Companies running randomized, controlled clinical trials of new cancer drugs should only use placebo controls in very select circumstances, according to a new guidance for the industry from the Food and Drug Administration. As a guidance, it is not binding, but nevertheless formalizes ethical principles that have existed for decades, drawing praise from a bioethics expert.
In particular, the FDA said, trial sponsors should consider only using placebo-controlled designs in circumstances such as when surveillance of the patient is the standard of care or when a trial uses an add-on design, whereby patients receive placebo in addition to an established treatment.
To be sure, oncology trials tend to involve a standard of care or best available therapy plus a new drug or placebo, whereby patients may receive the new drug or placebo in addition to a commonly used chemotherapy combination or one of a set of therapies from which the physician can choose. But the guidance is particularly important from an ethics perspective, said Jennifer Miller, a bioethics professor at Yale University.
“The issue here is that if you have a serious or life-threatening condition where there’s an available therapy, you should be able to get access to that,” she said in a phone interview.
The ethical principles governing the use of placebo in clinical trials go back to the Declaration of Helsinki, which the World Medical Association enacted in 1964 and was most recently updated in 2013. Generally speaking, a new intervention must be tested against the best proven intervention. However, placebo is permissible in cases when no proven intervention exists; there is a compelling scientific or methodological reason to use any intervention less effective than the proven one; and there is no additional risk of serious or irreversible harm to the patient.
“This principle has been around from an ethics perspective for a while, as enshrined in the Helsinki Declaration,” Miller said. “So it’s good to see it make its way into an official FDA guidance.”
A Deep-dive Into Specialty Pharma
A specialty drug is a class of prescription medications used to treat complex, chronic or rare medical conditions. Although this classification was originally intended to define the treatment of rare, also termed “orphan” diseases, affecting fewer than 200,000 people in the US, more recently, specialty drugs have emerged as the cornerstone of treatment for chronic and complex diseases such as cancer, autoimmune conditions, diabetes, hepatitis C, and HIV/AIDS.
Still, while the idea of comparing a new intervention against a standard of care may seem straightforward enough, Miller said ethicists have debated what it means to have a standard of care because there may not be routine access to that in many emerging markets. In such cases, she said, the ethical thing for drugmakers to do is to offer the U.S. standard of care in clinical trials, even in countries where it may not be available, given that they have the funding and capability to do so.
The guidance went on to list factors companies should take into account when considering a placebo-controlled study. First and foremost, they should provide a rationale for using such a design, especially when it involves something like a sham surgical procedure in which invasive methods are needed to administer a placebo, when prophylaxis is required for adverse events, when a therapy is available or when placebo is given by itself. While it is generally considered advisable to unblind patients and investigators in the event of disease progression or recurrence or a drug-related adverse event, the guidance stated that if trial sponsors intend to maintain patient-level blinding, informed consent documents should acknowledge the added risk and provide justification for it. Moreover, trial protocols and statistical analysis plans should include detailed descriptions of the proposal for blinding and planned unblinding.
Photo: FDA, Flickr (free of copyright protection)
