FDA draft guidance addresses clinical development of drugs to treat early Lyme disease

The US Food and Drug Administration (FDA) Center for Drug Evaluation Research (CDER) has issued a draft guidance to help sponsors develop new drugs to treat the early stages of Lyme disease.

The draft addresses criteria for clinical trial enrollment, efficacy endpoints, and clinical microbiology considerations for treating early stages of the disease when manifested by erythema migrans (EM), a rash that is often one of the first symptoms.

In North America, Lyme disease is primarily caused by the bacterium B. burgdorferi transmitted by the bite of infected lxodid ticks. A different bacterium, B. mayonii, is an emerging Lyme disease pathogen appearing in the US upper Midwest. In Europe and Asia, Lyme disease is caused by B. afzelli and B. garinii; and in some cases of B. burgdorferi is also reported in Europe.

Lyme disease can be divided into an early disseminated stage of the disease and late disease. Early localized disease occurs within one month following the tick. It is characterized by EM, or a rash at the site of the tick bite that can be followed by nonspecific symptoms, such as fatigue, as well as neurologic or cardiac symptoms. Late disease occurs months after the onset of infection and is characterized by arthritis in a large joint.

Trial subjects should include those with early localized forms of the disease who reside in or have traveled to a Lyme-endemic area. Sponsors should exclude patients with musculoskeletal, neurologic, or cardiac manifestations of the disease, including arthritis, myocarditis, meningitis, or cranial neuropathy.

Trials should be randomized and double-blinded, and sponsors should also treat subjects in placebo-controlled trials. Drug efficacy should be demonstrated by two “adequate and well controlled” trials. In some cases, FDA is willing to accept efficacy findings from a single, adequate, and well-controlled trial.

Treatments are deemed successful if they result in a “resolution of EM and continued absence of objective manifestations of Lyme disease without need for additional antibacterial treatment for Lyme disease.” They are deemed not successful if EM continues to be present, if other objective manifestations of the disease appear, or if patients need additional antibacterial treatment.

To demonstrate efficacy in non-inferiority trials, sponsors should use an active control with known activity in early Lyme disease, such as oral doxycycline.

The size of the safety database depends on the adverse event profile of the drug, while FDA recommends a minimum size of 300 subjects for drugs with no known prior experience. The agency also encourages sponsors to meet with them to discuss the appropriate size of the premarketing safety database.

The deadline for commenting is 3 April 2023.

FDA guidance

FDA draft guidance addresses clinical development of drugs to treat early Lyme disease

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