of time. If the
patients have been on a similar compound previously, discontinuance
of that compound and a wash-out period before the controlled study
starts is required. Tests using the rating scales previously discussed
are given, before, during and after the trial. Any blood work, urine or
special imaging is also done during this time. After the first half of
the trial, a wash-out period is followed before starting the second
half of the trial with the placebo if the real compound was used in
the first half or vice versa.
 
At the end of Phase 2, the results can be correlated according age,
duration of treatment, etc., allowing the company to know what targets
do best on this compound.  If no significant improvement is shown, or if
the results are not significantly better than a competing product already
on the market, the drug company has the opportunity to withdraw and
cut their losses. If all goes well, they can proceed to the next phase.
 
Additional adverse reactions discovered in the phase 2 trial are reported
to the FDA.
 
Phase 3 Clinical Trial
 
 The phase 3 clinical trial is a larger scale, multiple center, double-
blind study that not only seeks to verify the efficacy of the compound
in target groups but also helps determine what optimum dosages are needed
to achieve the desired effect without causing adverse effects.
 
 Placebo effects of being a patient of "the worlds most famous researcher"
are eliminated in a multi-center study.
 
 Adjunct studies, testing the efficacy of the compound and recording
interactions with other compounds, used in the treatment of the disease,
are also done.
 
 Additional studies may also be done on patients, diagnosed but untreated
to test the efficacy and help identify other target groups.
 
 Phase 2 and 3 can take three or more years to complete.
 
 
NEW DRUG APPLICATION
 
 With all the clinical trials done and all the numbers crunched, the
company delivers the thousands of pounds of paperwork, developed from
day 1. A new drug application (NDA) is filed.
 
 The review process can take 3 years, after which the product with a
new name can appear on pharmacy shelves and be prescribed by your doctor.
 
SIDE BAR
 
 Drugs presently in clinical trials are tolcapone and entacapone, which are
competitors, lazabemide which could be a competitor for deprenyl, and
GM1/LIGA20. Somatrix is also doing gene therapy research.
 
 Information on which phase a compound is in the clinical trial process is
hard to come by since the companies consider this proprietary information
in a highly competitive industry. Progress reports in the journals are
most times a year after the phase has been completed due to the lag time
in crunching numbers, writing the report and the lag time until publication.
Reports in peered journals, on compounds that aren't doing well in trials
are rare.
 
 
 
 
 
 
John Cottingham                     "KNOWLEDGE is of two kinds: we know
[log in to unmask]                      a subject, or we know where we can
OR                                   find information upon it."
[log in to unmask]            Dr. Samuel Johnson