Ethical Issues in Clinical Trial Participation

Ann Heesters
Director of Ethics and Spiritual Care
Toronto Rehabilitation Institute

Marleen Van Laethem
Research Ethicist
Toronto Rehabilitation Institute

What is a major misunderstanding people have about clinical trials?

A clinical trial is a research study testing a new potential treatment. “Therapeutic misconception” is the name ethicists give to the misconception or confusion people have that what’s being offered is always therapeutic (or for their benefit). Let’s say, you have been newly-diagnosed and your healthcare provider says, “These are the current available treatments. They all have some potential problems or side-effects; however, we have a research study looking at something new.” The patient may think, these are all potential therapies for me, but if they look more closely at the details of the clinical trial, they may find that the study is going to compare a new treatment against placebo, which is essentially a non-treatment. It is important that people read the details of clinical trials very carefully.

Where does conflict of interest arise?

One form of conflict of interest is known as a tension of obligations. A physician-researcher wears two hats: As a physician, the primary obligation is to recommend the best treatment for the patient. But as a researcher, the primary obligation is to the integrity of the study, which could mean that half the patients will go on placebo as a control and the other half will get the active new substance. The patients on placebo may later wonder: Why did my doctor put me in that group? However, researchers typically don’t have control over that. Participants are assigned to groups through mass randomization to try to eliminate bias.

Conflict of interest may also relate to financial incentives. A researcher may have a patent on a new molecule or new device that is being tested. He/she may accept speaker’s fees, or act as an advisor to the company sponsoring the research. In cases like these, financial interests may influence judgement. An interest in making money shouldn’t take precedence over sound research principles or the obligation to care for patients, and most of the time the potential for conflict will be manageable with appropriate disclosure. However, financial interests should be described in the informed consent document because they may affect a participant’s desire to be involved in a trial.

What is the purpose of informed consent?

“Informed consent” means providing people with all the information they need to make a full decision concerning whether they want to be in a study. Many ethicists refer to it as “informed choice.” It has to be voluntary. You make a choice based on all the information that is relevant to you. The information should include the procedures you have to undergo, the time commitment, the known side-effects and any other potential harms. These may include physical harm, psychological harm and, in this computer age, informational harm. For example, if participation in a genetic study could have insurance or employment implications for the participant, that risk should be spelled out in the consent form, in plain language, so that people know there is a potential risk to their privacy.

Is the informed consent document a contract?

No. Contracts have binding qualities. They impose obligations. Informed consent documents are not binding at any stage. Participants must be able to withdraw from a trial without damaging the relationship with their clinical team and without offending the researchers or upsetting the hospital or organization sponsoring the research.

Can a trial participant withdraw at any time?

In principle, you can withdraw from a study at any time. However, if a study includes a surgical procedure, and the procedure has already taken place, the surgery cannot be undone. A person can say: “I don’t want to continue with this study. I don’t want you to continue collecting my data and I don’t want my data being used in your research analysis.”

Is the use of placebo ethical?

Many hold the view that when there is an established effective therapy for a condition it would be unethical to place some participants on a placebo. Ethically, it is easier to defend comparing an experimental drug against the current established effective therapy. If researchers believe that it is essential to compare the experimental drug against a placebo they must meet stringent conditions. (It may be argued, for example, that a sub-set of patients find current treatment intolerable or ineffective or there may be no other way to isolate the effects of the new drug.)

Another way that a placebo could be used is to add it onto existing treatment. If there is an established effective therapy and there are two arms in the trial: group A gets the established effective therapy plus placebo and group B gets the established effective therapy plus the experimental drug. In this scenario, the placebo arm is not placed at a disadvantage.

What happens if the trial reveals new side-effects?

Those running trials are obliged to share new information concerning side-effects which may affect research subjects’ desire to continue to participate.

Should participants have access to beneficial treatment after a trial ends?

People often enrol in trials hoping to get early access to experimental treatments. Treatments can be expensive but in clinical trials they are usually provided free of charge. If a research participant finds an experimental treatment to be beneficial, he/she may want to continue taking the treatment until it is Health Canada-approved and available on the market. Some may even argue that they are owed access because they have placed themselves at risk by participating in a trial. At minimum, the informed consent form should state clearly whether or not the person will have access to the treatment after the trial concludes. Researchers don’t want to make promises that they can’t keep. Also, there is no guarantee that the treatment will be found to be effective.

Can a trial participant sue?

If people have been negligent in the way they conducted the trial, or if the research ethics board has been negligent in reviewing the trial proposal, then trial participants can exercise any and all of their legal rights. You don’t waive your legal rights by agreeing to participate in a trial.

Resources

Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans

World Medical Association Declaration of Helsinki
(Ethical Principles for Medical Research Involving Human Subjects)

Ann Heesters
Ann Heesters
Marleen Van Laethem
Marleen Van Laethem

New directions in Parkinson’s treatments

Slowing down or modifying disease progression

Current drugs for Parkinson’s treat the symptoms but do not stop the progression. One of the biggest investments in Parkinson’s research is in trying to find a drug that will slow down or modify the disease progression.

Azilect®

The drug rasagiline (Azilect®) was studied recently to determine if it could slow down the rate of progression in Parkinson’s. Researchers conducted a double-blind, delayed-start trial in which 1176 people who were not on Parkinson medications were randomly assigned to either receive rasagiline (at a dose of 1 mg per day or 2 mg per day) for 72 weeks or placebo for 36 weeks, followed by rasagiline (at a dose of 1 mg per day or 2 mg per day) for 36 weeks (the delayed-start group).

The study results were mixed: people who had an early start with rasagiline at a dose of 1 mg per day had a smaller increase in worsening of their Parkinson’s symptoms than the placebo group; however, early treatment with rasagiline at a dose of 2 mg per day did not show similar results.

The study concluded: “Early treatment with rasagiline at a dose of 1 mg per day provided benefits that were consistent with a possible disease-modifying effect, but early treatment with rasagiline at a dose of 2 mg per day did not. Because the two doses were associated with different outcomes, the study results must be interpreted with caution.”

The study’s authors noted that it will be important to determine whether these results can be confirmed and whether the benefits seen at 18 months will endure and translate into reduced cumulative disability in clinically meaningful areas such as impairment of gait and balance and cognitive function.

A Double-Blind, Delayed-Start Trial of Rasagiline in Parkinson’s Disease
New England Journal of Medicine 361:13 September 24, 2009

 

Continuous dopaminergic stimulation

The standard oral medication for handling motor fluctuations in Parkinson’s is levodopa which is a short-acting drug. However, for some people, levodopa’s beneficial effects wear off before the next dose of medication is due. Infusion therapies for Parkinson’s aim to provide a more continuous stimulation of the brain receptors for dopamine, when oral medications are no longer effective. This type of treatment is known as continuous dopaminergic stimulation.

Infusion therapies / DUODOPATM

Infusion therapies have been examined in Europe and the UK, in the form of pumps that infuse the drugs apomorphine or lisuride into the tissue under the skin where the medication is then absorbed into the bloodstream.

“What’s new is there is now an alternative infusion technology that uses the best available drug for oral use, levodopa, but infuses it through the duodenum, so it goes into the bowel, on a continuous basis,” says Dr. Anthony Lang, director of the Morton and Gloria Shulman Movement Disorder Centre at Toronto Western Hospital.

In this technology, Duodopa, a form of levodopa/carbidopa that is concentrated into a gel, is pumped through a small tube that is placed through the stomach and into the duodenum.

One advantage of this style of medication delivery is that “you can formulate the exact dose, at certain times of the day, in a much more precise way than when using oral preparations; so you can adjust the dose by 1 mg rather than in 50 mg steps,” says Dr. Mark Guttman, director of the Centre for Movement Disorders in Markham, Ontario.

However, Duodopa therapy also has some drawbacks: it requires a surgical procedure, which could lead to complications; the equipment, such as the pump and tubing, could be subject to technical problems; managing and maintaining the equipment and medication requires careful monitoring and nursing support; some people might find it burdensome having to carry a pump at all times.

“It’s a complicated way of giving a medication, so the average person with Parkinson’s would not be a candidate because they would do well with taking oral medications three to five times a day,” says Lang. “It’s better suited to people who are taking levodopa many times a day and have bad and often unpredictable motor fluctuations.”

Guttman notes, “It could be seen as an option for people who are considering deep brain stimulation (DBS) surgery but either don’t qualify for DBS or don’t want to take the risks. This may be a reasonable strategy for small numbers of people.”

Duodopa has been approved by Health Canada under the Notice of Compliance with Conditions policy.

It is not yet available in Canada and is not funded by provincial governments. The biggest stumbling block for all the infusion technologies is likely the expense. Duodopa, for instance, is expected to cost $60,000 – $70,000 a year.

There are two sides to the issue.

Lang says, “The challenge is that the studies that have been done on this form of treatment are rather small and, because of the complex nature of the treatment and the way it’s provided, it’s very difficult to do the standard randomized, double-blind controlled studies that are done with the usual medication therapy.”

“When these drugs– apomorphine, lisuride and Duodopa – are provided in very controlled, careful, experienced environments, as is the case in Europe and elsewhere, patients have shown very striking improvements; so I think that these treatments are quite valuable and should be available to patients in Canada and the United States. Importantly, I am not advocating widespread, uncontrolled use of these treatments but rather limited availability for carefully selected patients through a small number of experienced movement disorders centres.”

Guttman is among the voices calling for a more measured approach to the introduction of Duodopa in Canada. He sees a need for “more formal studies, especially in Canada, so researchers and clinicians can get some experience with it.” He acknowledges, “We’ve never had anything in Parkinson’s that costs $60,000 a year for the rest of a person’s life; so the provincial health authorities want to make sure that there is good utility for it and that there is an economic model that can show that this will be money well spent.”

Enhancing the effect of dopamine

A new monoamine-oxidase B inhibitor

Monoamine-oxidase-B inhibitors (MAO-B compounds) enhance the effect of dopamine by preventing its breakdown. International phase III clinical trials are underway for a new investigative drug to determine its effectiveness and safety as an add-on dose to either levodopa or dopamine agonist medications.

Looking ahead…

Dr. Jonathan Brotchie, senior scientist at the Toronto Western Research Institute, University Health Network, highlights three promising drugs that are currently being studied and that could change Parkinson’s treatment:

Fipamezole:

Fipamezole is a drug which, when taken with dopamine medication, appears to do two things: reduce the problem of dyskinesia and increase the time the dopamine medication works. “I think this could change the way we treat Parkinson’s in a relatively short time,” says Brotchie.

BIIB014

The experimental drug BIIB014 is one of the first non-dopamine approaches to treating Parkinson’s. “It reverses a different chemical imbalance in the brain than our current therapies,” says Brotchie. “Because it is non-dopaminergic, we anticipate that it won’t have the same side-effects as current dopamine therapy.”

Preliminary studies have shown that BIIB014 can successfully do two things: One, alleviate Parkinson’s symptoms, when given on its own. “That’s probably the first time we’ve had a drug which isn’t replacing dopamine that can do that,” says Brotchie. Two, it appears that, when added to existing therapies, BIIB014 can improve the action of those therapies, decreasing the “off” time between the action of each pill. “This means that you either have to take fewer tablets every day or each tablet works longer.”

PYM50028 / Cogane

PYM50028, also known as Cogane. “Cogane has potential to restore the dopamine system in the brain, not just provide symptomatic benefit,” says Brotchie. “It could be disease-modifying, meaning it has the potential to change the course of the disease and maybe even reverse the disease progression.”

For the past decade, scientists have been exploring ways to increase the levels of glial cell-derived neurotrophic factor (GDNF) in the brain in Parkinson’s to help brain cells survive or even grow back. GDNF is a protein that is made in the brain and helps brain cells grow when the brain is developing or recovering from injury. Previous approaches have involved injecting GDNF into the brain through surgery or gene therapy. However, Cogane offers the possibility of delivering GDNF to the brain via a pill. The idea is that after you swallow the pill, the drug gets into the brain and then switches on the brain’s ability to make GDNF.

Noting that the animal data and early human data on safety and dosage look promising, Brotchie says, “I think Cogane offers the best hope today for a drug that could actually reverse the disease. And if you could reverse the disease early enough, you could change its impact on your life. Parkinson’s would then be something that you could be diagnosed with but, if you received the drug early enough and if the drug lives up to its promise, you could imagine that it might start to reverse symptoms and even reverse the disease process.”

National Study of Neurological Conditions Gets Underway

It is with great excitement that we announce that the first-ever national study of neurological conditions in Canada is now underway.

Parkinson Society Canada (PSC) has played a lead role in advocating for this study which aims to improve our understanding of the experience and impact of neurological conditions, like Parkinson’s, so that policy makers can make more appropriate program and policy investments. This represents a tremendous opportunity to effect significant and meaningful change for Canadians with Parkinson’s.

In addition to determining incidence and prevalence, the study will have:

  • one team of researchers investigating health and community systems to identify gaps and recommend programs and tools to improve the system of care and support;
  • another team exploring the impact of living with a neurological condition on individuals, families and society; and
  • a third team focusing on prevention, by working to better understand risk factors or the elements that contribute to the development of specific conditions and to their progression.

Rooted in the input received from over 3,000 stakeholders in early 2009, the study is jointly led by the Public Health Agency of Canada and Neurological Health Charities Canada, of which PSC is a founding member.

The study concludes in early 2013, with a report to the Minister of Health. The results will be used to improve the quality of life for Canadians with neurological conditions and their families. A continued participant in this project, PSC will provide regular updates to keep you informed.