Clinical Research: Phase 1 - Phase 4

To Placebo or Not to Placebo? The Great Debate in Rare Disease Trials

Small patient populations. Geographic dispersion. Competing studies. Sound familiar? If you’re a sponsor of a rare disease study, you know all too well the challenges that come with recruiting patients. These challenges lead to immense pressure to design and implement studies that limit the burden of participation, while keeping patients engaged and generating high-quality data that can support regulatory approval. While randomized, double-blind, placebo-controlled studies are considered the gold standard of clinical research, it may be difficult to recruit patients with rare diseases into such trials.

Why placebo control is so challenging in rare disease studies

More than 90% of rare diseases have no approved therapy.1 Even when clinical trials are their only opportunity to receive any form of therapy, patients—and their caregivers and clinicians—may be reluctant to participate in studies with a placebo arm due to the risk of non-treatment. Alternatively, if an approved therapy does exist, clinical trial inclusion criteria may require participants to stop that treatment, which may be providing some benefit, to be eligible for enrollment. Reluctance to participate in studies with a placebo arm may be magnified in severe or rapidly progressive diseases, where the use of placebo control may also raise ethical concerns due to a greater risk of harm for patients who do not receive active treatment.

Proponents of placebo argue that placebo-controlled trials are superior to active-control trials and are crucial for proving efficacy and safety. However, in practice, the appropriateness and acceptability of placebo control—and the likelihood of successful study enrollment—may depend on the type of therapy or the disease under investigation. With gene therapies, patients may be less willing to participate in a trial with a placebo arm if administration of the therapy requires an invasive procedure. Further, in rare diseases where there is no standard of care, allocating patients to a placebo arm may be interpreted as unethical.

When in doubt, consider these important factors

Given the potential ethical, scientific, and practical implications, the use of placebo in rare disease studies should be carefully considered and thoughtfully justified. Several important factors should be taken into account, including:

  • Severity of the disease. Placebo may be more acceptable in studies for less severe forms of a rare disease, where the risks of not receiving active treatment may be lower.
  • Availability of existing therapies. If a proven, effective treatment is available, an active-control design may be more appropriate.
  • Study design. The trial must be designed such that it will provide meaningful information about the safety and efficacy of the investigational therapy.

If the decision is made to proceed with placebo control, it is crucial to ensure that appropriate measures are taken to provide patients who received placebo with appropriate treatment options as part of the overall development program.

When placebo is not possible, options are available

In situations where placebo control may be unethical or where neither an active control nor a standard of care exists, external controls offer a potential solution.

Using real world data

A single-arm design with an external control may be a viable alternative. For single-arm studies, the U.S. Food and Drug Administration (FDA) recognizes an external control group generated using real-world data (RWD) as a valid comparison. A review of FDA regulatory approval decisions between 2000 and 2019 identified 45 approvals where the agency accepted external control data in pivotal studies.2 External controls can be derived from several different sources, including:

  • Prospective or retrospective natural history studies
  • Published literature
  • Previous clinical studies
  • Patient baseline data, where data is collected over a period of time prior to initiation of treatment and compared to data collected while on therapy

Robust natural history data has the potential to reduce or eliminate the need for a placebo arm in a clinical trial. In 2021, the National Organization for Rare Disorders (NORD) launched the HOME study, a pilot project funded by the FDA to accelerate a cure for metachromatic leukodystrophy (MLD). This study involved researchers, drug developers, patients, caregivers, clinicians, and regulators, all of whom collaborated to advance their knowledge of MLD and design a study focused on limiting participation burden, while still producing sufficient data to augment placebo control.

The HOME study utilized a completely virtual format, where patients participated in video study visits and updated pertinent health information through online surveys. With this virtual approach, participants did not need to travel and were more likely to continue participating for the duration of the study. The HOME study collected data on the effects of MLD and how the disease progresses over time. These data could serve as an external control for future clinical trials or be used to supplement the number of patients needed for a placebo arm.3

Using in silico modeling and simulation as a virtual control

Another approach may be to use an in silico method to construct a virtual patient control arm. In silico trials use sophisticated computational modeling and simulation techniques to generate synthetic (or virtual) control patients and then test investigational therapies against the external synthetic patient arm. A virtual patient is generated using a computational mechanistic model that effectively characterizes the disease in question and is based on a set of disease sub-models that represent biological, physiological, pharmacokinetic, or other genetic processes that may describe the disease in a real human subject. The success of in silico methods relies heavily on the ability to create a robust and clinically meaningful disease model, which is not always feasible.

Both the FDA and the European Medicines Agency (EMA) have recognized the use of in silico methods for generating evidence to support submissions and are open to the use of these novel approaches in generating external control data4. 

Making the decision for your study

The use of placebo control in rare disease trials can be challenging. The decision to include a placebo arm should take into account all relevant ethical, scientific, and practical considerations. When placebo control is deemed unethical or unfeasible, the FDA has demonstrated a willingness to base approval on trials with historical or synthetic external controls which may not only reduce the need for placebo, but also facilitate study recruitment and potentially result in faster trial conduct.

With more than 240 rare disease studies conducted in the last five years, Premier Research brings extensive experience managing rare disease trials with complex and innovative study designs. To learn more about our experience with in silico modeling, read more about our partnership with InSilico Trials here.

[1] NORD. New Report Finds Medical Treatments for Rare Diseases Account for Only 11% of US Drug Spending; Nearly 80% of Orphan Products Treat Rare Diseases Exclusively, March 4, 2021. Available at

[2] Jahanshahi M, et al. The use of external controls in FDA regulatory decision making. Ther Innov Regul Sci. 2021;55(5):1019-1035.

[3] AcademyHealth. Innovative Study Design Alleviates Challenges Associated with Rare Disease Clinical Trials, August 23, 2021. Available at

[4] US/FDA guideline, Submitting Documents Using Real-World Data and Real-World Evidence to FDA for Drugs and Biologics Guidance for Industry; 2019 & EMEA CHMP Guideline, Clinical Trials in Small Populations; 2006