Anatomy 101: Human Research
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What is a Clinical Trial?
Clinical trials are scientific experiments design to closely examine a specific treatment for a specific disorder in humans, and the subjects in experiment are humans. Because clinical trials are so costly, the majority are paid for by pharmaceutical and biotechnology companies looking to market new products. The clinical trial process starts in the laboratory with an idea for some intervention to improve some human medical problem, be it allergies or spinal cord injury. The clinical trial process is a long and difficult one. It is possible to go from the development phase to full approval in about 7 years, but 11-15 years is much more the norm. If anything goes wrong during the trial, dosages need to be adjusted or some participants have trouble with the treatment, the time from lab bench to bedside can be considerably longer. That the process is difficult and very strict is probably a good thing. All the animal work that we do before hand means that we are as sure as we can be that when a human undergoes the treatment or takes the drug that not only will no harm come to them, but they will feel better for it. Without that strong database, we may be putting humans at risk in ways that are unacceptable. The worse case scenario for spinal cord injury is a treatment that makes the situation worse, for example you not only do not have improved function but are now in chronic pain as well. If this should happen it could set spinal cord injury research back 10 years, with the FDA saying no approvals without even more evidence that humans will not have adverse reactions. This is why we take the process set forth by the FDA so seriously, and while we work to move forward as fast as possible, we do so very carefully and cautiously.The FDA Approval Process
The FDA approval process for a new treatment can be long and rigorous, but it is long and rigorous for good reason. The FDA seeks to ensure that a potential treatment is safe, as well as effective, for treating an illness or condition. To get a new drug or treatment to the public, it will go through several steps, including pre-clinical studies, submission of an Investigational New Drug application (IND) and approval for testing in humans, human clinical trial phases, and then finally official review and either approval or not for widespread use. Step 1: Pre-clinical TestingPre-clinical testing moves a potential treatment from an idea a researcher has to the point of testing in humans. Many things must happen during this phase, most of them in animals. The data have to show that the treatment is safe and has a significant positive benefit, usually in at least 2 animal species. If it looks as if the treatment is helpful and safe, a convincing amount of evidence must be gather that shows the treatment does not cause harm in an unexpected way, for example damage the liver or kidneys, or cause seizures or high blood pressure. Step 2: Investigational New Drug Application (IND)
An Investigational New Drug Application, or IND, is a formal request to the FDA to test a treatment in humans. It makes the case for the treatment as being ready to try in humans. The IND includes 3 types of information: (1) Animal studies, including all the animal safety and efficacy data, (2) Manufacturing information, information about the composition, manufacturer, stability of the treatment, and (3) Clinical protocols, detailed information on how the treatment would be tested in humans. The IND is reviewed by the FDA and an Institutional Review Board (IRB). The IRB is a panel of scientists and laypeople who examine the IND in detail and from many different perspectives, including regulations, applicable law, and community attitudes. After the review, the treatment is either given the go ahead for clinical trials or not. Step 3: Clinical Trials
There are 3 clinical trail phases that lead to a treatment being approved for the public. A fourth clinical trial phase takes place after approval. Under certain circumstances a disease or disorder may be given "compassionate advancement", this allows phases to be collapsed or modified to get a treatment out to a specific population faster. Aids drugs are an example of this, where the disease course is rapid and lethal, and there were no treatment options. Spinal cord injury treatments may also be given compassionate advancement because of the lack of current treatments.
Phase I clinical trials: Researchers test a new drug or treatment in a small group of people (10-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
Phase II clinical trials: The drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
Phase III clinical trials: The drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
Phase IV clinical trials: These are done after the drug or treatment has been FDA approved and is available to the public. These studies continue testing the drug or treatment to collect information about their effect in various populations and any side effects associated with long-term use.
Step 4: New Drug Application (NDA)
This is the formal request to the FDA for approval to use/market the treatment in the US. The New Drug Application, or NDA, contains all the information gathered in the IND and all the information from the clinical trials. The FDA assigns a review board to evaluate all the information on the treatment’s safety and effectiveness. If given a positive review, the FDA then decides what information should be put on the drug’s labeling or included about the treatment, inspects the facilities where the drug or treatment will be manufactured, and decides whether the treatment is approvable or not. If the treatment is approved, it may be used or prescribed by doctors in the U.S.
Informed Consent
Before participating in any clinical trial, the researchers are required to explain the details of the experiment, including what the purpose of the trail is, what the researchers plan to do, and what your role in the study will be. You are given an opportunity to ask questions and voice concerns. The researcher should also make clear how participants are selected for each of the study groups indicating if the selection process is random and if it is blind (see above for definitions of these terms). If, after hearing all about the study, you want to participate, you will be asked to sign a consent form. This document outlines all the information about the study and your signature indicates that you understand what it means to be a subject in the study.Institutional Review Board (IRB)
Universities and companies that undertake research have oversight committees, often called an Institutional Review Board (IRB), that reviews studies researchers would like to do and determines if the studies are ethical. Usually there are 2 separate committees or boards, one for animal experiments and one for human experiments. Before a researcher is allowed to begin a project, they must have approval from the IRB. For those of us undertaking rodent spinal cord injury research, our studies, or research protocols, are examined very closely to ensure that the animals receive the best possible care before, during and after an injury. We must indicate exactly what we plan to do, how we will do it, and what the consequences are for the animals. The same information must be provided to the human committee before a project with human subjects can proceed. The IRB is often the first checkpoint on the way to clinical trials, the FDA being the final checkpoint before proceeding. =Importance of clinical trial design and outcome measures
How you design a clinical trial, the blueprint for the study, is very important and will in large part determine the type of information you get. A poorly designed study will give you meaningless data. Each clinical trial must be thought through very carefully to ensure that we are confident that the information that comes out of the study, positive or negative, is accurate and result of the treatment and not something else. As a worst-case scenario example, if a clinical trial is designed poorly a promising treatment could be found worthless, when in fact it really does have potential. We cannot afford to rule out treatments unless the decision is based on well designed and run studies. The outcome measures included in the clinical trial design are also critical. Outcome measures are the analysis tools used to determine if a treatment did what you hoped. But, if you are not measuring the right things or are using measure that are not very sensitive, important information could be missed. If, for example, you only measure recovery of walking, you might miss that the treatment improved bladder function. It is also not a good idea to measure everything under sun as this approach dilutes the power of the trial, so a great amount of though must be put into which measures are most likely to show changes after treatment.Double blind randomized controlled trial
In order for the data from a scientific experiment to be meaningful, several important rules must be followed. First of all, it's important to realize that there are many different ways to set up an experiment, depending on what type of questions you are asking. However, if you want to determine if a treatment works or not, the gold standard is the double blind randomized controlled trial. In this type of experiment, also called a trial, there are at least 2 groups, the experimental group and the control group. The experimental group receives the experimental intervention, be it a surgical procedure, drug, or type of physical therapy. The control group is the comparison group. The control group does everything the experimental group does, but subjects in this group do not receive the experimental intervention. For example, if the intervention is a drug, the control group would take a pill that looks exactly like the experimental drug, but is just a sugar pill (also know as a placebo). Control groups are absolutely critical. If you just give a group of people an experimental treatment, we don't know if any changes are due to the treatment or to something else. We simply can't tell. With a control group who had the same exact experience as the experimental group minus the treatment, we can be sure that any differences between the groups are due to the treatment. This is why controlled trials are so important. To make the controlled trial even more powerful and meaningful, people participating in the trial should be randomized into experimental and control groups. That is, each person who signs up for the trial will be placed in to one or the other group by luck of the draw. Literally an experimenter pulls a number out of a hat and that determines which group a subject will go into. A blinded trial means that the subjects in the experiment do not know which group they are in. A double blind trial means that the scientists collecting the data also do not know which group the participants are in. Both scientists and participants likely want the experimental treatment to work very badly. Because of this, with all the best intentions in the world, subjects may report things or scientists may record things in a biased fashion. Blinding participants and data collectors means that this bias will not effect the study and the results are therefore more believable. A double blind randomized controlled trial is the best way to remove any doubt about the reason or cause of changes seen in participants after an experimental treatment. If a double blind randomized controlled trial shows that the experimental group got much better than the control group or that there was no difference between the 2 groups, we can be confident that the results were not due to any kind of bias.ASIA Scale
American Spinal Injury Association (ASIA) Impairment Scale is the gold standard for assessing the extent of a spinal cord injury. The ASIA Scale builds on a scale developed during WWII and brought to the forefront in the 70’s as the Frankel Scale. Injuries are assessed through careful and specific examination of sensory and motor abilities and injury levels are reported on a 5-point scale.
ASIA A is defined as an injury where no motor or sensory function is seen in the sacral segments S4-S5. The scale uses S4-5 because this is the end of the spinal cord proper. This makes the ASIA A designation useful for both cervical and thoracic injuries.
ASIA B is defined as an injury where sensory, but not motor, function is seen below the level of neurological damage and includes the S4-S5 sacral segment.
ASIA C is an injury where motor function is seen below the neurological level of damage, and more than half of the key muscles below the neurological level have a muscle grade less than 3. (In muscle grade 3, the muscle being assessed can move through a full range of motion against gravity but not against any additional resistance. Muscle grade 0 is complete paralysis; in grade 1 muscle contraction is seen but is insufficient to produce motion; in grade 2 the muscle can move through a full range of motion only if gravity is eliminated.)
ASIA D is an injury where motor function is seen below the neurological level, and at least half of the key muscles below the neurological have a muscle grade of 3 or more. (In grade 4 the muscle can move through a full range of motion against gravity and against moderate resistance; grade 5 is normal strength.)
ASIA E is normal motor and sensory function.
While the ASIA scale is very useful, it does have weaknesses and may not capture a person’s entire clinical profile. For example, missing are evaluations of spasticity and pain.
ASIA A is considered a complete injury, while ASIA B-E are incomplete injuries.
Generally a complete injury is defined by the absence of sensory and motor functions in the lowest sacral segments, while incomplete is the preservation of some sensory or motor function below the level of injury, including the lowest sacral segments.