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The number of clinical research trials being conducted has tripled over the
last 10 years, and the trend looks to continue, particularly in the field of
neuroscience. There is no better time to consider participating in these
trials. This article will address future developments, different phases, and
the steps to carry out clinical research trials.
Introduction. The New Wave of Clinical Research Trials. Pharmaceutical drug
companies will spend more than $20 billion this year in the discovery and
development of new medicines. This investment represents nearly an 11%
increase as compared to 1997, according to an annual survey by the
Pharmaceutical Research & Manufacturers of America (PhRMA). The industry’s
research and development budget has more than tripled in the past 10 years.
“As we prepare to enter the 21st century, the pharmaceutical pipeline is
bursting with potential cures and innovative treatments,” according to
PhRMA president Alan F Homer. Sidney Taurel, PhRMA chairman and president of
Eli Lilly and Co., agree, “We are at the dawn of a golden era for
pharmaceuticals, helped by new research tools, such genomics, we are opening
up the opportunity to revolutionize health care and thereby raise
expectations of patients throughout the world.”1
The Food and Drug Administration (FDA) granted New Drug Approvals on 39 new
molecular entities (NME) in 1997, the second highest rate in FDA history in
an average of just 16.2 months. That compares with the record-setting 53 new
drugs ratified in 1996, when the agency was dealing with a considerable
backlog. The time it takes the FDA to clear a new drug began decreasing
after the industry agreed to pay user-fees
dedicated to hiring more drug reviewers. Nine of the NME represented major
advances in medical treatment and were given accelerated review by the FDA.
The 39 new drugs and biologics approved in 1997 will treat or prevent 39
diseases affecting more than 160 million people.2
Good News for CNI. As a free standing research center, there will be more
opportunities for CNI to participate in the growing number of clinical
trials that are available. In the late 1970’s and early 1980’s,
university medical centers were conducting 85% to 90% of the clinical trials
in the United States. Today, these centers are conducting just under 50% of
the clinical trials. The other 50% percent of these trials are being done in
free standing research centers, such as CNI.
There are several advantages when pharmaceutical companies utilize free
standing research centers. These advantages include less bureaucracy,
decreased overhead costs, expedited institutional review board (IRB) review
and approval processes with the option of using faster central IRB’s,
prompt study start-up time, timely patient enrollment and recruitment, the
availability of recognized specialists to serve as principal investigators,
and experienced nursing professionals to function as research coordinators.
In addition to CNI having the above-mentioned advantages, there will be a burgeoning of research in
neurosciences over the next 10 years. CNI is a regional center
of excellence in the neurosciences and is actively carrying out a variety of
clinical research projects.
How Trials are Conducted. The period of time from the beginning of the
pre-clinical phase until the drug is approved by the FDA can take a number
of years to complete. A detailed description of the key phases in drug
development follows.
Pre-clinical Phase. New chemical entities or new drugs are identified by
scientists whether they are created based on an idea or are discovered
during other research. These entities are studied in vitro, in a cell
culture or in vivo, using animal models to evaluate safety and potential
effectiveness in treating the targeted diseases. Through these studies
scientists are able to obtain a significant amount of information about how
a
drug may act when used in humans. The pre-clinical phase takes from 1 to 3
years to conduct. Once this phase is completed, the pharmaceutical company
submits the data to the FDA and requests approval to begin testing the drug
in humans. This is called the Investigational New Drug Application (IND).
Phase One. These studies are primarily concerned with assessing drug safety.
This initial phase of testing in humans is done with a small number of
healthy volunteers (20 to 100 subjects). The study is designed to determine
what happens to the drug in the human body, how it is absorbed, metabolized,
and excreted. A Phase One study will investigate side effects that occur as
dosage levels are increased. This initial phase of testing typically takes
several months. About 70% of experimental drugs pass Phase One of testing.
Phase Two. Once a compound has been shown to be safe, it must be tested for
efficacy. This second phase of testing may last from several months to 2
years, and involves exposure to several hundred patients. Most Phase Two
studies are randomized trials. One group of patients will receive the
experimental drug while a second “control group” will receive either a
standard treatment or a placebo. These studies are most often “blinded,”
meaning neither the patient nor the researchers know who is getting the
experimental drug. The study can provide both the pharmaceutical company and
the FDA with comparative information about the relative safety of the drug
and its effectiveness. Approximately one-third of experimental drugs
successfully complete both Phase One and Phase Two studies.
Phase Three. In this phase, the 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 range of possible adverse reactions. Most Phase
Three studies are randomized and blinded trials and typically last several
years. Of the drugs that enter Phase Three studies, 70% to 90% successfully
complete testing. Once the data from a Phase Three study is analyzed, a
pharmaceutical company can request FDA approval for marketing the drug.
Late Phase Three and Phase Four.
Phase Four studies are also referred to as post-marketing studies.
Pharmaceutical companies can achieve several objectives in these studies.
These include comparing the drug with other drugs already on the market,
monitoring a drug’s long-term effectiveness and impact on a patient’s
quality of life, and determining the cost-effectiveness of a drug therapy to
other traditional and new therapies.3, 4 These studies are open-label,
meaning they do not include a placebo control group.
Steps to Doing a Clinical Research Trial. Many physicians who want to
participate as principal investigator (PI) miss out on the opportunity
because they either don’t know where to begin the process or the steps
required to carry out clinical research trials.
The first step is to acquire a suitable study that is a good fit for the
physician’s speciality and patient population. Contacting pharmaceutical
companies who are doing clinical trials in the area of specialization is one
way to identify an appropriate study. Many pharmaceutical companies are now
“out-sourcing” the selection of clinical trial sites to Site Management
Organizations (SMO) or to Clinical Research Organizations (CRO). Getting to
know these groups and providing them with information about the area of
specialization is very important in order to be selected as a potential
clinical research site.
Reviewing the protocol is a critical step for a potential PI. During this
evaluation the PI needs to answer the following questions:
Q: Does the patient population meet the inclusion/exclusion criteria to
recruit and enroll into this study? Can the recruitment and enrollment of
patients be completed in the time frame requested by the protocol?
A: Taking on a study that will be difficult to fill is not only frustrating
for the PI, but also for the sponsoring pharmaceutical company. This can
result in lost time and money for both parties.
Q: Is the budget adequate and are the PI and research coordinators being
paid appropriately for their time and expertise?
A: This is an important consideration especially when there are various
scales and evaluation tools that the PI or coordinator must complete at a
visit.
Q: Does the budget adequately cover those services being vended out to other
providers such as electroencephalograms with cardiologist interpretation?
A: This point is critical in studies that involve an inpatient hospital
stay.
Q: Does the agreement between the PI and sponsor address such issues as
indemnity?
A: Considerations which fall into this category include the establishment of
a study payment schedule, identification of the ownership of data and
publication rights, and compensation for physician time at the investigator
meeting, as well as for the possibility of screen failures, study delays, or
study termination by the sponsor.
Additional steps needed to get a study activated include obtaining IRB
approval, attendance of the PI and coordinator at an investigator meeting,
site visits, acquisition
of study-related supplies, and a search of the patient data base to identify
potential study patients.
Once these steps have been accomplished, it is then a matter of carrying out
the study according the protocol. Having a competent research coordinator
who can manage the study and also serve as a case manager for the study
patients is very important.
During the course of the research trial, the study site will be monitored
periodically by a representative from the drug company, SMO, or CRO. The
site will be checked for protocol compliance and review the patient’s case
report forms and source documents for accuracy and completeness. Occasional
interaction is required with the IRB, in terms of requesting continued
review and notification of amendments to the protocol, changes in the
patient informed consent, IND safety reports, placement of patient
recruitment ads, and occurrence of serious adverse events.
After the study is closed there will be a time that the sponsor will request
data queries or clarifications. Once the sponsor has locked the data, all
documentation, including regulatory and patient case report forms, must be
archived for 5 years by the PI.
Current Clinical Research Trials in Movement Disorders. The CNI Movement
Disorders Center is currently involved in many clinical trials in various
trial phases for treatment of Parkinson’s Disease, Huntington’s Disease,
Cervical Dystonia, and Tourette’s Syndrome. Phase Two clinical
trials in Parkinson’s Disease include the following; Recombinant-Methionyl
Human Glial Cell Lined-Derived Neurotrophic Factor (r-metHuGDNF) for the
treatment of Idiopathic Parkinson’s Disease.
Phase Three studies in PD include Entacopone as adjunct to Levodopa/Carbidopa
(Sinemet) therapy in PD patients without motor fluctuations, Selegiline
transdermal system (Eldepryl) as adjunct to Levodopa/
Carbidopa (Sinemet) therapy in PD patients with motor fluctuations, and a
study using Sub-Thalamic Deep Brain Stimulation for advanced Parkinson’s
disease patients. Phase four studies in PD include a study with the
Parkinson’s Study Group and the National Institute of Health, studying
early verses late effects of a gradual or acute switch from Pramipexole (Mirapex)
to Ropinerole (Requip) in advanced Parkinson’s disease patients on Levopa
(Sinemet).
In Huntington’s Disease a phase two study is being conducted using the
drug remacemide and Coenzyme Q10 with the Huntington’s Study Group and the
National Institute of Health. Two phase three studies are being conducted in
Cervical Dystonia. These trials involve the use of botulinum type A toxin (Dysport)
and botulinum type B toxin (Neurobloc) in the treatment of dystonia. Two
other phase three studies being conducted using the botulinum type A (BOTOX)
include a study for upper limb spasticity post stroke, and a study for
migraine headache. In Tourette’s syndrome a phase four study is being
conducted with the Tourette’s Syndrome Study Group and the National
Institute of Health. The study is looking at the treatment of attention
deficit hyperactivity disorder (ADHD)
in children with Tourette’s syndrome. This double-blind, parallel study is
using the
drugs Methylphenidate (Ritalin) and Clonidine (Catapres).
In addition to the above studies, several studies are scheduled to begin in
early to late spring of 1999. Of the medications and devices that have come
on the market within the last year, the CNI Movement Disorders Center was
involved with drug trials for ropinerole (Requip) and tolcapone (Tasmar),
and a device study for the deep brain thalamic stimulator (Activa-tremor
Control System).
Conclusion. With the burgeoning increase of research and development of new
drugs and devices, particularly in the neurosciences, now is an excellent
time for physicians to consider becoming involved with clinical research
trials. CNI’s research department is available to assist CNI physicians in
obtaining and performing clinical research trials.
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