Pain News and Research
Clinical Research Trials
By: Jim Hagan, MS
Has anyone ever asked you to participate in a "drug study" or a test of a new medical device to help relieve your pain? Have you seen advertisements in newspapers looking for people that have certain illnesses for which doctors will provide free treatment? These are usually known as clinical trials.
Clinical trials are research techniques used to study new drugs or therapies on human subjects. By scientifically collecting the results, researchers can determine if the new drugs or therapies are safe and effective for the illness that they are treating. For the person living with pain, for example, researchers for a drug company might have studied a new medication in the laboratory. The researchers have found that it is effective in treating pain in animals without damaging any vital organs and is non-addictive. Now, they wish to try this new medication in humans. The next step is to carry out a drug study, or a clinical trial.
Clinical trials first were recorded in biblical times. In the Old Testament, King Nebuchadnezzar II ordered that a diet of red meat and wine was to be followed for three years. Daniel and three others ate bread and drank water instead of the prescribed diet. After only 10 days, those on the King's diet became ill and Daniel's group was quite healthy!
In 1747, James Lind carried out what is thought to be the first experiment using control groups. A control group in research is the group that receives the standard treatment or a placebo (defined below). The experimental group receives the new treatment. Lind added citrus fruits to the diet of a group of sailors at sea and compared the incidence of scurvy to the control group (ie, sailors who did not receive citrus fruit). He proved that scurvy could be prevented by adding citrus fruits to the sailors' normal diet. Prior to this, the men in the Navy routinely had scurvy because citrus fruit was too expensive to stock on long sea journeys. Once Lind proved this preventive fact via clinical trial, lime juice was provided to the British Navy, hence the nickname "limeys."
The first documented use of the placebo was seen in 1863. A placebo, commonly referred to as a "sugar pill" is simply a tablet, capsule, liquid, spray or suppository that resembles the medication that it is being compared to in the clinical trial. It has no medical properties. Its Latin meaning is, "I will please."
The first randomized trial was conducted in 1923. This is a study where those participating in the trial are chosen to be in one of two or three different groups, or arms of the study. Each of these arms receives a different treatment with one group getting the study treatment or medication and one group possibly receiving a placebo. In 1948, the first randomized, double-blind study was reported. This type of trial is where neither the subject nor the doctor knows which treatment the patient is receiving. This is the way clinical trials are conducted to this day. Double-blind studies provide the researchers with information that is not influenced by either patients reporting feeling better because they want a treatment to work, or by doctors wanting a certain medication to work for their patients.
Clinical trials are divided into four phases. Phase I trials are the first studies to find out the effects of a new treatment, device or medication in healthy humans. Sometimes patients will be used in Phase I trials, but usually these are seriously ill patients who have no other treatment options. Side effects, dosage ranges and safety issues are monitored during this stage. This phase usually lasts less than one year.
Phase II trials use a larger group of patients. This type of trial is used to evaluate how well a particular treatment or drug works for a particular illness or diagnosis. Many more patients are used in Phase II trials than in the smaller Phase I studies. Effective dosage ranges are measured in this phase if a medication is being studied. The side-effect profile compared to the dosage of the drug used is critical, meaning researchers determine at what dosage does the drug produce minimal side effects while still working to relieve or cure the disease. These are randomized, double-blinded studies and can take two to three years to accomplish.
In Phase III trials, thousands of patients are studied. This part of the trial will take many years and millions of dollars to complete. Once the side-effect profiles and the effectiveness of the treatment have been successfully evaluated in this phase, the drug or device company applies to the United States Food and Drug Administration (FDA) for permission to market the drug or medical device. The FDA approves approximately 80% of the medications that complete Phase III clinical trials.
There is one more type of clinical trial: Phase IV. There are multiple uses for this type of study: testing the treatment in populations that were not eligible for admission in the prior studies, such as the young or elderly, or those with illnesses that would not allow them to take part in other phases of the study. In this phase, additional information is also studied about side effects of the treatment over a longer period of time.
Although medications are more commonly studied with patients in clinical trials, we need to talk about devices used to treat pain. The most well known medical devices for persons living with pain are the implants that orthopedic and neurosurgeons use to stabilize the spine. The other advances that we see now are the exciting implantable neurostimulators that surgeons use to apply an electrical current to different types of nerves, which relieve many different types of painful conditions. The other device can be an implantable drug delivery system (pump).
There are many regulations that manufacturers must adhere to in order to obtain approval from the FDA to market new medical devices. Safety and efficacy are the most important, just as with new drugs. If similar implantable products are currently on the market, it is easier for companies to obtain approval to sell new products.
Often, persons in pain are tempted to try anything to relieve their pain. Remember, taking part in a drug study or device trial is your decision. It is only one of your treatment options. TALK to your nurse, doctor and any member of your health care team before making a commitment. In addition, if you decide to participate in a clinical trial, you may stop or remove your consent at any time without jeopardizing your medical care.
Questions to Ask Before Signing the Consent Form
One interesting factor in the practice of medicine and the FDA is off-label use. In many areas of medicine, doctors have inadvertently found effective uses for medications and medical devices that have not been approved by the FDA.
For example, say a number of doctors noticed that women who were taking a certain birth control pill had significantly fewer migraine headaches and the migraine headaches they did have were much milder. In the event that indeed this proved to be statistically significant, the researcher would be responsible to report this finding. This would be an advance in the field of medicine that would show an "off-label use" of a medication originally designed for another purpose.
When you participate in a study about medications for your pain, the researchers are required to report any "adverse events" that patients report. Let us say that you were in a drug trial and you noticed that your skin became clearer. You had acne before starting the "pain medication" and your pain did decrease, but your acne also went away. This would be reported to the FDA as part of the "adverse events" of the project, even though it was a good thing.
In the world of pain medicine, those living with chronic pain have been fortunate to benefit from these interesting discoveries. Many people with long-term pain suffer from depression. One of the common classes of drugs used to treat depression is called tricyclic antidepressants (TCAs). When many of these people with both pain and depression were treated with TCAs in moderate dosages, many of these patients reported a decrease in their pain symptoms. It is interesting to note that quite a few of these people had a lessening of their pain without any relief of their depression! In patients without depression but with neuropathic pain, the TCAs are now considered by all experts as drugs of first choice. Because of clinical trials demonstrating their efficacy in many different neuropathic pain conditions, the manufacturers of these medications have not bothered to undertake an FDA review to obtain an "FDA Indication" (on-label status) because they are proven by studies and widely used already. Until many clinical trials were completed, the use of TCAs for pain was considered "off-label."
Another type of medication that we now use for some patients living with neuropathic pain is used for seizure disorders. The most common drug that we use of this type is called gabapentin. This anti-seizure medication, just like the antidepressant mentioned above, was reported to lessen a type of burning pain, which we call neuropathic, in people taking it to prevent their seizures. Physicians were fascinated about this finding and began to study this effect. Once again, they began to write prescriptions for gabapentin for neuropathic pain, but this was an off-label use of a medication because the drug was FDA-approved for seizure disorders.
The FDA has approved use of this anti-seizure medication for use in post-herpetic neuralgia (PHN), a type of neuropathic pain syndrome. Many researchers are using gabapentin for a multitude of other chronic and acute painful conditions, which again are off-label indications. There are clinical trials now underway to attempt to have gabapentin approved for other pain problems.
If a spinal cord stimulator that was implanted for arm pain, but additionally removed all symptoms from the patient's chest pain (ie, intractable angina), wouldn't the health care provider feel compelled to report this?
Clinical trials of any type, which allow the patient, physician and researcher to discover and study interesting things that can assist in treatment of disorders that were not the focus of the original clinical trial, are wonderful, unexpected gems.
You will be informed if any adverse factors are reported at any time during your participation in a clinical trial. You also will be told if, at any time during your involvement in a study, any information about any possible harm is discovered. When new facts are learned about the study, you will be asked to sign a new consent form that explains any new known risks. At this time, you will be able to stop your participation in the study.
The Institutional Review Board (IRB) protects you as a patient who participates in a clinical study. This group consists of a variety of people who have an interest in research involving people and their safety. Usually, this group is composed of physicians and nurses who themselves conduct research, so are acutely aware of what people are exposed to during drug and medical device trials. The committee usually has members of the clergy, lay people and often pharmacists who can judge the possible side effects of medications that might be used during a trial. In addition, when the National Institutes of Health (NIH) funds a study, it will be involved to approve the study and to make sure that the study protocol is safe.
Most likely, the name of a member of the IRB and a telephone number for that person will be given to you on the consent form. This is made available to you so that you will have an impartial person to contact to answer questions about the study that you are thinking about joining. Often, patients feel pressure to participate in a clinical trial when asked by their doctor or nurse. You must understand that you have the right to refuse to participate in a clinical trial and you will still receive the same quality of medical care that you were getting before the offer of joining a study was presented to you.
NEVER agree to be part of a drug or medical device trial when first asked. Take time to investigate and ask questions.
ALWAYS get a copy of the consent form to take with you to read and discuss with trusted family members, friends and other medical professionals.
MAKE a written list of questions to take with you to be answered by the doctor, nurse or study coordinator before signing the consent form.
REMEMBER that you can stop participating in a clinical trial at anytime without your medical treatment being affected. If you feel that you are being treated unfairly or your medical care is of lower quality than it used to be, contact the IRB contact person listed on your consent form, your hospital administrator or your state medical board.
Clinical trials are research techniques used to study new drugs or therapies on human subjects. By scientifically collecting the results, researchers can determine if the new drugs or therapies are safe and effective for the illness that they are treating. For the person living with pain, for example, researchers for a drug company might have studied a new medication in the laboratory. The researchers have found that it is effective in treating pain in animals without damaging any vital organs and is non-addictive. Now, they wish to try this new medication in humans. The next step is to carry out a drug study, or a clinical trial.
Brief History and Types of Clinical Trials
Clinical trials first were recorded in biblical times. In the Old Testament, King Nebuchadnezzar II ordered that a diet of red meat and wine was to be followed for three years. Daniel and three others ate bread and drank water instead of the prescribed diet. After only 10 days, those on the King's diet became ill and Daniel's group was quite healthy!
In 1747, James Lind carried out what is thought to be the first experiment using control groups. A control group in research is the group that receives the standard treatment or a placebo (defined below). The experimental group receives the new treatment. Lind added citrus fruits to the diet of a group of sailors at sea and compared the incidence of scurvy to the control group (ie, sailors who did not receive citrus fruit). He proved that scurvy could be prevented by adding citrus fruits to the sailors' normal diet. Prior to this, the men in the Navy routinely had scurvy because citrus fruit was too expensive to stock on long sea journeys. Once Lind proved this preventive fact via clinical trial, lime juice was provided to the British Navy, hence the nickname "limeys."
The first documented use of the placebo was seen in 1863. A placebo, commonly referred to as a "sugar pill" is simply a tablet, capsule, liquid, spray or suppository that resembles the medication that it is being compared to in the clinical trial. It has no medical properties. Its Latin meaning is, "I will please."
The first randomized trial was conducted in 1923. This is a study where those participating in the trial are chosen to be in one of two or three different groups, or arms of the study. Each of these arms receives a different treatment with one group getting the study treatment or medication and one group possibly receiving a placebo. In 1948, the first randomized, double-blind study was reported. This type of trial is where neither the subject nor the doctor knows which treatment the patient is receiving. This is the way clinical trials are conducted to this day. Double-blind studies provide the researchers with information that is not influenced by either patients reporting feeling better because they want a treatment to work, or by doctors wanting a certain medication to work for their patients.
Clinical trials are divided into four phases. Phase I trials are the first studies to find out the effects of a new treatment, device or medication in healthy humans. Sometimes patients will be used in Phase I trials, but usually these are seriously ill patients who have no other treatment options. Side effects, dosage ranges and safety issues are monitored during this stage. This phase usually lasts less than one year.
Phase II trials use a larger group of patients. This type of trial is used to evaluate how well a particular treatment or drug works for a particular illness or diagnosis. Many more patients are used in Phase II trials than in the smaller Phase I studies. Effective dosage ranges are measured in this phase if a medication is being studied. The side-effect profile compared to the dosage of the drug used is critical, meaning researchers determine at what dosage does the drug produce minimal side effects while still working to relieve or cure the disease. These are randomized, double-blinded studies and can take two to three years to accomplish.
In Phase III trials, thousands of patients are studied. This part of the trial will take many years and millions of dollars to complete. Once the side-effect profiles and the effectiveness of the treatment have been successfully evaluated in this phase, the drug or device company applies to the United States Food and Drug Administration (FDA) for permission to market the drug or medical device. The FDA approves approximately 80% of the medications that complete Phase III clinical trials.
There is one more type of clinical trial: Phase IV. There are multiple uses for this type of study: testing the treatment in populations that were not eligible for admission in the prior studies, such as the young or elderly, or those with illnesses that would not allow them to take part in other phases of the study. In this phase, additional information is also studied about side effects of the treatment over a longer period of time.
Although medications are more commonly studied with patients in clinical trials, we need to talk about devices used to treat pain. The most well known medical devices for persons living with pain are the implants that orthopedic and neurosurgeons use to stabilize the spine. The other advances that we see now are the exciting implantable neurostimulators that surgeons use to apply an electrical current to different types of nerves, which relieve many different types of painful conditions. The other device can be an implantable drug delivery system (pump).
There are many regulations that manufacturers must adhere to in order to obtain approval from the FDA to market new medical devices. Safety and efficacy are the most important, just as with new drugs. If similar implantable products are currently on the market, it is easier for companies to obtain approval to sell new products.
Pros and Cons of Participation in Clinical Trials
Often, persons in pain are tempted to try anything to relieve their pain. Remember, taking part in a drug study or device trial is your decision. It is only one of your treatment options. TALK to your nurse, doctor and any member of your health care team before making a commitment. In addition, if you decide to participate in a clinical trial, you may stop or remove your consent at any time without jeopardizing your medical care.
Questions to Ask Before Signing the Consent Form
- What are the risks involved in participating in this study?
- What benefits might I expect to see?
- If I am in a placebo group, will I automatically be switched to the real drug or device?
- Will there be any financial cost to me for participating in this trial?
- If I am hurt in any way, or if I have side effects that have to be treated, who pays for the costs?
- Will I be paid anything for my time and additional costs for extra visits to the office or hospital?
Off-Label Use
One interesting factor in the practice of medicine and the FDA is off-label use. In many areas of medicine, doctors have inadvertently found effective uses for medications and medical devices that have not been approved by the FDA.
For example, say a number of doctors noticed that women who were taking a certain birth control pill had significantly fewer migraine headaches and the migraine headaches they did have were much milder. In the event that indeed this proved to be statistically significant, the researcher would be responsible to report this finding. This would be an advance in the field of medicine that would show an "off-label use" of a medication originally designed for another purpose.
When you participate in a study about medications for your pain, the researchers are required to report any "adverse events" that patients report. Let us say that you were in a drug trial and you noticed that your skin became clearer. You had acne before starting the "pain medication" and your pain did decrease, but your acne also went away. This would be reported to the FDA as part of the "adverse events" of the project, even though it was a good thing.
In the world of pain medicine, those living with chronic pain have been fortunate to benefit from these interesting discoveries. Many people with long-term pain suffer from depression. One of the common classes of drugs used to treat depression is called tricyclic antidepressants (TCAs). When many of these people with both pain and depression were treated with TCAs in moderate dosages, many of these patients reported a decrease in their pain symptoms. It is interesting to note that quite a few of these people had a lessening of their pain without any relief of their depression! In patients without depression but with neuropathic pain, the TCAs are now considered by all experts as drugs of first choice. Because of clinical trials demonstrating their efficacy in many different neuropathic pain conditions, the manufacturers of these medications have not bothered to undertake an FDA review to obtain an "FDA Indication" (on-label status) because they are proven by studies and widely used already. Until many clinical trials were completed, the use of TCAs for pain was considered "off-label."
Another type of medication that we now use for some patients living with neuropathic pain is used for seizure disorders. The most common drug that we use of this type is called gabapentin. This anti-seizure medication, just like the antidepressant mentioned above, was reported to lessen a type of burning pain, which we call neuropathic, in people taking it to prevent their seizures. Physicians were fascinated about this finding and began to study this effect. Once again, they began to write prescriptions for gabapentin for neuropathic pain, but this was an off-label use of a medication because the drug was FDA-approved for seizure disorders.
The FDA has approved use of this anti-seizure medication for use in post-herpetic neuralgia (PHN), a type of neuropathic pain syndrome. Many researchers are using gabapentin for a multitude of other chronic and acute painful conditions, which again are off-label indications. There are clinical trials now underway to attempt to have gabapentin approved for other pain problems.
If a spinal cord stimulator that was implanted for arm pain, but additionally removed all symptoms from the patient's chest pain (ie, intractable angina), wouldn't the health care provider feel compelled to report this?
Clinical trials of any type, which allow the patient, physician and researcher to discover and study interesting things that can assist in treatment of disorders that were not the focus of the original clinical trial, are wonderful, unexpected gems.
You will be informed if any adverse factors are reported at any time during your participation in a clinical trial. You also will be told if, at any time during your involvement in a study, any information about any possible harm is discovered. When new facts are learned about the study, you will be asked to sign a new consent form that explains any new known risks. At this time, you will be able to stop your participation in the study.
Who Protects Your Safety and Rights as a Patient?
The Institutional Review Board (IRB) protects you as a patient who participates in a clinical study. This group consists of a variety of people who have an interest in research involving people and their safety. Usually, this group is composed of physicians and nurses who themselves conduct research, so are acutely aware of what people are exposed to during drug and medical device trials. The committee usually has members of the clergy, lay people and often pharmacists who can judge the possible side effects of medications that might be used during a trial. In addition, when the National Institutes of Health (NIH) funds a study, it will be involved to approve the study and to make sure that the study protocol is safe.
Most likely, the name of a member of the IRB and a telephone number for that person will be given to you on the consent form. This is made available to you so that you will have an impartial person to contact to answer questions about the study that you are thinking about joining. Often, patients feel pressure to participate in a clinical trial when asked by their doctor or nurse. You must understand that you have the right to refuse to participate in a clinical trial and you will still receive the same quality of medical care that you were getting before the offer of joining a study was presented to you.
Things to Consider Before Signing The Consent Form:
NEVER agree to be part of a drug or medical device trial when first asked. Take time to investigate and ask questions.
ALWAYS get a copy of the consent form to take with you to read and discuss with trusted family members, friends and other medical professionals.
MAKE a written list of questions to take with you to be answered by the doctor, nurse or study coordinator before signing the consent form.
REMEMBER that you can stop participating in a clinical trial at anytime without your medical treatment being affected. If you feel that you are being treated unfairly or your medical care is of lower quality than it used to be, contact the IRB contact person listed on your consent form, your hospital administrator or your state medical board.