Placebos in Clinical Trials

“Sugar Pill” Myth Busted!

I am a science geek. I enjoy watching medical dramas such as NBC’s “Chicago Med,” however, episode 8 of the show’s first season entitled “Us” left me fuming. I believe it set back clinical trial accrual by at least 10 years. One common misconception that many cancer patients have concerning clinical trials is that they will receive a “sugar pill” or  placebo to treat their cancer.

The episode’s storyline depicted a dying cancer patient who had been assigned to the placebo arm of a clinical trial. The doctor on this episode was very upset because he discovered that the patient he enrolled in a cancer clinical trial was not receiving the investigational agent. He stated, “They are treating her cancer with a sugar pill.” The patient ended up dying after her disease progressed. She was never taken off the trial.

This scenario was very misleading. Placebos are rarely used in cancer clinical trials. In the rare event that a cancer patient was receiving a placebo, the patient will be taken off the trial at first notice of disease progression (the point at which the disease continues to grow or spread). Misconceptions like these hamper accrual into trials that can advance research leading towards a cure. Cancer trials are designed so patients will get no less than the standard of care. It is unethical to give a cancer patient with progressive disease a placebo when an effective or potentially curative therapy is available.

A placebo is a product that looks exactly like the investigational drug or treatment but is inactive. A placebo does not cause harm or good.  Randomized double-blinded placebo controlled trials in which neither patients nor their doctors know who is receiving the investigational agent and who is receiving the inactive substance are the “gold standard” in most fields of research—except cancer.

Researchers have found some people begin to feel better even if they just think they’re being treated. This has been dubbed the placebo effect. Randomized placebo controlled trials ensure that results are unbiased and the placebo effect is minimized.  They also discover that people who know they’re getting a placebo don’t report all the health problems that come up, while those on the treatment do. This can make a treatment’s side effect profile appear worse. This is why trials need to be blinded.

Although this scientific approach is very sound, ethical considerations that outweigh this outstanding scientific design arise when treating cancer patients. In trials for a life-threatening condition such as cancer, placebos are inappropriate.  All participants need to receive active treatment.

When investigators design randomized controlled trials that evaluate the efficacy of a potentially new cancer treatment, the randomization is usually between the arm using the investigational agent and the arm using the standard of care guidelines, but NOT a placebo. For example, if researchers were testing the efficacy of a new drug to treat relapsed/refractory multiple myeloma, the research arm of the trial would be the investigational agent and the control arm would be the standard of care protocol that a myeloma patient not participating in the trial will receive. If participants in either arm of the trial experience disease progression they will leave the trial and seek another line of therapy. Placebo-controlled trials are not employed when an effective therapy is available for a patient.

There are a few exceptions when a placebo may be used in a clinical trial designed for cancer patients.  If there were any possibility you might receive a placebo, that would be made very clear in the informed consent process. One exception is when the clinical trial design is using a placebo in combination with a proven effective treatment: An “add-on” trial design.  For example, let’s say that a promising new treatment is in development for myeloma. It would not be appropriate for a clinical trial to randomize patients between the new treatment and a placebo because effective therapies to treat myeloma exist. However, it might be appropriate to randomize between standard of care plus the new drug or standard of care plus placebo because in both cases, patients will receive the standard, proven effective therapy. Researchers may then investigate if the combination therapy is more effective than a single agent.

Another time a randomized double blinded placebo controlled cancer trial may be designed is when the standard of care is no treatment. For example, the standard of care for smoldering myeloma is watch and wait.  Smoldering myeloma patients are monitored for disease progression but they do not receive therapy until their disease becomes active. A clinical trial designed to see if early treatment intervention for a smoldering myeloma patient will delay progression could use a placebo arm and a treatment arm, since patients being followed outside of the clinical trial would typically receive no treatment.

A randomized placebo controlled trial testing a new investigational agent may be ethical in cases when the patient has already tried every available option and there is no known effective treatment for the patient’s stage of disease. To minimize risks to the patient, many of these placebo controlled trials permit crossover to the investigational agent at the time of disease progression. In these clinical trials, all patients have the opportunity to receive the new treatment, although some receive it sooner than others do. This is ethical because patients outside the trial will not have access to the investigational therapy thus receiving only supportive/palliative  care.

It is not ethical to treat your cancer with a “sugar pill” if there is evidence of the efficacy of an available treatment or “good evidence” that the investigational therapy is effective.  A myeloma maintenance therapy trial was stopped early when the interim results revealed maintenance therapy after a stem cell transplant showed superior progression free survival results (PFS) to no therapy.

I am on an Institutional Review Board (IRB) at the University of Pennsylvania. It is the job of the IRB to make sure trial designs are ethical and the rights of the human trial participants are protected. It is NOT ethical to knowingly allow a cancer patient to receive less than the standard of care. We can’t believe everything we see on TV, even medical drama shows.  Let’s debunk the “sugar pill” myth today.

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Cindy Chmielewski Precision Medicine Advocate

Cindy Chmielewski Precision Medicine Advocate

Cynthia Chmielewski was diagnosed with multiple myeloma, a blood cancer, in 2008. Cindy’s induction therapy stopped working after a few cycles and she proceeded with a stem cell transplant which failed to put her into remission. Depressed and scared she continued her fight using newly FDA-approved targeted therapies which eventually put her in remission. Cynthia continues treatment with a maintenance protocol.  Cynthia is using her passion for education to teach a new group of “students” – myeloma patients, their caregivers and others interested in myeloma.  She is a trained mentor, advocate and Patient Ambassador.
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