Clinical trials can offer hope for patients with intractable conditions when current medicine can’t offer satisfactory treatment. Whatever the outcomes, these patients can still contribute to the growth of scientific knowledge.
Certain patients may be among the most troubling in a clinician’s practice. The diagnosis is clear. The disease is debilitating. But modern medicine has no good answer.
Endocrinology is replete with these conditions — consider Cushing syndrome, invasive pituitary tumors, nonresectable neuroendocrine tumors, many aspects of infertility, inborn metabolic defects, and glycogen storage diseases to name just a few. Even most treatments for the condition that dominates the field — diabetes — are aimed at staving off complications and comorbidities rather than effecting a cure.
One important alternative that a physician can offer these patients is a clinical trial. A clinical trial comes with no guarantees. But it offers the patient the important commodity of hope, at times can offer a breakthrough treatment, and always contributes to the growth of scientific knowledge.
‘I think patients benefit from being in clinical trials because the questions that
we study arise when we really don’t know whether one treatment is better than the other. So people who are in clinical trials are really getting state-of-the-art treatment,’ says Judith Fradkin, MD, director of the Division of Diabetes, Endocrinology, and Metabolic Diseases at the National Institute of Diabetes and Digestive and Kidney Diseases. ‘The trials are comparing what we think is the best treatment or two different strategies when we aren’t sure which is the best treatment, so people in clinical trials get very good care.’
“I think patients benefit from being in clinical trials because the questions that we study arise when we really don’t know whether one treatment is better than the other. So people who are in clinical trials are really getting state-of-the-art treatment.” — Judith Fradkin, MD, director of the Division of Diabetes, Endocrinology, and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md.
Fradkin says that the benefits of a clinical trial can last for many years. The Diabetes Control and Complications Trial ran for 10 years and proved the benefits of tight control of blood glucose. Patients who received intensive intervention and achieved lower hemoglobin A1c levels are still displaying benefits years after the study ended in 1993. In the years since the
study, the glucose control of both study groups has been essentially the same, but a recent study found the mortality rate of patients in the intervention group is half that of the control group.
How to Find a Trial
The go-to place to look for a trial is www.clinicaltrials.gov. Run by the National Library of Medicine, the website describes almost every clinical trial of consequence, including studies funded by the National Institutes of Health (NIH) as well as pharmaceutical company tests of new drugs. It currently lists 190,000 trials in 190 countries, with 46,000 of them currently recruiting participants. It includes information on a trial’s objectives, inclusion criteria for participants, and contact information for the investigators and study sites. It describes what a participant can expect in terms of drugs to be taken, whether some participants will receive a placebo, and requirements for site visits. The website can be searched by key phrases and conditions, by institutions sponsoring the trials, by city, and more.
Fradkin recommends also visiting the NIH website to look for the ‘intramural’ studies that the NIH conducts in-house. Although these may require visits to the NIH campus in Bethesda, Md., or a satellite branch in Phoenix, Ariz., sometimes they can pay for a patient’s travel, particularly in cases of rare conditions.
Another route to finding a trial is old-fashioned networking with your colleagues and other experts, according to Richard Auchus, MD, PhD, professor of internal medicine at the University of Michigan Health System in Ann Arbor: ‘Email somebody that you know who is a leader in the field or who works at a place that has particular expertise in the condition.’ “I contact someone who I know is an expert in the area to ask, ‘Do you know of anything that is ongoing,’ to find out what is happening,” says Nanette Santoro, MD, E. Stuart Taylor Chair of Obstetrics and Gynecology at the University of Colorado School of Medicine in Aurora.
Prepping the Patient
Deciding whether a trial is the best option for a patient “requires a pretty sophisticated discussion,” Santoro says. Many patients harbor a “therapeutic misconception” and assume that they will benefit from a trial. A physician may need to explain the concept of randomization, and make sure patients understand that they may receive a placebo rather than active drug — and that even if they receive the drug, the drug may not be effective, and can even be harmful. Patients need to understand that “the only reason the investigators are doing the clinical trial is they don’t know whether the treatment is actually better, so patients should not assume that the treatment is better.”
“The only reason the investigators are doing the clinical trial is they don’t know whether the treatment is actually better, so patients should not assume that the treatment is better.” — Nanette Santoro, MD, E. Stuart Taylor Chair of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, Colo.
And a patient may not be a good fit for the conditions of a trial. “Sometimes as an investigator, you just have to say, I am not comfortable with having that patient on placebo, so I won’t enroll them in that trial,” Auchus says. “You have to make that judgment as the treating physician, as an investigator.”
He adds that study designs must be approved by an institutional review board, which will consider how to ameliorate the consequences of a receiving a placebo. For example, Cushing syndrome causes hyperglycemia and hypertension, so participants in a Cushing trial would be likely to receive medications to control glucose and blood pressure. “If the trial design does not provide some patients adequate treatment for the Cushing’s, provisions must be in place to treat the co-morbidities,” he says.
Studies contain other safeguards as well. For example, in the study of lanreotride for gastrointestinal neuroendocrine (carcinoid) tumors, if patients required a specified amount of rescue treatment to control diarrhea, the randomization code could be broken and they could be crossed over to the active drug. “Many times placebo-controlled trials are designed such that if patients on placebo continue to the primary endpoint, then they can get crossed over to actual drug. So, many times patients will eventually get the drug, and often the sponsor will offer continued treatment to patients who respond well in an extension phase until the drug gets approved,” Auchus says.
And of course, many trials do not involve placebos, but can be head to head tests to see which treatment is best and follow myriad other formats.
Patients also need to be aware that there can be costs of participating, such as having to take time off from work, travel to the study site, take a drug with little-known effects, and other inconveniences. Some of these costs may be reimbursed.
In some cases, participation can entail substantial financial benefits. “People can receive thousands of dollars of medicine as well as free blood testing, EKGs, and various other health measures,” Auchus says.
Participants in a current NIH-funded comparative effectiveness study of diabetes drugs known as the GRADE study will receive seven years of diabetes medications and supplies, care visits, lab tests, and diabetes education at no charge.
The cost issue can be important in reproductive medicine, but Santoro says that her specialty is somewhat unusual with respect to the patients’ motivations to seek their own solutions: “We really are sort of emerging out of the dark ages with fertility treatments, because there has been so little evidence for so many of them. Patients will often come in recommending things that range from the utterly off the wall — stuff that is being advertised without proof — to things that have various levels of plausibility, but inadequate evidence. In those kinds of settings, I encourage patients to participate in clinical trials because then not only will they get a possible exposure to the treatment, but it will actually contribute to the answer and make it better for the next person who has that same decision to make.”
No Substitute for Experience
Patients must thoroughly understand and have their questions answered before they sign a consent form, and Santoro’s final piece of advice is that physicians should consider participating in a trial themselves so they can tell their patients what it is like. She has done this “just so I know what I am asking people to do. Then I was able to tell people, this is what I am asking you to do. It gives you a whole new take on the burden of the trial.”
— Seaborg is a freelance writer based in Charlottesville, Va. He wrote about the microbiome in the May issue.