Single-Arm Versus Randomized Trials for FDA Approvals of Cancer Drugs

The use of single-arm trials, in which all patients receive the same investigational drug, has been increasing over the past to evaluate and potentially support an approval from the Food and Drug Administration (FDA), although randomized-controlled trials continue to be the preferred approach, an expert said.

“Single-arm trial designs have been a common development strategy to support regulatory approval for anti-cancer therapies and have allowed for transformative therapies to be made available to patients expeditiously,” said Dr. Sundeep Agrawal, acting supervisory associate director of the Division of Oncology 1 and acting clinical director of project renewal for the Oncology Center of Excellence at the FDA, in an interview with CURE®. “While single-arm trials will continue to play an important role, the randomized clinical trial remains the preferred approach to support the approval of new drugs, when feasible.”

Agrawal and colleagues recently published a study in JAMA Oncology, which analyzed the use of single-arm trials in supporting FDA approvals of anti-cancer drugs from 2002 to 2021.

The findings demonstrated that 176 new cancer indications for drugs approved by the FDA were based on single-arm trials, which included 116 accelerated approvals and 60 traditional approvals.

Single-Arm Versus Randomized-Controlled Trials

In single-arm trials, all patients receive the same drug, where in a randomized trial, patients are randomly selected to receive one of two (or more) therapies, which are compared.

All patients in single-arm trials receive an investigational drug, and the researchers aim to evaluate its safety and effectiveness. In contrast, patients in a randomized trial are assigned to one or several different treatment groups. For example, some patients may be assigned to the investigational therapy and the rest of the patients to another drug or standard of care for the same disease.

Some patients in randomized trials may receive a placebo, which is an inactive drug. Of note, it is rare for placebos to be used in cancer clinical trials without the patient also receiving — at the very least — another approved or standard-of-care regimen. Patients will be fully informed on potential placebo usage before the start of the trial.

That there are positive and negative components to both trial options.

“Single-arm trials are generally less complex, have (fewer) patients enrolled, used for earlier efficacy outcomes like tumor response rate and have shorter time to completion than a randomized trial,” Agrawal said. “Unfortunately, this efficiency comes at a cost. Because single-arm trials do not have a comparator arm, they cannot be used to assess important points like progression-free survival (the time after treatment when a patient with cancer lives without disease worsening) or overall survival (the time when a patient with cancer is still alive), and have a more limited safety assessment.”

Agrawal said not only are fewer patients assessed for a drug’s safety in single-arm trials, but without another drug to compare it with, it may be difficult to determine whether side effects are associated with the therapy or the disease itself.

That’s where randomized trials come in, which allows researchers to perform a robust safety evaluation and assess tumor progression and survival, among other factors. Randomized trials take longer to complete, require more patients and may be challenging to perform in patients with rare diseases.

“In addition, there have been situations where an investigational therapy has shown remarkable tumor response rates in early studies, and the standard treatment is not particularly effective or is quite toxic,” Agrawal explained. “In these situations, patients and physicians may have a preference for the investigational therapy and may not participate in a randomized trial where there is a chance that they receive standard treatment that is perceived to be inferior.”

Agrawal added that randomized trials are the preferred approach for evidence to determine whether a drug can be approved by the FDA, but single-arm trials are also an option if researchers feel that randomized trials are not feasible to conduct.

Recent Drug Approval Withdrawals

In the published study, Agrawal and colleagues noted that 10 FDA approvals of oncology drugs out of the 176 new cancer indications based on single-arm trials were withdrawn between 2002 and 2021, meaning that their approvals were no longer valid. He noted that the pulled FDA approvals were accelerated approvals which required a confirmation of benefit.

Of note, accelerated approvals are part of a program within the FDA that allows for earlier approval of drugs that fill an unmet need and treat serious conditions, according to the Agency’s website.

That doesn’t mean that the FDA uses those data alone for the approval. It requires drug companies to conduct studies after the accelerated approval to confirm its anticipated clinical benefit, also known as phase 4 trials. If these confirmatory trials demonstrate that the drug offers patients a clinical benefit, then the drug is granted traditional approval from the FDA.

“The most common reason for withdrawal was an inability to verify clinical benefit for these drugs rather than due to safety reasons,” he explained. “Many approvals based on single-arm trials were for drugs that were already approved in other disease settings and had well understood safety profiles.”

Even with the intricacies of each type of clinical trial, Agrawal stated his gratitude towards patients who participate in clinical trials.

“As a medical oncologist, I have a great appreciation for patients who participate in clinical trials to advance our understanding of cancer and potential ways to treat this devastating disease,” he said. “Patients seeking clinical trial participation may be presented with both single arm and randomized trial opportunities, and each of these approaches may be reasonable depending on the individual patient’s situation.”

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