Diabetes Forecast

The Basics of Clinical Trials

How you can be part of advances in medical care

color model of insulin molecule

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[Participants] need to know everything about the trial, what’s going to be expected of them, all the potential risks of the trial, and that it’s completely voluntary. And there is no punishment or repercussion if you decide to say no.
—Sue Kirkman, MD

When you choose to take the stairs, inject insulin, or check your blood glucose, you might think you are just following your doctor's orders to manage your diabetes. You may not realize that those actions trace back to knowledge gained from an important scientific process known as a clinical trial. Trials are responsible for the evolution of new treatments and guidelines in diabetes care, and they influence many of the decisions you make to manage your health.

"Without clinical trials, there [would] not be advances in medical therapy," says Marc Reitman, MD, PhD, branch chief and senior investigator of diabetes, endocrinology, and obesity at the National Institute of Diabetes and Digestive and Kidney Diseases. "They are absolutely essential. You cannot get a new drug without clinical trials, nor should you be able to."

A clinical trial, by definition, means a study involving human subjects. Because of this, there is a rigorous approval and review process that ensures the trials are ethical, the risks are minimal, and the participants' rights are protected. There can even be some incentives, such as free medications, screenings, and access to specialized medical care. Read on for some basics to help you decide whether enrolling in a clinical trial is right for you.

What Is Clinical Research?

These types of studies can fall into several different categories and examine any number of scientific questions, but they all look at new ways to better prevent, detect, treat, or understand diseases. Clinical trials to investigate treatments may focus on a new drug, combination of drugs, surgical procedure, device, or a novel use for existing therapies. Other studies simply look at how a disease progresses in a person in order to understand it better.

For instance, researchers might take blood samples to see how pregnant women's blood changes with gestational diabetes. Other clinical trials may look at volunteers who don't have diabetes to better care for those who do. "We are just trying to understand the physiology," Reitman says. Physiology is the study of how our cells, muscles, and organs interact and work together in our body.

Generally, Reitman says, clinical trials can be split into two categories: those that involve drugs and those that do not. But first, all clinical trials start with an idea.

How Does a Clinical Trial Begin?

Clinical trials, particularly those looking at new drugs, often start after successful animal studies. The most promising treatments then move into clinical trials.

Other trials start within the academic community, says Sue Kirkman, MD, professor of medicine and principal investigator of the Glycemia Reduction Approaches in Diabetes (GRADE) trial at the University of North Carolina–Chapel Hill. "There are a lot of things that we don't really know when we are treating people one by one in a clinical scenario," she says. "So in that case, often academic physicians or scientists will come up with an idea for a larger trial to try to rigorously answer some of these questions."

This is the case with the GRADE trial, which is comparing the effectiveness of currently available diabetes medications in combination with metformin, the first-line medication for people with type 2 diabetes. A group of physicians and scientists put together a grant proposal for the National Institutes of Health, which decided to fund the trial. Kirkman says that because they investigate already approved medications over a long period of time, trials like GRADE aren't often conducted by pharmaceutical companies. Those companies typically conduct shorter trials intent on getting a drug cleared by the Food and Drug Administration (FDA). They also compare their drug with a placebo, rather than other drugs.

No matter a clinical trial's origin, it starts with a protocol, which is a carefully designed plan for how the research is to be conducted. The plan outlines who is eligible to participate, the length of the study, and what information will be collected. It also provides details about every aspect of the study, including tests, procedures, medications, and dosages. A principal investigator, who is often a medical doctor, leads the study, and the study team constantly monitors the health of the participants.

Trials are sponsored or funded by a number of medical organizations and individuals, including foundations, institutions, corporations, pharmaceutical companies, physicians, voluntary groups, and federal agencies.

What Are Ethical Guidelines?

Protocols are subject to review and approval by an institutional review board, which is an independent committee of physicians, statisticians, and other members of the scientific community. The board makes sure the risks are minimal and are outweighed by any potential benefits. It also ensures that the trial is ethical and the rights of the participants are protected. All clinical trials go through initial institutional review board approval and then are periodically reviewed.

"The bigger the study, the more scrutiny there is in terms of safety considerations," says Anastassios Pittas, MD, MS, principal investigator of the Vitamin D and Type 2 Diabetes (D2d) clinical trial and professor of medicine at Tufts University School of Medicine in Boston. D2d is a diabetes prevention study coordinated at Tufts Medical Center looking at whether vitamin D supplementation is safe and effective at delaying the onset of type 2 diabetes in people at risk for the disease. The study is currently enrolling 2,400 at-risk people at 21 sites throughout the United States.

There are extensive guidelines that inform the conduct of clinical trials, says Pittas, and there are many independent ethics committees whose primary role is participant safety. For example, the D2d trial is not only monitored by a national ethics committee, called the Data and Safety Monitoring Board, but by an ethics committee at each of the 21 institutions conducting the trials, too. "There is a lot of objective supervision to make sure the investigators at every site follow the ethical guidelines," he says.

Reitman, who led the development of obesity drugs at Merck for nine years, adds that invariably everyone is looking out for the patient, including the researchers. "The whole system is looking out for the patient," he says. "Personally, when I wrote trial protocols, I would only write a protocol that I would be willing to participate in, if I were not excluded based on the criteria, and I think that was true of my colleagues, too."

What Is Informed Consent?

Another very important protection for clinical trial participants is called "informed consent." This means that a potential participant is made aware of and understands the risks and benefits of a particular trial, as well as what participation entails. After going over all these details, the person may then decide whether to sign the consent document and participate in the trial. Reitman says the material should be easy to read and not include technical medical terms. Also, it's important to remember that informed consent is not a contract, so a participant can withdraw from the study at any time.

"The whole informed consent process is very important," says Kirkman. "[Participants] need to know everything about the trial, what's going to be expected of them, all the potential risks of the trial, and that it's completely voluntary. And there is no punishment or repercussion if you decide to say no."

Types of Clinical Trials

There are four categories of clinical trials. The fourth occurs after the FDA has cleared a certain drug or therapy and continues to track the safety of the treatment.

Phase 1. The goal of a Phase 1 trial is to evaluate the safety of a new drug or treatment and identify any side effects. This is the first time the new drug or therapy is used in humans, and in this phase the group of participants is small, between 20 and 80 people.

At this stage, trials aren't looking at efficacy, or how effective the drug or therapy is at treating a condition, but rather pharmacokinetics (what the body does to the drug) and pharmacodynamics (what the drug does to the body). The first-in-man studies typically involve young, healthy volunteers with no abnormalities, Reitman says. The goal: to see if anything shows up.

Phase 2. Phase 2 trials involve 100 to 300 people and continues to gain safety data as well as efficacy data on the experimental drug or treatment. At this stage, the therapy is tested in patients with the disease. For drug trials specifically, this is when researchers determine effective dosages, Reitman says.

Phase 3. By the time the trial gets to Phase 3, researchers should have an idea of what the "correct" dose is in a wide cross section of people, including different ethnicities. This phase involves 1,000 to 3,000 people to confirm effectiveness, look at side effects, and compare with approved treatments. In Phase 3 diabetes trials, there are two goals: "One is to show efficacy for diabetes, and the marker of course will be the A1C," Reitman says. "The other thing that you want to be sure of is some sort of hard cardiovascular end point."

For studies on blood glucose medications in particular, A1C—average blood glucose over the past two to three months—is a good predictor of microvascular diseases, such as retinopathy (eye disease) and neuropathy (nerve damage), but it doesn't necessarily predict macrovascular diseases and events, such as stroke and heart attack.

"That's why you need these large-outcome trials to make sure that even though you are doing well [with] your diabetes, there is not something else [about the investigational drug] creating risk that you didn't appreciate," Reitman says.

What Are the Potential Benefits?

Pittas says clinical trials are most beneficial to people not involved in the study. "We do not know whether a specific participant will benefit from the intervention," he says. "Mostly, it's a benefit to others in the future based on the knowledge [that] is gained from the study."

While advancing science and improving diabetes care are the big, hoped-for outcomes of clinical trials, there are some direct potential benefits to participants, which vary from study to study. These include access to medical care, educational programs, and medications that they might not otherwise have.

Are There Disadvantages?

Clinical trials can be a big time commitment, says Kirkman, and you may have to alter your usual routines in order to stick to the protocol. She says a trial might require participants to go to the doctor more often or refrain from eating certain foods or starting other medications without notifying researchers. "In clinical trials for diabetes, for example, we don't want people to go on a weight-loss drug or get bariatric surgery, because that would complicate the data," she says.

Participants may be exposed to additional risks if they are part of a study group randomly assigned to take an experimental drug. Researchers are not yet sure if the drug is safe, which is why they are conducting the study.

Despite potential downsides, however, Kirkman says that "hopefully most people will find the advantages outweigh the disadvantages."

How Do Outcomes Make a Difference?

Large clinical trials are the way medicine makes progress, says Pittas. "Clinical trials answer definitively very specific and critically important clinical questions," he says.

A couple examples of clinical trials that have changed the way diabetes is treated and managed are the Diabetes Control and Complications Trial (DCCT), which proved the importance of intensive insulin therapy and blood glucose control in people with type 1 diabetes in reducing the risk of long-term damage to the eyes, nerves, and kidneys, and the Diabetes Prevention Program (DPP), which proved the effectiveness of weight loss and exercise in preventing type 2 diabetes.

Clinical trials drive the revision of recommendations and guidelines, says Reitman. Kirkman agrees that clinical trials help determine the best treatments for people living with diabetes and other conditions. "All kinds of questions are best supported in guidelines by an actual clinical trial that can prove that it's the best recommendation," she says.

Terms to Know

  • Placebo-controlled study: Participants may be assigned a placebo, such as a tablet with no medication in it, rather than an active drug. Researchers can then study the action of the test drug compared with not taking the drug.

  • Randomization: Participants are assigned by chance to be in an intervention group (which receives a drug or other treatment) or a control group (which receives a placebo and/or usual care). Neither the researchers nor the participants can choose the group, which allows the treatments they receive to be compared objectively.

  • Double-blind study: In a double-blind study, the participants do not know which medicine is being used, nor does the research team. The only person who does know is the pharmacist. This allows the participants to describe their experience without influence from personal beliefs or outside factors, and allows the research team to make observations without bias.

Thinking about enrolling in a clinical trial?

See what two participants have to say about their experience at diabetesforecast.org/trials.

Find a Diabetes Trial Near You

The American Diabetes Association co-supports several large, national diabetes studies, which are mostly funded by the National Institutes of Health. All four of these studies are currently recruiting participants to enroll.

D2d Vitamin D and Type 2 Diabetes

What is it investigating?

This type 2 diabetes prevention study is looking at whether vitamin D supplementation is safe and effective in preventing diabetes in people who are at risk for the disease.

What are the study's goals?

The study is looking at whether vitamin D supplementation can make the body more sensitive to insulin and potentially encourage the body to make more insulin.

How can I learn more?

Visit d2dstudy.org.

GRADE Glycemia Reduction Approaches in Diabetes

What is it investigating?

GRADE aims to determine the best medication choice for people with type 2 diabetes who are already taking metformin—the most commonly used diabetes drug.

What are the study's goals?

Researchers want to determine which combination of two diabetes medications is best for achieving blood glucose control—with the fewest side effects—and is the best long-term treatment for people living with type 2 diabetes.

How can I learn more?

Visit gradestudy.com.

RISE (Restoring Insulin Secretion)

What is it investigating?

The study hopes to find out whether aggressive glucose lowering will lead to the recovery of function for insulin-producing beta cells in the pancreas in people with prediabetes or early type 2 diabetes.

What are the study's goals?

Researchers want to know whether beta cell function can be maintained after a year of treatment, plus three months without treatment.

How can I learn more?

Visit risestudy.org.

Type 1 Diabetes TrialNet

What is it investigating?

TrialNet, an international network of centers, is studying the natural history, prevention, and early treatment of type 1 diabetes.

What are the study's goals?

There are several studies taking place within TrialNet with different goals, including determining risk for the disease, understanding risk factors, and testing treatments.

How can I learn more?

Visit trialnet.org.



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