Clinical Trials / Parkinson's Disease
Medical research has helped us lead longer, healthier lives, but it has also sparked ethical concerns and contentious political debate. Through a Parkinson's Disease case, panelists explore the controversial world of clinical trials and debate the potential gains and pitfalls of science on the edge.
An aging population, and increase in Parkinson's Disease
The age 60+ population in the United States will more than quadruple within the next decade [Source: Census 2000]. Since most people with Parkinson's disease start developing it in their 60s, health experts expect a corresponding increase in the number of baby boomers being newly diagnosed with the disorder. The result will be a great deal of human suffering as well as a substantial drain on society. When we combine today's price tags for treatment, Social Security payments and lost income from premature disability, Parkinson's disease already costs our nation in excess of $6 billion annually [Source: The National Institute of Neurological Disorders and Stroke].
Medical research has visibly transformed the practice of medicine over the past fifty years, and even greater benefits may be possible in the next fifty years. Without doubt, it holds the promise of easing the growing burden for Parkinson's disease as well as other age-related chronic diseases.
About Parkinson's Disease
The disease begins when a class of brain cells that produce dopamine start to die. Dopamine is a neurotransmitter (chemical messenger) critical to relaying brain messages that control both balance and movement. When dopamine isn't sufficient, cells don't signal each other properly and people eventually develop symptoms such as resting tremor, slowness of movement, rigidity and instability in walking, as well as a variety of non-motor symptoms such as depression and sleep disturbances. However, Parkinson's symptoms manifest differently in different patients. Many patients experience some symptoms and not others, and even the pace at which the disease worsens varies on an individual basis.
Parkinson's generally progresses gradually and people can have many years of productive living after being diagnosed. When symptoms get worse, though, even the simplest tasks can be an ordeal. Parkinson's itself is not fatal. However, as symptoms worsen they can cause complications that result in death.
Current treatments relieve symptoms but nothing exists to arrest the disease or cure it.
About Parkinson's Disease research
There are many types of medical research including:
- Basic medical research to create new knowledge through the study of cells, molecules and chromosomes. This type of research helps us to understand the genetic and environmental factors that increase the odds of developing a disease and points to new ways to prevent, diagnose, manage and even cure a variety of disorders.
- Translational research to use the knowledge discovered through basic research to develop new drugs, vaccines, devices and medical procedures. It is the research stage where laboratory and clinical activities are closely aligned.
- Clinical research to test patients or tissue samples from patients for information about specific illness and conditions. Clinical research includes studies called clinical trials where a treatment or therapy is tested in people to see whether it's safe and effective.
- Outcomes-based research to provide evidence upon which clinicians can more scientifically select among existing treatment options for individual patients.
Active research projects in Parkinson's disease are taking place at all levels to find ways to prevent Parkinson's disease, diagnose it at earlier stages, treat symptoms, halt its progression and even repair damage.
About Parkinson's DiseaseParkinson's disease is the second most common neurodegenerative disease in the US.
- Nationwide, as many as 1.5 million people suffer from Parkinson's and about 50,000 Americans are diagnosed with the disease yearly.
- While the average age at onset is 60, disease onset starts by age 40 in an estimated five to 10 percent of patients, and people as young as 30 can also be affected.
- Parkinson's strikes slightly more men than women and more whites than blacks in the U.S.
- If we combine the price tags for treatment, Social Security payments and lost income from premature disability, Parkinson's disease already costs our nation in excess of $6 billion annually.
- Every person living with Parkinson's disease experiences a different range of symptoms.
- At present, there is no cure for Parkinson's disease. Both medical and surgical interventions offer only symptom relief and do not affect the underlying pathology of the disease.
About Clinical Trials
- A clinical trial is a research study in which a treatment or therapy is tested in people to see whether it is safe and effective.
- There are clinical trials for healthy people (for example, to prevent disease) and trials for many different types and stages of diseases and conditions.
- All clinical trials have guidelines about who can participate. Before joining a clinical trial, a participant must qualify for the study.
- Informed consent is the process of learning the key facts about a clinical trial before deciding whether or not to participate. It is also a continuing process throughout the study to provide information for participants.
- Clinical trials are sponsored or funded by a variety of organizations or individuals such as the federal government, pharmaceutical companies, biotechnology companies, device manufacturers, diagnostic manufacturers, medical institutions, physicians, foundations and voluntary groups.
- Clinical trials can take place in a variety of locations, such as hospitals, universities, doctors' offices, or community clinics.
- While there are many benefits to being involved in a clinical trial, there are also risks. Not all new treatments being studied will turn out to be better or even as good as the standard available care, and there may also be unknown side effects with the new treatment.
Ask Your Doctor
About Parkinson's Disease
- Are there other conditions that might be causing my symptoms?
- What stage do you think my illness is in now?
- How quickly do you think my disease will progress?
- What treatments are available for me at my stage of Parkinson's disease? Which is best for me? Why?
- How soon can I expect the new treatment to start working?
- If drugs are prescribed: What are the side effects? If so, how can they be managed?
- At what point should I consider surgery?
- Do I have to restrict or change my daily routine?
- Will Parkinson's disease affect my ability to work?
- Can I drive?
- Should I change my diet in any way? Take vitamins? Change my exercise regimen?
- How often will I need a checkups?
- Will I need to arrange for help?
- What resources are available for education and support for my family and myself?
- Are there any clinical trials in which it would be appropriate for me to participate?
About Parkinson's Disease Clinical Trials
- What is the purpose of the trial and what do they expect to learn?
- What are the reasons why it might make sense for me to be part of this trial?
- What phase is the trial?
- Who is going to be in the trial?
- How big is the trial?
- How many will be in the trial?
- Is it being conducted in one place or in many places?
- Who is sponsoring or paying for the study? Do any of the members of the research team:
- Have a financial interest in the outcome of the study?
- Own stock in the company testing the drug or medical device?
- Receive money for any reason from the company making the medicine or medical device?
- What conflict of interest policies are in place at this location?
- What kinds of tests and treatments are involved?
- Why do researchers believe the treatment being tested may be effective? How likely is it that I will experience a benefit?
- Have there been similar studies that used the same type of drugs, devices, etc? What happened in those studies?
- How do the possible risks, side effects, and benefits in the study compare with my current treatment?
- Will everyone in the trial receive the same drugs, devices, procedures or will there be different groups that are treated differently? If so:
- Is it possible that I won't receive the experimental treatment even if I'm in the study?
- Will the research team know what group I'm in?
- In an emergency, can someone find out what group I've been in and share the information with my doctor?
- How will they monitor my safety during the trial?
- What are the risks and how likely is it that I'll experience a problem? What happens then?
- Will any of the procedures or tests that are part of the study hurt or cause me discomfort? If so, how much and for how long?
- Will being in the study mean that there are drugs or treatments I won't be able to have?
- Could my condition get worse during the study? What will happen if it does?
- Will hospitalization be required?
- How many times will I have to visit the hospital or doctor's office during the study? How long would each visit be?
- Will I have to fill out any paperwork during the study? How much?
- Who will be in charge of my care?
- Will I continue to see my current medical team during the study?
- How will the study staff work with my primary physician to keep him or her informed about my care?
- How might this trial affect my daily life?
- How long will the trial last?
- What type of long-term follow up care is part of this study?
- Who will pay for the treatment?
- Will I be paid for participation or reimbursed for out-of-pocket expenses?
- Who would be able to look at the records of my participation in the research?
- Will results of the trials be provided to me? If so, when?
- How much time do I have before I must decide?
- If I enroll in a study, can I change my mind?
- What other options are available if I don't participate in the study?
Key Point 1
Treatment options for Parkinson's Disease, as with other diseases, change over time. Therapies are researched and some standard therapy may be unproven. You need to be informed.
Coping with chronic illness can be overwhelming. But, by learning as much as you can about your condition, you'll be better able to make informed decisions. The more information you have, the more in control you'll feel.
Because Parkinson's symptoms vary from individual to individual there's no "one-size-fits-all" treatment. Care can be complex and you should look to your primary care physician to provide coordination. In addition to your PCP, you may see specialists such as neurologists, physical therapists, speech therapists and psychiatrists.
It's important to understand that, at present, there is no cure for Parkinson's disease. Both medical and surgical interventions offer only symptom relief and do not affect the underlying pathology of the disease.
In the early stages of Parkinson's, your doctor may advise you to wait to take medication and, instead, try to manage symptoms with other therapies.
- Physical therapy can be helpful both in the early stages and later to improve mobility, range of motion, balance and muscle tone.
- Speech therapy can help improve problems with speaking and swallowing.
- Massage therapy can improve quality of life by helping to relieve stress (stress can aggravate symptoms) and may provide some relief from muscle rigidity.
Levodopa has been the mainstay of therapy for Parkinson's disease for several decades. Most patients experience a dramatic improvement in symptoms when they start taking it. However, over time (in about four to five years) its effectiveness declines and adverse side effects increase.
There's no absolute right time to start taking medication. Your doctor's job will be to balance symptom relief against side effects. Your doctor may:
- Have you take levodopa only when your symptoms are causing difficulty (this is called rescue medication or rescue levodopa)
- Delay levodopa therapy as much as possible by using alternative drugs
- Start levodopa early at a lower dose, increasing it as needed
- Use levodopa in combination with other medications
Levodopa is a chemical found naturally in plants and animals. Nerve cells use it to make dopamine. Unlike dopamine itself, levodopa can cross the blood-brain barrier (cells in the walls of the brain's capillaries that screen out certain substances), though only a small amount actually reaches the brain. That's why levodopa is usually combined with carbidopa. Carbidopa delays the conversion of levodopa into dopamine until it reaches the brain, enhancing its effectiveness and diminishing side effects.
Problems with levodopa or levodapa-carbidopa therapy may include:
- Wearing-off effect (doses becomes less effective more quickly)
- On-off effect (symptoms appear and disappear suddenly and unpredictably)
- Involuntary movements such as nodding, jerking, abnormal twisting
- Drop in blood pressure when standing
- Hallucinations and confusion
Other drugs may be used alone or in combination with levodopa and include:
- Dopamine agonists. Mimics the effects of dopamine in the brain.
- MAO-B inhibitors. Prevents the breakdown of dopamine.
- Catechol-O-Methyltransferase (COMT) inhibitors. Prolongs the effect of carbidopa-levodopa.
- Amantadine. Provides short-term relief of mild, early-stage Parkinson's disease; helps control involuntary movements caused by carbidopa-levodopa in later stages.
- Coenzyme Q10 supplements. May slow the progression of early-stage Parkinson's in some patients (based on a limited study).
- Anticholinergics. Helps control tremor in the early stages of the disease.
Surgery may be considered when medication either fails to control symptoms or causes disabling side effects. However, as with medication, no currently available surgical treatment has been proven to either slow disease progression or restore the nerve cells affected by Parkinson's. Postoperative improvement usually lasts several years in most patients, but symptoms may return or other symptoms appear after surgery as the disease progresses. Procedures include deep brain stimulation (DBS) and ablation surgery.
- Deep brain stimulation (DBS) involves implantation of tiny electrodes within the brain. The electrode wires are connected to a pacemaker-like unit implanted in the upper chest. This device delivers controlled pulses of energy through the electrodes to block brain signals that cause symptoms. The pulses are adjustable, so they can be tailored to the individual patient. Electrodes placed in the thalamus reduce tremor; those placed in the globus pallidus or subthalamus are most effective in treating stiffness and dyskinesias.
- Ablation (or lesion) surgery involves destroying cells in the brain to block the pathways of messages that can lead to symptoms. These lesions are not reversible. Pallidotomy targets the globus pallidus to reduce stiffness and dyskinesias. Thalamotomy targets the thalamus to reduce tremor.
On the Horizon
The research being done today, both in the laboratory and in clinical research with Parkinson's patients, holds real promise that a cure could be near. In the meantime, a wide range of approaches to better manage or slow the progress of the disease are now in clinical trials. Many leading Parkinson's groups and the National Institute of Neurological Disorders and Stroke, are leading a nationwide effort to accelerate the development of new treatments for Parkinson's disease by increasing awareness and participation in clinical research. To learn about the importance of clinical trials and to find trials in your area, contact the information request line for PDTrials at (888) 823-8889 or visit www.PDtrials.org
Key Point 2
Well-designed clinical trials are essential to developing new treatments and possible cures. Participation in a clinical trial is a selfless act that may help many other people in the future. It's research, not therapy.
Experiments in test tubes and mice may show great potential, but what works in the laboratory doesn't necessarily translate to humans. We have to test new approaches, drugs, biologics (such as vaccines) or procedures with people to show what really works and that's the role of the clinical trial.
There are many types of clinical trials including studies to prevent, delay, detect, and cure disease, manage symptoms and improve quality of life. The U.S. Food and Drug Administration (FDA) requires trials to be successfully completed before a new product can be brought to market.
Clinical trials are done in phases, with each phase designed to answer specific questions about the safety, tolerability, and effectiveness of the potential treatment.
- Phase 0 is a recent designation for an exploratory trial to establish very early on whether an agent behaves in human subjects as was anticipated from preclinical studies.
- Phase I tests for safety. It involves relatively few patients.
- Phase II tests a larger group of people, and researchers begin to look for signs of effectiveness.
- Phase III tests even larger groups of people to confirm effectiveness, monitor side effects, and make comparisons to existing treatments.
- Phase IV occurs after the treatment has been approved to oversee its effect on various populations and determine the consequences of long-term use.
Enrollment in clinical trials is always voluntary. Choosing whether or not to take part in a one is an important personal decision. To make a choice that's right for you, you need to understand the differences between medical therapy and a clinical trial.
|Is undertaken to treat a patient and improve his or her health||Is undertaken to gain knowledge so that treatment can be improved for future patients|
|Can be adjusted to meet the needs of the patient||Follows a strict protocol|
|Has been deemed safe by clinical testing in the past||May involve a degree of risk despite safeguards designed into the protocol|
|Has a history that can be used to predict potential side effects and outcomes||Has a limited history from earlier trials that may be useful for Phase III participants|
You also need to understand there are no guarantees in clinical trials. A new treatment is not always better, and can sometimes be worse than existing treatments. Plus, some participants may not receive the experimental treatment. Typically, trial subjects are randomly divided into groups. One group receives the treatment and the other does not. The people in the latter group may receive the standard treatment or a placebo.
All that being said, there are many reasons to participate in a clinical trial.
- Clinical trials are an essential and necessary component of the scientific research process. New and better treatments will come only if people volunteer for trials. People who participated in the past are responsible for the treatments everyone enjoys today.
- Participating in a clinical trial can be a satisfying and worthwhile experience. People can feel good about contributing to the advancement of medical knowledge and helping others in the future.
- If all approved treatment options have failed, or none exist, the possibility of gaining access to an advantageous alternative may be enough. While researchers cannot guarantee outcomes, patients who participate in clinical trials sometimes have higher survival rates than patients who receive standard treatment.
- Patients in clinical trials receive very close monitoring by medical professionals who are leaders in their fields.
In the case of Parkinson's disease, we're on the brink of many exciting new treatments including new methods to deliver dopamine to critical areas in the brain, protecting nerve cells from premature death, and replacing dead nerve cells with transplanted tissue.
However, to move these and other promising concepts from the research stage into the hands of patients who need them, more people with Parkinson's need to take part in clinical trials. According to the Parkinson's Disease Foundation, the approximately 5,000 people with Parkinson's who participate in clinical research today is far short of the 10,000 to 15,000 who will be needed to conduct clinical studies over the next two to three years. This disparity could result in severe delays in the availability of new treatments.
Key Point 3
There are ethical considerations in all clinical trials, and participation can have personal and societal benefits. It is important that research be done ethically at all times.
Both medical therapy and clinical trials are governed by law and strict ethical codes. Does that mean that all ethical questions have been solved? Not at all. There are still many unknowns and even competing ethical principles that surface in standard clinical practice. Because research is a leap into the unknown by its very nature, the complexity of ethical issues with clinical trials is infinitely greater.
The most basic of ethical dilemmas surrounds why people participate in clinical trials. When someone chooses to enroll in the hope that the study will possibly yield a cure for others in the future, there's no conflict. But, statistics show that most people sign up for the chance of a cure for themselves. Should we protect desperate people from unnecessary discomfort that might be involved in a clinical trial and disappointment if they don't receive a benefit? Or, should they be encouraged to continue to hope, despite the odds?
Researchers and regulators walk the fine line of defining good ethical practice every day. Basic principles demand that:
- The trial is scientifically worthy and well designed
- Those conducting the trial are qualified
- Those conducting the trial are free of bias, including issues related to financial interests
- Risks are as low as possible and are reasonable when compared to the importance of what may be learned
- Studies are suspended or terminated if the risks turn out to be greater than expected
- Participants are given the information they need and in a form they can understand so they can make an informed choice about whether to volunteer or to stay in the trial
- Neither coercion (such as a threat of harm) nor undue influence (such as an excessive reward) is used to persuade someone to enroll
- The selection of subjects and assignment to groups is equitable
Initially, these sound straightforward. But, on closer inspection, these seemingly simple concepts are not always as clear-cut as they seem. For example, the majority of clinical trials assign participants to groups. One group receives the new therapy; the other group (or groups) receives either the standard treatment for their disease or a placebo. Assignment is done by chance (called randomization). While the potential for bias is removed by random selection, the fact remains that unless both therapies turn out to be equal some people will receive inferior treatment.
Medical research holds ethical questions for society at large as well as for the individuals who are involved in them. Right now the use of stem cells is being hotly debated at all levels of government and the scientific community.
Stem cells are undifferentiated cells that have the potential to develop into any cell type in the body. In the case of Parkinson's disease, researchers hope that stem cells can be coaxed into becoming healthy dopamine neurons, which can then be transplanted into the brain.
Much of the controversy surrounding the use of stem cells has to do with how they're obtained. Harvesting embryonic stem cells destroys the embryo (though researchers are now working on promising ways to prevent this). Right-to-life advocates view embryo destruction as equivalent to murder. Another technique is to use a person's own genetic material to source stem cells. The process is called therapeutic cloning and many fear it to be the first step on the path to the reproductive cloning of humans.
Bottom line, ethics is anything but an exact science and there's rarely one correct answer for any issue. While clinical trials are conducted far more ethically and are far safer now than they were thirty years ago, many ongoing dilemmas remain to be debated and resolved.