FDA finalizes early Lyme disease drug development guidance

The US Food and Drug Administration (FDA) has finalized a guidance detailing its expectations for the clinical development of drugs to treat early Lyme disease. The final guidance includes several significant changes, including patient-reported outcomes (PRO) and pharmacology and toxicology testing considerations.

Most of the guidance remains identical to the draft version, which was released for comment in February 2023. It still addresses topics such as clinical trial enrollment, efficacy endpoints, and clinical microbiology considerations for treating early stages of the disease when manifested by rash known as erythema migrans (EM); often one of the first symptoms. (RELATED: FDA draft guidance addresses clinical development of drugs to treat early Lyme disease, Regulatory Focus 2 February 2023)

The guidance reiterates that trial participants should include people with early localized forms of Lyme disease who reside in or have traveled to a Lyme-endemic area. It also states that sponsors should exclude patients with musculoskeletal, neurologic, or cardiac manifestations of the disease, including arthritis, myocarditis, meningitis, or cranial neuropathy.

In the draft guidance, FDA said that clinical trials should be randomized and double-blinded, and sponsors should also treat subjects in placebo-controlled trials. However, the agency elaborated more on its thinking in the final guidance.

“Trials are expected to be randomized and controlled because of the challenge with making causal inferences for this disease in a nonrandomized setting with potential differences between treatment groups in baseline disease characteristics such as time from infection, degree of dissemination, or symptoms,” said FDA. “Trials are also expected to be double-blinded due to potentially subjective elements in recommended endpoints (discussed below) and the unknown extent of possible open-label biases that could affect patient management and follow-up.”

The draft guidance only addressed primary and secondary endpoints, but the final guidance also includes some flexibility for PROs that could be used as alternate endpoints. Sponsors are asked to talk to the agency before considering such efficacy endpoints.

“Currently, FDA is not aware of any specific patient-reported outcome (PRO) instruments that have been demonstrated to be fit-for-purpose to assess symptoms of early Lyme disease as manifested by EM to support regulatory decision-making and drug product labeling,” said FDA. “Sponsors should discuss existing, new, or modified PRO instruments for this use with FDA.”

FDA again reiterated that there are historical data that could support the use of noninferiority (NI) trials when treating Lyme disease. It also reiterated that the justification of NI trials will depend on the active control used, trial population, and trial endpoints. However, in the final guidance, FDA also adds that as an example, sponsors should provide an NI justification if proposing a novel endpoint or a certain trial population with early disseminated Lyme disease.

FDA elaborated on its expectations for trial participant follow-up and missing data in the final guidance. While in the draft guidance, the agency said that participants should be followed throughout the trial unless they withdraw consent, are lost to follow-up, or die, the final guidance states that sponsors should try to encourage participants to stay in the trial when possible.

"Trial participants may choose to discontinue study treatment during the trial for various reasons, such as experiencing adverse events or perceived lack of efficacy," said the guidance. "Unless the participant withdraws consent, sponsors should encourage participants who discontinue study treatment to remain in the study and to continue follow-up for key safety and efficacy assessments.

"Sponsors should discuss strategies for minimizing loss to follow-up with FDA, such as virtual follow-up assessments for remote data collection," the guidance added. "The protocol should clearly outline how the sponsor will handle the outcomes of participant with missing data in the primary analysis."

A key addition to the final guidance is that the FDA includes pharmacology and toxicology testing considerations. The agency said that sponsors should conduct nonclinical studies for general toxicity of their drug before submitting an investigational new drug application (IND).

Final guidance

FDA finalizes early Lyme disease drug development guidance

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